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The Therapeutic Voyage of Pyrazole and Its Analogues: A Review

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 European Journal of Medicinal Chemistry 120 (2016) 170e201

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Review article

The therapeutic voyage of pyrazole and its analogs: A review

Mohemmed Faraz Khan, Mohammad Mumtaz Alam, Garima Verma, Wasim Akhtar,
Mymoona Akhter, Mohammad Shaquiquzzaman*
Drug Design & Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi, 110062, India

a r t i c l e i n f o a b s t r a c t

Article history: Pyrazole, a five membered heteroaromatic ring with two nitrogen atoms is of immense significance.
Received 22 January 2016 Presence of this nucleus in the pharmacological agents of diverse therapeutic categories viz. antianxiety,
Received in revised form anti-inflammatory, antipsychotic, anticancer, antiobesity, analgesic, antipyretic etc. has made it an
25 April 2016
indispensable anchor for design and development of new pharmacological agents. Owing to the
Accepted 28 April 2016
development of novel and new pyrazole based therapeutic agents at a faster pace, there is a need to
Available online 10 May 2016
couple the latest information with previously available information to understand status of this moiety in
medicinal chemistry research. The review herein highlights the therapeutic worth of pyrazole de-
Keywords:
Heterocyclic
rivatives. Several therapeutically active pyrazole based derivatives developed by numerous scientists
Pyrazole across the globe are reported here.
Pharmacological activity © 2016 Published by Elsevier Masson SAS.
Anticancer
Antimicrobial
Antiviral
Analgesic
Anti-inflammatory

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
2. Pharmacological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
2.1. Anti-Alzheimer’s activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
2.2. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
2.3. Antiglaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
2.4. Antihypercholestrolemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
2.5. Antihyperglycaemic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
2.6. Antihypertensive activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
2.7. Anti-inflammatory and analgesic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
2.8. Antileishmanial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
2.9. Antimalarial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
2.10. Antimicrobial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
2.11. Antiparkinsonian activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
2.12. Antipsychotic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
2.13. Antitubercular activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
2.14. Antiviral activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
2.15. Neuroprotective activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

* Corresponding author.
E-mail address: shaqiq@[Link] (M. Shaquiquzzaman).

[Link]
0223-5234/© 2016 Published by Elsevier Masson SAS.
 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201 171

Abbreviations L. braziliensis Leishmania braziliensis

LE lignad efficacy
A. fumigates Aspergillus fumigates LRRK2 leucine-rich repeat kinase 2
ACC acetyl-CoA carboxylase LTP long term potentiation
ACE angiotensin converting enzyme M. tuberculosis Mycobacterium tuberculosis
AChE acetylcholinesterse MDR multi drug resistant
AT1 angiotensin-1 MET mesenchymaleepithelial transition factor
ATP adenosine triphosphate MeV measles virus
B. cereus Bacillus cereus mGlu metabotropic glutamate
B. subtilis Bacillus subtilis MIC minimum inhibitory concentration
BACE1 beta-secretase 1 MR mineralocorticoid receptor
CaMKII Ca2þ/calmodulin dependent protein kinase II MRSA methicillin resistant Staphylococcus aureus
CC50 50% cytotoxic concentration mTOR mammalian target of rapamycin
CNS central nervous system MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
COX cyclooxygenase bromide
DPP IV dipeptidyl peptidase IV nAChR nicotinic acetylcholine receptor
E. coli Escherichia coli NNRTIs non-nucleoside reverse transcriptase inhibitors
EC50 half maximal effective concentration NSAID non steroidal anti-inflammatory drug
ED50 median effective dose P. falciparum Plasmodium falciparum
EeAChE Electrophorus electricus acetylcholinesterase P. aeruginosa Pseudomonas aeruginosa
EGFR epidermal growth factor receptor P. berghei Plasmodium berghei
GI50 half maximal growth inhibitory P. notatum Penicillium notatum
GPCRs G protein coupled receptors PD Parkinson’s disease
GSK3b glycogen synthase kinase-3 b PPAR peroxisome proliferator-activated receptor
HAV hepatitis A virus QRSA quinolone resistant Staphylococcus aureus
hCA human carbonic anhydrase RAGE receptor for advanced glycation end products
HCC hepatocellular carcinoma S. aureus Staphylococcus aureus
HCV hepatitis C virus SAR structure activity relationship
HDAC histone deacetylase SGLT sodim glucose co-transporter
HIV human immunodeficiency virus SI selectivity indices
hNK3 human tachykinin NK3 TB tuberculosis
HSV herpes simplex virus TP thymidine phosphorylase
IC50 half maximal inhibitory concentration VEGFR 2 vascular endothelial growth factor receptor 2
Ki inhibition constant WNS west nile virus
L. amazonensis Leishmania amazonensis

1. Introduction 2. Pharmacological activities

Heterocyclic compounds, bearing atoms of at least two different Owing to the diverse pharmacological activities of this ring, a
elements as a member of its ring have attracted considerable number of researchers across the globe are engaged in the devel-
attention in the development of pharmacologically active mole- opment of pharmacologically active agents bearing it. Recent de-
cules and advanced organic materials [1,2]. Pyrazole (Fig. 1), a five velopments made by researchers in this field are documented
membered simple aromatic ring comprises of two nitrogen atoms below.
at adjacent position [3,4]. It has attained considerable popularity
due to its manifold uses. Pyrazole and its derivatives represent one
of the most active classes of compounds, which exhibit broad 2.1. Anti-Alzheimer’s activity
spectrum of pharmacological activities like antimicrobial [5,6],
anticonvulsant [7,8], anticancer [9,10], analgesic [11], anti- Alzheimer’s deisease is a chronic neurodegenerative disease
inflammatory [12,13], antitubercular [14,15], cardiovascular [16] that accounts for 60e70% cases of dementia [51]. It is mainly
etc. marked by short-term memory loss, i.e. the difficulty in remem-
This five membered ring can be traced in a number of well bering recent events [52,53]. It usually starts slowly, but with the
established drugs belonging to different categories with diverse advancement of disease it gets worse with symptoms like problem
therapeutic activities. Such drugs are enlisted in Table 1. with language, mood swings, disorientation, behavioural issues, etc
[54,55]. There is still no treatment to reverse or stop the progres-
sion of the disease, though some may just improve the symptoms
temporarily [56,57]. Therefore, the search for the development of
newer anti-alzheimer’s drugs is unrelenting. Several pyrazole
based anti-alzheimer’s agents have been synthesized by medicinal
chemists (Fig. 2).
Khoobi et al. developed a series of pyrazole derivatives as po-
tential anti-alzheimer’s agents. Amongst the synthesized com-
Fig. 1. Structure of pyrazole. pounds, compound 1 was reported as the most potent inhibitor of
172 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201

Table 1
Pyrazole bearing pharmacological agents.

S. no. Name of the drug Structure Pharmacological class

1. Indiplon O Antianxiety [17]

CH3
O
N
S
N N
N CH3

CH3

2. Zaleplon CN Antianxiety [18]

N

N
N

N CH3

CH3

3. Celecoxib F F Anti-inflammatory [19]

F

N
N
CH3

O S O

NH2

45. CDPPB Antipsychotic [20]

N N

HN
N

5. Lonazolac O OH Non steroidal anti-inflammatory drug (NSAID) [21]

N
N

Cl

6. Crizotinib Anticancer [22]

N
N
NH2
N

O
HN
H3C Cl

H3C F

7. Tepoxalin OH NSAID [23]

N
HC O

HC
O

Cl
 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201 173

Table 1 (continued )

S. no. Name of the drug Structure Pharmacological class

8. Surinabant H3C Antiobesity [24]

O
Br
N
N
H
N N

Cl

Cl

9. Antipyrine (Phenazone) NSAID [25]

N O
H 3C
N

H 3C

10. Phenylbutazone NSAID [26]

O
N
N
CH3

11. Novalgin (Dipyrone) Analgesic, antipyretic and antispasmodic [27]

O
O
N
S
N N OH
HC O
CH
CH

12. Ramifenazone NSAID [28,29]

O
N CH3
H3C N
N CH3
H
H3C

13. Rimonabant Cl Cl Antiobesity [30,31]

Cl

N H
N
N
N

O
CH3

14. Deracoxib H2N NSAID [32,33]

O
S
O

H 3C N
N
O
F
F
F

15. Apixaban O Anticoagulant [34,35]

NH2

N
N
N

O
N

O
O CH3

(continued on next page)

174 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201

Table 1 (continued )

S. no. Name of the drug Structure Pharmacological class

16. Pyrazofurin HOH C Anticancer, antibiotic [36]

O
HO OH
O

HO C
N
N NH
H

17. SC-560 F Cyclooxygenase COX inhibitor [37,38]

CH3
F N
N O
F

Cl

18. Sildenafil O Drug for erectile disfunction [39,40]

CH3
H3C
N N
O HN
N N
S
N
O

O CH3
CH3

19. Betazole H2-receptor agonist [41]

N
N
H NH2

20. Fomepizole H3C Antidote for methanol poisoning [42,43]

N
N
H

21. Fezolamine (CH2)3N(CH3)2 Antidepressant [44]

N
N

22. Pyrazomycin H
Anticancer [45]
N
N
CONH
HO O

OH
OH
HO

23. Difenamizole Analgesic [46]

CH3 O
N
N
H 3C N N
H
CH3

24. Mepirizole OCH NSAID [47]

H C N N OCH
N

CH

25. AS-19 5-HT7 receptor agonist [48]

H 3C

N
N CH3
CH3 N
H 3C
CH3
 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201 175

Table 1 (continued )

S. no. Name of the drug Structure Pharmacological class

26. Mepiprazole Minor tranquilizer [49]

HN N
H3C
N

N Cl

27. Tartrazine O Anticancer [50]

O-
S
O
O
O
N N
-
O S
NH N
O
O
O-

acetylcholine esterase. This was found to be even more active than 2.2. Anticancer activity
the reference drug, tacrine [58]. A series of pyrazole-5-
carboxamides were developed by Han et al. and evaluated for Cancer, characterized by uncontrolled growth of abnormal cells
anti-alzheimer’s activity. Extensive structure activity relationship [67] is a serious life-threatening health problem worldwide [68,69].
(SAR) analysis lead to the discovery of 4-fluorophenoxy derivative It is a group of various diseases [70], which is found to be most
(2) that inhibits RAGE (Receptor for Advanced Glycation End lethal after cardiovascular diseases in terms of morbidity and
Products) which exhibited significant aqueous solubility. Its ability mortality [71,72]. Despite, enormous novel and effective solutions
of amiloideb lowering effect in brain was found to be very prom- to cancer problem, there are still clear limitations in treatment of
ising and hence, was considered as an important anti-alzheimer’s cancer and hence, it is projected as the major cause of death in
agent [59]. Zou et al. synthesized a series of pyrazole based com- future [73]. Currently pharmaceutical industries are spending bil-
pounds and reported them as novel C-terminus Beta-secretase 1 lions of dollars for the discovery of potent, safe and selective anti-
(BACE1) inhibitors. Further, modification over pyrazole scaffold cancer drugs [74,75]. Consequently, many pyrazole based
lead to the identification of compound 3 as a potent inhibitor of antiproliferative agents have been developed by researchers
BACE1 with half maximal inhibitory concentration (IC50) value of (Fig. 3).
0.025 mM [60]. Probst et al. developed a series of metabolically A series of pyrazolecyclopentyl derivatives was prepared and
stable g-secretase inhibitors selective for inhibition of Ab forma- evaluated for insulin-like growth factor receptor inhibitory activity.
tion. Two of the most potent compounds i.e. 4a and 4b entered Compounds 10a and 10b were reported as the most active com-
human clinical trials, out of which compound 4a significantly pounds of the series [76]. Amongst the compounds developed by
lowered Ab in the CSF of healthy human volunteers [61]. Design and Ibrahim et al., compounds 11a and 11b were found to be selective
synthesis of 1-Phenylpyrazolo[3,4-e]pyrrolo[3,4-g]indolizine- inhibitors of carbonic anhydrase isoforms IX and XII [77]. Wen et al.
4,6(1H,5H)-diones was done by Pietra et al. The synthesized com- synthesized pyrazole based compounds and determined their his-
pounds were evaluated for their glycogen synthase kinase-3b tone deacetylase inhibitory activity. Compound 12 demonstrated
inhibitory action. Compound 5 expressed good anti-alzheimer’s significant in vivo antitumor activity in HCT-116 xenografted model
activity by inhibiting GSK-3b with an IC50 value of 0.24 mM [62]. [78]. Zhao et al. reported compound 13 as the most active anti-
In a medicinal chemistry effort towards the development of a7 cancer agent with IC50 of 0.12 and 0.16 mM against WM266.4 and
nicotinic acetylcholine receptor (nAChR) agonist preclinical candi- MCF-7 cell lines respectively [79]. Amongst the compounds syn-
date, Zanaletti et al. developed compound 6 as a potent and se- thesized by Kamal et al., compound 14 exhibited significant cyto-
lective full agonist of the (nAChR). Compound 6 also exhibited toxic potential [80]. Hu et al. reported compound 15 to have
improved plasma stability, brain levels and efficacy in behavioural appreciable inhibitory activity against BCR-Bal kinase with IC50
cognition models [63]. Another class of a7 nAChR agonists was value of 14.2 nM [81]. Nitulescu et al. synthesized a series of pyr-
found by Zanaletti et al. which led to the identification of com- azole derivatives and evaluated their anticancer potential.
pound 7 as a full agonist of the a7 nAChR in both in vivo and in vitro Following in vitro evaluation, it was reported that compound 16
studies. The molecule was also proved to be potent and selective could be a promising anticancer agent [82]. Pyrazole derivatives
with an excellent pharmacokinetic profile and promising efficacy in synthesized by Rai U et al. were screened for their anticancer po-
rodent behavioural cognition models [64]. Several pyrazolotacrines tential. Compound 17 was found to have comparable anticancer
were synthesized by Silva et al. via Friedlander-type reaction and activity to the standard drug doxorubicin [83]. Nitulescu carried out
were evaluated for inhibition of Electrophorus electricus acetylcho- ultrasound-assisted synthesis of pyrazole derivatives and deter-
linesterase (EeAChE). The results revealed that compound 8 was the mined their anticancer potential. Compound 18 was reported as the
most potent inhibitor of EeAChE, which inhibited the aforemen- most potent antiproliferative agent [84]. Amongst the sulfonamides
tioned enzyme with an IC50 value of 0.069 ± 0.006 mM [65]. A series synthesized by Khloya et al., compounds 19ae19d were found to be
of novel tricyclic sulphonamide-pyrazoles was designed and several folds better inhibitors of carbonic anhydrase in comparison
developed by Mattson et al. The compounds were investigated to the standard drug, acetazolamide [85]. Zhang et al. developed a
against g-secretase proteins. Consequently, compound 9 expressed series of pyrazole fused 23-hydroxybetulinic acid derivatives and
the best inhibition of g-secretase with IC50 value of 4 nM. The high assessed their antitumor activity. Compound 20 was found to be
potency of compound 9 was supposed to be due to the formation of most active with IC50 values of 5.58 and 6.13 mM respectively [86].
two hydrogen bonds with g-secretase [66]. Amongst pyrazole derivatives developed by Tao et al. compound 21
176 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201

Fig. 2. Anti-Alzheimer’s Activity of pyrazole derivatives.

was found to be a potent anticancer agent with IC50 values of compounds, compound 28 was reported as the most potent anti-
0.26 mM and 0.20 mM against EGFR and HER-2 tyrosine kinase cancer agent [94]. Zhang et al. designed a novel series of pyrazolyl
respectively [87]. Reddy et al. developed pyrazole derivatives and hydroxamic acid analogues and tested them to determine their
assessed their anticancer potential. Compounds 22a-22c elicited ability to inhibit the growth of A549 cancer cells. Of them, com-
potent growth inhibition against all the tested cell lines with IC50 pound 29 exerted the maximum antiproliferative activity with IC50
values in the range of 0.83e1.81 mM [88]. Kamal et al. synthesized of 1.72 mM [95]. 39 derivatives of imidazo[1,2-b]pyrazoles were
pyrazole-oxindole conjugates as anticancer agents targeting synthesised by Grosse et al. and investigated by 3-(4,5-
tubulin polymerization. Compounds 23a-23c significantly inhibited dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
tubulin assembly [89]. Amongst the pyrazole derivatives developed colorimetric assay for anticancer activity. Out of the designed se-
by Shi et al., compound 24 emerged as the most potent anticancer ries, compound 30 was reported to be the most active antitumor
agent [90]. Yao et al. synthesized various 1,3-disubstituted pyrazole agent with IC50 less than 5 mM against 5 human and 1 murine
derivatives and evaluated them against Histone deacetylase (HDAC) cancer cell lines [96]. Pirol et al. synthesized a series of novel amide
enzyme. Amongst them, compound 25 exhibited promising class I derivatives of 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic
and IIb HDAC isoforms selectivity and were reported to elicit acid and determined their cytotoxic activities against various hu-
antiproliferative activity against various carcinoma cell lines [91]. man cancer cell lines. Compound 31, bearing 2-chloro-4-pyridinyl
Several derivatives of imidazo[2,1-b] thiazoles bearing pyrazole group in the amide part displayed the best antiproliferative activ-
moieties were synthesized by Ali et al. and screened for antitumor ity against all the tested cell lines [97]. Jin et al. developed a pyr-
activity. The in vitro antiproliferative evaluation demonstrated azole based series of 4-([1,2,4]triazolo[1,5-a]pyridine-6-yl)-5(3)-(6-
compound 26 as the most potent anticancer agent against CNS SNB- methylpyridin-2-yl)imidazoles and assessed them for their ALK5
75 and Renal UO-31 cancer cell lines [92]. A series of pyrazole-fused inhibitory activity. Amongst the series, compound 32, the most
23-hydroxybetulinic acid derivatives was developed by Zhang et al. active compound, inhibited ALK5 phosphorylation with an IC50
and analysed for in vitro and in vivo antiproliferative activity. Out of value of 0.018 mM and exhibited 95% inhibition at 0.03 mM con-
the synthesized compounds, compound 27 was found to be the centration. As per the results of the docking studies performed by
most potent anticancer molecule having an IC50 values of 5.58 and the authors, it was seen that the most active compound was
6.13 mM against the cancer cell lines B16 and SF763 respectively binding well with the adenosine triphosphate (ATP) binding cavity
[93]. Reddy et al. synthesized a series of pyrazolo-pyrimidinones of ALK5 [98]. Different trisubstituted pyrazole-based ROS1 kinase
and evaluated their biological activities. Amongst the synthesized inhibitors were synthesized by Park et al. and subjected to enzyme
M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201 177

Fig. 3. Anticancer activity of pyrazole derivatives.

178 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201

Fig. 3. (continued).

based screening. Following screening, compound 33 was reported active antitumor complex against PC3 (prostate adenocarcinoma)
to express 5 fold potency in comparison to crizotinib [99]. Wang cell line [102]. Based on the molecular hybridization technique,
et al. synthesized various analogues of 5-phenyl-1H-pyrazole con- Sangani et al. synthesized a new series of pyrazole-quinoline-
taining niacinamide moiety and evaluated for in vitro anti- pyridine hybrids through one pot multicomponent reaction by a
proliferative activity. The biological assay revealed that compound base catalyzed cyclocondensation reaction. All compounds were
34 the most cytotoxic agent with IC50 value of 2.63 and 3.16 mM evaluated against both Epidermal Growth Factor Receptor (EGFR)
against WM266.64 and A375 respectively [100]. Li et al. synthesized Kinase A549. Upon cytotoxicity evaluation, it was observed that
a new series of 4-pyrazolyl-1,8-naphthalimide and subjected them compound 37 showed the most potent inhibitory activity against
to in vitro antitumor activity evaluation. Amongst different com- EGFR (IC50 ¼ 0.51 ± 0.05 mM) and A549 (IC50 ¼ 0.18 ± 0.09 mM)
pounds of the series, compound 35 displayed excellent cytotoxicity carcinoma lines [103]. Kamal et al. prepared a series of several
with IC50 value of 0.51 mM against MCF-7 cells [101]. Hopa et al. heteroaromatic linked conjugates of 4b-amidopodophyllotoxin and
prepared Cd(II) complexes of tridentate nitrogen donor ligand and evaluated them for anticancer activity. Amongst them, compound
tested them for anticancer activity against various human mela- 38 showed noteworthy antitumor activity in A549 (lung cancer) cell
noma cell lines. As a result, compound 36 was found to be the most line. Further analysis proved that compound was responsible for
 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201 179

the apoptosis, as it arrested the cell cycle in the G2/M phase assessed against different human malignant cell lines. Amongst
resulting in caspade-3 depending apoptotic cell death [104]. A new two of the synthesized series, cytotoxicity of the one bearing pyr-
pyrazole based series of substituted carbothiamide was synthesized azole moiety (48) was found to be more promising in comparison to
by Zhu et al. and investigated for in vitro anticancer activities. From the other one, with the IC50 values of 2.71, 3.18, 1.09, and 13.52 mM
the results, it was observed that compound 39 had the highest against SGC 7901, A549, Raji and HeLa cells respectively [114]. Li
cytotoxic effect against Raji cells with IC50 value of 6.51 mM [105]. et al. designed a novel series of N,1,3-triphenyl-1H-pyrazole-4-
Zheng et al. designed and synthesized several pyrazole based hy- carboxamide analogues, and evaluated their anticancer activity as
brids of benzimidzole, and screened them against various carci- well as the binding potential against Aurora-A kinase. As per the
noma cell lines. They were also evaluated for their in vitro Aurora A/ results, it was found that, compound 49 was the most potent
B kinase inhibitory activity. Further, it was reported that compound molecule against HCT116 and MCF-7 cell lines with IC50 values of
40 was the most remarkable inhibitor of Aurora A/B kinase, and a 0.39 ± 0.06 mM and 0.46 ± 0.04 mM respectively. The compound was
good cytotoxic molecule against all cancer cell lines as well [106]. better in comparison to the rest of the molecules in terms of
Miyamoto et al. discovered TAK-593 (compound 41), an extremely Aurora-A kinase inhibition with IC50 value of 0.16 ± 0.03 mM [115].
potent inhibitor of Vascular Endothelial Growth Factor Receptor 2 Mohareb et al. used pregnenolone as a template to design and
(VEGFR2) kinase by the hybridization and optimization of two develop steroidal anticancer compounds. Thiosemicarbazone de-
distinct imidazo [1,2-b]pyridazines having an IC50 value of 0.95 nM. rivative of pregnenolone was first synthesized and further hetero-
The compound was also found to be a significant suppressor of cyclized into pyrazolyl semicarbazidoandrostane derivatives. The
VEGF-induced proliferation of human umbilical vein endothelial newly synhesized molecules were examined for antiproliferative
cells with an IC50 of 0.30 nM [107]. Based on the computational activity against three different human malignancies, namely, breast
modelling approach, Bavetsias et al. discovered imidazo [4,5-b] adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460)
pyridine derived pyrazole as highly selective inhibitors of Aurora-A and CNS cancer (SF-268). Compounds 50a and 50b demonstrated
kinase over Aurora-B. All of the synthesized compounds were high inhibitory effects against all the three cancer cell lines, which
found to be highly Aurora-A selective in nature. For instance, were even higher than the standard, doxorubicin [116]. In another
compound 42 showed an IC50 value of 0.067 mM for Aurora-A ki- research, exploiting the same pregnenolone template, Mohareb
nase, unlike its IC50 value of 12.71 mM for Aurora-B kinase [108]. Sun et al. synthesized a hydrazide-hydrazone derivative, which subse-
et al. developed several derivatives of pyrazole coupled with a quently went through heterocyclization reaction to produce the
thiourea moiety and investigated them for cyclin dependent kinase pyrazole and several other heterocyclic derivatives of pregneno-
(CDK) inhibitory activity. Out of the synthesized molecules, com- lone. Likewise the previous research, the newly synthesized com-
pound 43 was reported to be the most active inhibitor of CDK2 with pounds were once again investigated against the three
an IC50 of 25 nM, it also countervailed tumor cell proliferation of aforementioned cancer cell lines. According to the cytotoxic eval-
three cancer cell lines, viz., H460, MCF-7 and A549 in the micro- uation, compounds 51a and 51b were found to be the significant
molar range from 0.75 to 4.21 mM [109]. A new series of optically inhibitors of all the three tumor cell lines, and their cytotoxicity was
active 2-ferrocenyl-7-hydroxy-5-phenethyl-5,6,7,8-tetrahydro-4H- even higher than the reference doxorubicin. Such high cytotoxic
pyrazolo [1,5-a] [1,4]diazepin-4-one derivatives was designed and effect of these compounds is mainly attributed to the presence of
prepared by Shen et al. The synthesized compounds were evaluated the highly electronegative Cl group over these molecules [117]. Liu
for antitumor activity against lung cancer cells. The cytotoxicity et al. synthesized a novel series of pyrazole based peptidomimetics
study revealed that the compound (R)- and (S)-44 bearing ferro- from 3-aryl-1-arylmethyl-1H-pyrazole-5-carboxylic acid and ester
cene excel in activity as compared to the ones deprived of the same of amino acid. Two of the synthesized compounds (52a and 52b)
[110]. In a study, Garrrido et al. tried to explore the anticancer effect showed effective inhibition of the growth of A549 lung cancer cells
of novel triazole and pyrazole derivatives of dehydroepiandroster- with IC50 value of 36.12 and 38.77 mM respectively. As per the
one series over PC-3, MCF-7 and SKLU-1 cell lines. Consequently, preliminary research on the mechanism of action, the inhibition
compound 45 elicited significant inhibitory effect on proliferation might be possible through combined effect of apoptosis, autophagy
of PC-3 cell. It also induced an apoptotic effect on SKLU-1 cell line and cell cycle arrest [118]. In one step reaction of ethyl 3-phenyl-
via the activation of the estrogen receptor [111]. Sun et al. synthe- 1H-pyrazole-5-carboxylate derivatives and N-arylalkyl-2-
sized various derivatives of pyrazolo [1,5-a] [1,3,5]triazine, and chloroacetamide, Lv et al. synthesized a series of substituted de-
tested whether they inhibit Thymidine Phosphorylase (TP) enzyme, rivatives of 5-benzyl-2-phenylpyrazolo [1,5-a]pyrazin-4,6(5H,7H)-
which is responsible for promoting tumor growth and metastasis. dione. One of the synthesized compounds (53) was found capable
Amongst the 52 designed compounds, compound 46 bearing a of selectively inhibiting the growth of H322 lung cancer cells
pentafluorousulfur group at para-position exhibited significant through induction of apoptosis of cells [119]. A novel series of 1-
cytotoxic activity with an IC50 value of 0.04 mM, which was 800 acyl-3-amino-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazole de-
folds more potent than its parent lead moiety, 7-deazaxanthine, a rivatives was designed and developed by Bai et al. It was evaluated
pre-reported TP inhibitor. It is evident from the study that a sub- for in vitro antitumor activity against human colon carcinoma HCT-
stituent with þs and þp properties at position 4 of a phenyl ring 116 cell line. The results were so appealing, that two of the com-
attached to position 8 of the basic scaffold would exhibit excellent pounds of the series, compounds 54a, 54b were selected for further
TP inhibitory action [112]. Al-Adiwish et al. synthesized novel series cytotoxicity evaluation against five more cancer cell lines. The most
of fused pyrazolo [1,5-a]pyrimidine and pyrazolo [5,1-c] [1,2,4] active compound 54a was found to transcend (R)-roscovitine, the
triazine derivatives from new 5-aminopyrazoles and assessed their standard by 4e28 fold in terms of potency against all of the six
in-vivo cytotoxicity using vero cells. As a result of the pharmaco- human cancer cell lines. In addition, the authors also evaluated
logical evaluation, compound 47 was proved to be a notable cyto- compound 54a for its activity against 12 kinases, as well as for its
toxic agent with a 50% cytotoxic concentration (CC50) value of interaction mode by docking experiments with CDK5 and glycogen
0.063 mg/ml. Moreover, in terms of selectivity, all of the tested synthase kinase-3 b (GSK3b) [120]. Shamsuzzaman et al. synthe-
molecules were found to possess significative selectivity, as they all sized novel steroidal derivatives bearing oxadiazole, pyrrole and
had selectivity indices (SI) of less than 10 [113]. Two stereoselective pyrazole moiety from cholest-5-en-3b-O-acetyl hydrazide using
series of isosteviol-fused pyrazoline and pyrazole derivatives were different reagents and evaluated them against human leukaemia
developed by Zhu et al. and their antiproliferative activity was cell line (HL-60). Amongst the three synthesized molecule, the one
180 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201

bearing pyrazole ring (55) displayed better results in comparison to against A549 and H322 lung cancer cells. Following evaluation, it
the rest two compounds in terms of antiproliferative activity. The was concluded that compound 65 displayed the best anticancer
presence of ‘[3’,5’-dimethylpyrazole-1-yl] carbonylmethoxy’ moi- activity against all the tested cancer cell lines [131]. Amongst the
ety attached at 3b position may be credited for the enhanced pyrazolopyrimidine developed by Abd El Hamid et al., compound
anticancer activity in compound 55 [121]. Several pyrazolo[3,4-d] 66 was found to be the most active anticancer agent with an IC50
pyrimidine derivatives were synthesized by Huang et al. via one pot value of 7.5 nM [132]. In another pyrazole based series synthesized
synthesis by reacting 5-aminopyrazoles and formamide in the by Vujasinovic et al., compound 67 demonstrated good potency,
presence of PBr3 as the coupling agent. Among the synthesized less toxicity and an excellent safety profile [133]. Yamamoto et al.
derivatives, compound 56a and 56b that bear phenyl and 2- designed a series of compounds based on pyrazole and evaluated
quinolinyl groups at N-1 and p-Cl-Ph and p-Me-Ph groups at C-3 them for anticancer activity. Compound 68 expressed significant
positions, respectively were found to be the most potent cytotoxic antiproliferative activity against CRPC model of LNCaP-hr cell line
agents against NCI-H226 and NPC-TW01 cancer cells with half [134]. Bavetsias et al. synthesized several pyrazoles containing
maximal growth inhibitory (GI50) values between 18 mM and 30 mM imidazopyridine derivatives and evaluated them for antitumor
[122]. Strocchi et al. optimized several pyrazole analogues, as ki- activity. Among the synthesized compounds, compound 69 was
nase inhibitors through molecular modelling and evaluated them found to be the most potent inhibitor of Aurora kinases [135].
against hepatocellular carcinoma (HCC) derived cancer cell lines. Pyrazolopyrimidine analogues developed by Hanan et al. were
Two of the synthesized compounds (compound 57a, 57b) elicited a assessed for janus kinase inhibitory activity. Among the synthe-
promising inhibitory growth activity against SNU449 cell line with sized molecules, compound 70 was found to be the most active
an IC50 value of 50e100 mM. The aforesaid compounds were also anticancer compound having an IC50 value of 7.4 nM [136]. New-
found to be capable of blocking cell cycle progression and induction house et al. synthesized various non-oxime pyrazoles and tested
of apoptosis as well [123]. A novel class of selective mesen- their anticancer activity. Among the compounds synthesized,
chymaleepithelial transition factor (c-MET) protein kinase in- compound 71 displayed significant inhibition of B-Raf kinase [137].
hibitors was discovered by Cui et al. Consequently, an extremely Pyrazolopyrazinone derivatives, synthesized by Zheng et al. were
potent and selective c-MET inhibitor, compound 58 (PF-04217903) screened for anticancer activity. Compound 72 was reported as the
was found to demonstrate effective anticancer activity against c- most potent growth inhibitor of A549 and H322 carcinoma cell lines
MET with an IC50 value of 0.005 mM. The compound was also found [138]. Jin et al. synthesized a few derivatives of the prototype 1-
to possess desirable pharmacokinetic properties and safety profile substituted-3-(6-methylpyridin-2-yl)-4-([1,2,4]triazolo [1,5-a]pyr-
in preclinical studies. The above compound also succeeded in idin-6-yl)pyrazoles, and evaluated them for in vitro cytotoxicity
progressing to clinical evaluation in a Phase I oncology setting activity. Following evaluation, compound 73 was reported as the
[124]. Metwally et al. synthesized several pyrazole and pyrazolo- most potent compound of the series with IC50 value of 0.57 nM
triazine derivatives and evaluated them for their cytotoxic activity. [139]. Maggio et al. synthesized a series of pyrazole based com-
As a result, compound 59 bearing the pyrazole moiety was found to pounds and assessed their antiproliferative potential. Upon evalu-
be the most potent anticancer agent against several cancer cell lines ation, compound 74 was found to be most active agent with GI50
[125]. A series of novel farnesyltransferase inhibitors based on values of 14 and 18 mM against apoptosis resistant cell lines, HL60
phenothiazine scaffold was designed and prepared by Baciu- and K562 respectively [140].
Atudosie et al. These compounds were tested for their antitumor
activity against a NCI-60 cancer cell line panel. Amongst the syn- 2.3. Antiglaucoma
thesized analogues, Indenopyrazole (60) demonstrated best cyto-
static activity by inhibiting the growth of HCT-116, LOX IMVI and SK- Glaucoma, the silent thief of sight is a group of eye disorders that
MEL-5 cell lines [126]. Bondock et al. synthesized a new series of results in damage to the optic nerve. The disease may damage the
hybrid compounds bearing 1,3,4-oxadiazole derivatives, and some affected eye’s vision permanently, if not treated in time. The major
other heterocyclic moieties like pyrazole, thiazole, etc. along with risk factor behind glaucoma is the ocular hypertension, i.e., the
it. The newly synthesized compounds were evaluated for in vitro increased pressure within the eye. Glaucoma can be mainly treated
anticancer activity, and consequently compound 61 displayed the by either medication (in order to reduce pressure) or several
most promising antiproliferative activity in the 4 cell line assay pressure-reducing glaucoma surgeries [141]. Several pyrazole
[127]. In a research based on marine alkaloids, granulatimide and based anti-glaucoma molecules designed by various chemists are
isogranulatimide, Deslandes et al., prepared two different series of reported below (Fig. 4).
pyrazolic analogues and evaluated them for their in vitro growth Khloya et al. designed and developed pyrazolylpyrazolines. The
inhibitory properties against eight cancer cell lines. The synthe- synthesized compounds were investigated for carbonic anhydrase
sized molecules were also analysed by computer-assisted phase- inhibitory action against human carbonic anhydrase (hCA) I, II, IX
contrast microscopy, amongst which, compound 62 displayed the and XII. Among the synthesized compounds, compound 75a was
most potent cytostatic anticancer activity, with IC50 of 11 ± 4 mM found to be the best antiglaucoma agent with inhibition constant
[128]. A novel combinatorial library of S-substituted-1,3,4- (Ki) value of 0.47 nM against hCA XII. Whereas, compound 75b
oxadiazole bearing N-methyl-4-(trifluoromethyl)phenyl pyrazole exhibited highest inhibition against hCA II with a Ki value of
moiety was designed and developed by Puthiyapurayil et al. Their 0.47 nM [142]. A series of pyrazole-3,4-dicarboxamides was syn-
in vitro cytotoxic potential was determined by MTT assay. Out of the thesized by Mert et al. and evaluated for their antiglaucoma ac-
synthesized compounds, compound 63 was found to possess sig- tivity. Consequently, compound 76 was found to be the most active
nificant antiproliferative activity with an IC50 value of 15.54 mM molecule having a highest inhibitory effect against both hCA-I and
against MCF-7 cells [129]. El-borai et al. synthesized a series of hCA-II [143]. A novel series of pyrazole-sulfonamide analogues
pyrazolopyridines under microwave irradiation reaction, and ana- prepared by Balseven et al. was tested for in vitro inhibition effects
lysed the synthesized compounds for antitumor activity. Among against hCA I and hCA II. Upon investigation of antiglaucoma ac-
the synthesized compounds, compound 64 displayed maximum tivity of compounds, it was observed that compounds, 77a and 77b
antiproliferative activity [130]. A novel series of ferrocenyl showed their inhibitory effects almost in nanomolar concentrations
pyrazole-containing chiral aminoethanol analogues were synthe- for hCA I and hCA II respectively [144]. Sechi et al. developed
sized by Shen et al. These compounds were evaluated for inhibition several pyrazole based analogues and evaluated them for
 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201 181

antiglaucoma activity by testing their potential to inhibit carbonic decrease in glucose concentration (115 and 138 mg/dL) at a dose of
anhydrases. Compound 78 appeared to be the best inhibitor of hCA 100 mg/kg [159]. Bhosle et al. synthesized a new series of 2-
I with Ki value of 0.042 mM [145]. Pyrazole based compounds syn- hydrazolyl-4-thiazolidinone-5-carboxylic acids utilising Michael
thesized by Kasimogullari et al. were screened for anti-glaucoma addition reaction of 1-((3-(4-substituted phenyl)-1-phenyl-1H-
activity. Amongst them, compounds 79a, 79b and 79c exhibited pyrazol-4-yl)methylene)thiosemicarbazides with maleic anhy-
good activity profile [146]. dride. The synthesized molecules were analysed for their anti-
hyperglycaemic activity in sucrose loaded rat model. Out of these
2.4. Antihypercholestrolemia compounds, compound 86a, 86b and 86c were found to be the
most potent antihyperglycaemic agents [160]. Hernandez-Vazquez
The presence of high levels of cholesterol in blood is termed to et al. synthesized a novel series of 1,5-diaryl pyrazole derivatives
as hypercholesterolemia or dyslipidemia. Increased level of lipo- and assessed them for their hypoglycaemic activity in an in vivo
proteins (carrying cholesterol) other than HDL (high density lipo- model. As a result of bioassay, compounds 87a, 87b and 87c
protein) may increase the risk of atherosclerosis and coronary heart expressed the most significant plasma glucose reduction with
disease [147]. In order to reduce the cholesterol production or ab- decrease of 60, 64 and 60 percent respectively [161]. A spirocyclic
sorption, lipid lowering medication is mainly required [148]. Some pyrazololactam based novel series of ACC inhibitors was developed
of the antihypercholesterolemic compounds based on pyrazole by Griffith et al. which was reported to be have significant chemical
scaffold have been reported by various researchers (Fig. 5). and metabolic stability. A quinoline amide (88) was discovered as a
Kick et al. developed a series of biaryl pyrazoles and evaluated result of optimization of the pyrazole and amide substituents,
their antihypercholestrolemic potential. Compound 80 was iden- which was found to be a potent hypoglycaemic agent having an IC50
tified as the selective partial agonist for Liver X Receptor b (LXRb) value of 10 nM and 4 nM against ACC1 and ACC2 respectively [162].
with potent induction of ATP binding transporters ABCA1 and Yu et al. developed GPR142 agonists containing amrinone-
ABCG1 in human blood with EC50 value of 1.2 mM [149]. Boatman phenylalanine as basic scaffold and after hypoglycaemic evalua-
et al. synthesized a potent and effective series of tricyclic pyrazole tion, concluded compound 89a and its prodrug compound 89b as
carboxylic acids that are selective agonists of GPR109a. Amongst the most active compounds with half maximal effective concen-
the synthesized compounds, molecule 81 advanced into phase 1 tration (EC50) value of 0.053 mM and 0.095 mM respectively against
clinical trial and exhibited a tremendous decrease in plasma free human GPR142 protein [163]. A preclinical profile of teneligliptin,
fatty acids. Based on these results, the compound 81 was also tested (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-
over humans in a phase 2 study [150]. Bagley et al. reported the yl]pyrrolidin-2-ylcarbonyl]thiazolidine) was established by Yosh-
synthesis of several 7-Oxo-dihydrospiro[indazole-5,40 -piperidine] ida et al. and was reported as dipeptidyl peptidase IV (DPPIV) in-
Acetyl- CoA Carboxylase (ACC) inhibitors from alkyl hydrazones by hibitor. Compound 90 showed significant inhibition of the increase
ring closure using Vilsmeier reagent. Following ACC inhibitory of the plasma glucose levels in Zucker fatty rats [164]. Amongst the
assay, compound 82a and 82b were found to be the most active derivatives synthesized by Rikimaru et al., compound 91 exhibited
agents for treatment of hypercholesterolemia [151]. Schmidt et al. significant antidiabetic activity by binding to peroxisome
developed a new series of bicyclic pyrazole carboxylic acids and proliferator-activated receptor (PPARg) with an IC50 value of 12 nM
investigated them for their potential to activate the niacin receptor. [165]. Fushimi et al. developed various sodium glucose co-
One of the synthesized compounds, 83 exhibited good therapeutic transporter (SGLT1) inhibitors and evaluated them for their anti-
potential and lowered the lipid profile of rats effectively [152]. diabetic activity. Consequently, compound 92 was found to be the
most potent molecule which inhibits SGLT1 with an IC50 value of
2.5. Antihyperglycaemic activity 67 nM [166]. Xiong et al. discovered a highly potent and selective
glucagon receptor antagonist 93, N-[(4-{(1S)-1-[3-(3,5-
When an excessive amount of glucose circulates in the blood dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]
plasma, it is termed as hyperglycemia [153,154]. If untreated hy- ethyl}phenyl)-carbonyl]-b-alanine. The compound 93 was found to
perglycemia sustains over a period of years, a wide variety of critical be a reversible and competitive antagonist of glucagon receptor
complications including kidney, cardiovascular and neurological with a good binding affinity and IC50 of 6.6 nM [167]. Pyrazole
damage may occur [155]. Long term hyperglycemia may also lead to derivatives developed by Huard et al. were screened for anti-
diabetic neuropathy and ketoacidosis [156]. Because of such severe hyperglycaemic activity. Compound 94 displayed maximum ACC
consequences of the disease, researchers are still exploring new inhibition with an IC50 value of 67 nM [168]. Shen et al. found a new
and effective antihyperglycemic agents [157]. Several pyrazole class of 1,3,5-pyrazoles and investigated their antidiabetic poten-
containing hypoglycaemic agents have also been reported by tial. Resultantly, compound 95 was found to be the most active
several chemists in this regard (Fig. 6). agent inhibiting human glucagon receptor very efficiently and was
Among the N-substituted pyrazoles developed by Doddar- found orally bioavailable in various clinical species. Moreover, it
amappa et al., compound 84 was found to be quite promising in was found to be selective towards a large panel of enzymes and
terms of hypoglycaemic activity. The compound 84 exhibited an receptors [169]. Faidallah et al. designed a series of 3-
IC50 value of 10 mg/mL and 15 mg/mL against a-amylase and a- trifluoromethylpyrazolesulfonyl-urea and thiourea derivatives
glucosidase respectively [158]. Various analogues of 6-substituted- and evaluated them for anti hyperglycaemic activity. Amonst them,
3-(1-(4-substituted)-4-((Z)-(5,6-dimethoxy-1-oxo-1H-inden- compound 96 displayed noteworthy antidiabetic activity by
2(3H)-ylidene)methyl)-1H-pyrazol-3-yl)-2H-chromen-2-one were reducing plasma glucose level by 20% [170]. A new pyrazole based
synthesized by Kenchappa et al. utilising ClaiseneSchmidt series of compounds was designed by Choi et al., in which com-
condensation of 3-(6-substituted-2-oxo-2H-chromen-3-yl)-1-(4- pounds 97a and 97b showed remarkable antihyperglycaemic ac-
substituted)-1H-pyrazole-4-carbaldehyde derivatives and 5,6- tivity by exhibiting a Log(% binding) of 1.98 and 1.99 respectively
dimethoxy-2,3-dihydro-1H-inden-1-one. The synthesized com- [171]. Humphries et al. synthesized a novel series of 4-
pounds were evaluated for in vivo antihyperglycaemic activity us- substituted-2-aminopyrimidines and described their hypo-
ing adult Wistar rats. These rats were induced with diabetes using glycaemic activity. Compound 98 was found to be most active
streptozocin dissolved in citrate buffer and nicotinamide in normal amongst all the synthesized compounds, as it exhibited an excel-
saline. Compounds 85a and 85b demonstrated a noteworthy lent c-Jun N-terminal kinase inhibition with an IC50 value of 98 nM
182 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201

Fig. 4. Antiglaucoma activity of pyrazole derivatives.

[172]. compound 99 exhibited excellent in vitro antihypertensive activity

with significant blood pressure lowering effect as well as good
2.6. Antihypertensive activity pharmacokinetic profiles on oral administration [174]. Poulain et al.
synthesized several derivatives of N-aryl-N-(1H-pyrazol-3-yl)
Hypertension can be defined as a chronic medical condition in acetamide with the application of Ullmann and Ull-
which blood in the arteries flows with a force greater than the manneFinkelstein reactions and evaluated them for angiotensin 1
normal. By the year 2025, it is predicted that the number of people (AT1) receptor antagonism. On exploring the regioselective N-ary-
living with hypertension would be 1.56 billion worldwide. Hence, lation determinants of pyrazoles, it was found that during Ullmann
control of hypertension has become a key priority for all the sci- reaction regioselectivity can be induced by acylamino substitution.
entists working in this field throughout the world [173]. Some of Consequently, compound 100, a nanomolar direct analogue of an
the antihypertensive agents bearing pyrazole scaffold have been AT1 receptor antagonist was discovered by performing the bio-
designed by several chemists (Fig. 7). isosteric replacement of the CH2 between the nitrogen heterocycle
Hasui et al. designed a series of novel benzoxazine analogues and the biphenyl system by an NH moiety for the first time [175]. A
containing pyrazole ring as the core scaffold and optimised it novel class of 2-butyl-4-chloro-1-methylimidazole embedded
further inorder to increase its mineralocorticoid receptor (MR) chalcones and pyrazoles were developed by Kantevari et al. and
binding activity. Amongst all of the synthesized compounds, evaluated for their inhibitory action against angiotensin converting
 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201 183

Fig. 5. Pyrazole derivatives with antihypercholesterolemic activity.

Fig. 6. Antihyperglycemic activity of pyrazole derivatives.

enzyme (ACE). Amongst the series, compound 101, (E)-3-(2-butyl- derivatives designed and developed by Hasui et al. was evaluated
4-chloro-1-methyl-1H-imidazol-5-yl)-1-(1H-pyrrol-2-yl)prop-2- for MR antagonism. As a result of scaffold hopping and optimisation
enone was identified to be the most potent ACE inhibitor with an studies, 6-[1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-
IC50 value of 2.24 mM [176]. A novel series of benzoxazin-3-one pyrazol-5-yl]-2H-1,4-benzoxazin-3(4H)-one (compound 102)
184 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201

exhibited significant antihypertensive effect and good selectivity in analgesic action. Among the synthesized compounds, compound
deoxycorticosterone acetate salt hypertensive rats with an IC50 of 110 exhibited highest analgesic action [195]. Among the pyazole
41 nM [177]. Bonesi et al. synthesized a series of pyrazoles and based molecules developed by Kumar et al., compound 111 was
evaluated them for their potential activity as ACE inhibitors. Out of found to be the most active anti-inflammatory agent [196]. Pelcman
the synthesized molecules, compound 103 exerted the highest et al. synthesized various N-Substituted pyrazole-3-carboxamides
activity with an IC50 value of 0.219 mM [178]. and tested them for their potential to inhibit human 15-
lipoxygenase. Following evaluation, compound 112 was reported
as the most active anti-inflammatory agent of the series [197].
2.7. Anti-inflammatory and analgesic activity
Pyrazole analogues synthesized by Alegaon et al. were tested for
analgesic activity. All the compounds exhibited potent analgesic
Inflammation is a protective biological response of body tissues
activity by inhibiting COX-2 with an IC50 range of 1.33e17.5 mM.
to harmful stimulus involving immune cells, blood vessels, and
However, compound 113 was found to be the most active and se-
molecular mediators [179,180]. Pain is a distressing and disagree-
lective COX-2 inhibitor with IC50 value of 1.33 mM [198]. Abdellatif
able sensation associated with any injury to the tissue or organ of
et al. synthesized various pyrazole based analogues and evaluated
the body [181,182]. Non steroidal anti-inflammatory drugs
them for analgesic activity. Amongst the synthesized molecules,
(NSAIDs) are an important class of drugs prescribed to combat
compound 114 displayed maximum anti-inflammaory activity after
inflammation and alleviation of pain [183,184]. However, prolonged
3 h of inflammation induction (89%) as compared to celecoxib (80%)
use of NSAIDs usually leads to several side effects such as damage to
[199]. A series of 1,3,4-trisubstituted pyrazole developed by Ale-
gastrointestinal mucosa, renal toxicity and intolerance [185,186].
gaon et al. was analysed to determine anti-inflammatory activity.
Hence, further development of pharmacological profile of anti-
Compounds 115a and 115b showed significant anti-inflammatory
inflammatory and analgesic drugs devoid of the undesirable ef-
and analgesic action with an IC50 value of 73 mM and 70 mM
fects is still to be discovered by pharmaceutical researchers
against COX-1 and 14 mM and 20 mM against COX-2 respectively.
[187,188]. In this regard, several pyrazole based agents have also
These compounds also expressed a selectivity index (COX-1/COX-2)
been developed by chemists (Fig. 8).
of 5.21 and 3.50 respectively [200]. Tewari et al. designed a novel
Wang et al. developed a series of pyrazole containing benza-
series of pyrazole derivatives and analysed their anti-inflammatory
mides and evaluated their retinoic acid receptor Y inverse agonistic
activity. Amongst the compounds synthesized, compounds 116a
potential. Compound 104 was reported to be the most potent
and 116b exhibited activity similar to the standard drug nimesulide
compound [189]. Li et al. synthesized pyrazole derivatives and
[201]. Compound 117a and 117b exhibited significant anti-
evaluated their anti-inflammatory potential. Compound 105 was
inflammatory activity in a study by Hassan et al. in which the au-
found to exhibit maximum anti-inflammatory activity. It was found
thors had synthesized several pyrazole derivatives [202]. In another
to be more potent than the reference drugs, ibuprofen and indo-
series of 2-phenyl-5-(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4-
methacin [190]. Amongst the compounds developed by Pelcman
oxadiazoles developed by Bansal et al., compound 118 was found
et al., compounds 106a and 106b were identified as the most potent
to be most potent. It elicited an IC50 value of 0.31 mM against COX-2
inhibitors of human 15-lipoxygenase [191]. In another series of
enzyme [203]. Among the various pyrazole derivatives developed
compounds synthesized by Pelcman et al., compound 107 was
by Abdel-Aziz et al., compounds 119a and 119b displayed a
identified as the most potent inhibitor of human 15-lipoxygenase-1
remarkable anti-inflammatory activity with an median effective
and was selectd for further clinical development [192]. Wang et al.
dose (ED50) value of 68 ± 2.2 and 51 ± 0.7 mg/kg, respectively. Anti-
designed a series of benzamide based pyrazoles and tested them for
inflammatory activity was carried out using in vivo rat carrageenan-
anti-inflammatory action. Among the synthesized molecules,
induced foot paw edema model [204]. Doma et al. synthesized
compound 108 exhibited the highest anti-inflammatory action
various pyrazole based analogues and evaluated them for anti-
[193]. A series of quinolines incorporated pyrazole derivatives was
inflammatory action by injecting carrageenan into subplantar re-
developed by El-Feky et al. and was evaluated for anti-
gion of right paw of rats. Compounds 120a, 120b and 120c were
inflammatory action. Consequently, compound 109 was found to
found to be most active compounds of the series [205]. Bandgar
be the molecule with highest anti-inflammatory activity and best
et al. developed a novel series of integrated benzophenones and
binding profile into the COX-2 binding site [194]. Kendre et al.
were evaluated for analgesic activity. Among the synthesized
synthesized a series of various heterocycles and assessed them for

Fig. 7. Antihypertensive activity of pyrazole derivatives.

 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201 185

Fig. 8. Anti-inflammatory and analgesic activity of pyrazole derivatives.

compounds, compound 121a, 121b and 121c exhibited significant pyrazoles were developed by Ragab et al. and were evaluated for
anti-inflammatory and analgesic activity [206]. Amongst the anti-inflammatory activity. Compound 125 was reported to have
several pyrazole derivatives developed by Chavan et al., compound significant inhibitory activity against COX-2 with an IC50 value of
carrying methoxy group (122) exhibited highest anti-inflammatory 0.20 mmol/kg [210]. Aggarwal et al. synthesized various pyrazole
activity against COX-2 enzyme [207]. Amongst the pyrazole de- based analogues and determined their analgesic potential.
rivatives synthesized by Jadhav et al., compound 123a and 123b Amongst the synthesized molecules, compound 126 displayed
displayed excellent anti-inflammatory activity higher than the remarkable anti-inflammatory activity (62e76%) when compared
standard drug Diclofenac [208]. Vijesh et al. designed and synthe- to indomethacin (78%) [211]. Amongst various compounds syn-
sized a novel series of pyrazole derivatives containing 1,2,4- thesized by Sunder et al., compound 127 emerged as the most
triazoles and benzoxazoles and evaluated them for anti- potent and safe anti-inflammatory agent. Evalaution was per-
inflammatory action. Amongst the synthesized compounds, com- formed using the principle of carrageenaninduced paw edema
pound bearing 2,5-dichlorothiophene substituent over pyrazole [212]. Among the compounds developed by Yewale et al., com-
and a triazole ring (124) demonstrated noteworthy analgesic and pound 128 was reported as the most active compound having su-
anti-inflammatory action [209]. A number of 1,3,4-trisubstituted perior anti-inflammatory activity in comparison to diclofenac
186 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201

sodium and comparable activity with celecoxib at a dose of 25 mg/ analogues by one pot three component cyclocondenstion reaction
kg [213]. using 5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazole-4-
carbaldehyde with different enaminones and various active
2.8. Antileishmanial activity methylene compounds. The developed molecules were screened
for their in-vitro antimalarial activity against Plasmodium falcipa-
Leishmaniasis is caused by the protozoan parasites of more than rum (P. falciparum). Following screening, compound 135 was re-
20 species of genus Leishmania. It is marked with several kinds of ported to elicit most remarkable antimalarial activity [222]. Several
skin sores or ulcers which remain from weeks to months after the derivatives of antiplasmodial aminomethylthiazole pyrazole car-
person is infected by the parasite. Currently, around 12 million boxamide were designed and synthesized by Cheuka et al. and
people are infected by the disease in about 98 countries worldwide. profiled for in vitro antimalarial activity against the drug sensitive
Even after being such a big danger to human health, still there is no P. falciparum malaria parasite strain, NF54. Of the synthesized
effective treatment against leishmaniasis. Thus, there is an urgent compounds, compound 136 succeeded to retain its activity in
need for the development of effective, safe and cheaper drugs for submicromolar concentration with an IC50 value 0.125 mM [223]. A
the treatment of leishmaniasis [214]. A range of potent pyrazole new series of flouro substituted pyrazolylpyrazolines was devel-
based antileishmanial drugs have also been developed by chemists oped from pyrazole chalcones and substituted phenyl hydrazine
(Fig. 9). hydrochlorides under microwave irradiation. The developed mol-
A series of hybrid molecules bearing pyrazole and several five- ecules were screened for their antimalarial activity against
membered heterocyclic molecules was synthesized by Bekhit P. falciparum. Compound 137 was found to be most noteworthy
et al. The developed series was evaluated for antileishmanial ac- antimalarial agent having excellent activity against P. falciparum
tivity. Compound 129 demonstrated significant activity among the stain with an IC50 value of 0.022 [224]. Cabrera et al. discovered an
synthesized molecules [215]. Faria et al. designed and developed a aminomethylthiazole pyrazole carboxamide lead 138 having an
novel series of 5-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1H-tetrazole excellent in vitro antiplasmodial activity with an IC50 value of
derivatives and performed their in vitro evaluation as anti- 0.08 mM (K1, chloroquine and multidrug resistant strain) and
leishmanials against Leishmania braziliensis (L. braziliensis) and 0.07 mM (NF54, chloroquine sensitive strain). The molecule 138 also
Leishmania amazonensis (L. amazonensis) promastigotes. Following displayed promising in vivo activity in the Plasmodium berghei
pharmacological evaluation, it was reported that compounds, 3- (P. berghei) mouse model at 4  50 mg/kg administration through
chlorophenyl (130a) (IC50/24 h ¼ 15 ± 0.14 mM) and 3,4- the oral route, exhibiting an activity of 99.5% and 9 days survival.
dichlorophenyl tetrazoles (130b) (IC50/24 h ¼ 26 ± 0.09 mM) Additionally, it had low in vitro cytotoxicity [225]. A series of pyr-
expressed remarkable antileishmanial activity, [216]. Several de- azole based platinum (II) and palladium (II) complexes with (N,N0 )
rivatives of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles and (C,N,N0 ) ligands was developed by Quirante et al. and tested for
and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyr- in vitro antimalarial activity against P. falciparum strains 3D7 and
azoles were synthesized by Santos et al. and investigated for in- W2. Cyclopalladated complex, 139 displayed significant antima-
vitro antileishmanial activity against different Leishmania species. larial activity with 10 times more potency than its platinum (II)
Out of the synthesized compounds, compound 131 emerged to be analogue against P. falciparum [226]. Mishra et al. synthesized a
the most promising compound against promastigotes forms of novel series of curcumin derivatives and evaluated them against
L. amazonensis with an IC50 value of 15.5 ± 6.8 mM [217]. A series of P. falciparum for their ability to inhibit the same. Several of the
1H-pyrazole-4-carbohydrazides developed by Bernardino et al. curcumin’s analogues were found to be more effective in inhibiting
were evaluated for in-vitro antileishmanicidal activities. Com- P. falciparum growth as compared to the parent molecule (Curcu-
pounds 132a and 132b were found to be the most active molecules min). Compound 140 was found to be the most active agent by
among all the 1H-pyrazole-4-carbohydrazide analogues against exhibiting seven fold and nine fold higher antimalarial potency
L. amazonensis with an EC50 value of 80 ± 7 and 50 ± 2 mM/l against chloroquine-sensitive and chloroquine resistant
respectively [218]. P. falciparum strain [227].

2.9. Antimalarial activity 2.10. Antimicrobial

Malaria is an infectious disease caused by the parasite of Plas- An agent that kills microorganism or inhibits their growth is
modium genera. It is transmitted from one person to another by an termed to be as an antimicrobial agent [228,229]. Nowadays, bac-
infected female Anopheles mosquito. According to World Health terial and fungal infections have become an important threat and a
Organization reports, there were around 584,000 to 855,000 major cause of deaths in immunocompromised persons [230,231].
deaths worldwide caused by malaria in 2013. It mainly targets However, with the emergence of resistance, much attention has
underdeveloped regions like African countries, which have poor been focussed on developing the drugs to combat multi drug
infrastructure and high population density. As there is no clinically resistant (MDR) bacteria and fungi [232,233]. Consequently, further
proven vaccine to stop malaria yet and the chemotherapy is facing a probe is undertaking in deriving and modifying novel antimicrobial
big loophole of resistance, the hunt for efficient antimalarial agents agents with potential efficacy [234,235]. Over the time, various
is a never ending task for medicinal chemists [219]. Numerous antimicrobial agents have been developed by researchers in this
antimalarial compounds based on pyrazole have been developed by regard (Fig. 11).
chemists in respect of the above cause (Fig. 10). Yu et al. synthesized pyrazole-fused tricyclic diterpene de-
Bekhit et al. developed a series of hybrid compounds bearing rivatives and determined their antibacterial activity. Compounds
pyrazole and its bioisosters. Upon antimalarial evaluation, com- 141a and 141b exhibited MIC values of 0.71e3.12 mg/mL against five
pounds 133a and 133b emerged as the most potent compounds. multi-drug resistant Staphylococcus aureus (S. aureus) [236]. Prasath
Their activities were found to be five times higher in comparison to et al. synthesized several pyrazole based analogues and evaluated
the reference drug, chloroquine [220]. Amongst the pyrazole de- them for antibacterial and antifungal activities. Among the syn-
rivatives synthesized by Balaji et al., compound 134 was found to thesized compounds, compound 142a and 142b were found to be
elicit maximum schizonticidal and parasiticidal activities [221]. the most potent antibacterial and antifungal compounds [237]. A
Kalaria et al. synthesized a new series of polyhydroquinoline series of pyrazole-fused tricyclic diterpene derivatives was
M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201 187

Fig. 9. Antileishmanial activity of pyrazole derivatives.

Fig. 10. Antimalarial activity of pyrazole derivatives.

188 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201

designed and synthesized by Yu et al. and upon evaluation, com- potent antimicrobial agent amongst the synthesized molecules
pounds 143a and 143b exhibited highest activity with minimum [253]. Amongst the compounds synthesized by B’Bhatt and
inhibitory concentration (MIC) of 1 mg/mL against Newman strain Sharma, compound 159 displayed good antimicrobial activity
of S. aureus. However, compounds 143c and 143d were found to be against E. coli with an IC50 value of 62.5 mg/mL [254]. In another
most potent against five multi-drug resistant S. aureus with MIC of series of pyrazole derivatives containing oxadiazoles developed by
0.71e3.12 mg/mL [238]. Wang et al. designed a series of multi- Malladi et al., compound 160 was reported to exhibit excellent
pyrazole derivatives and evaluated them for antibacterial activity. potency against S. aureus, E. coli and P. Aeruginosa [255]. A series of
Compound 144 demonstrated maximum inhibition against Bacillus 3-(4chlorophenyl)-4-substituted pyrazole analogues was synthe-
subtilis (B. subtilis) amongst the synthesized compounds [239]. sized by Pathak et al. and evaluated for antimicrobial activity. As a
Ningaiah et al. synthesized a novel series of pyrazole and 1,3,4- result, compound 161 showed good activity with MIC value of 0.06
oxadiazole based hybrids and evaluated their antimicrobial po- and 0.028 mg/mL against S. aureus and E. coli respectively [256].
tential. Consequently, compound 145 emerged to be the best Shelke et al. synthesized various fluorinated pyrazole derivatives
antibacterial agent against different Gram negative and Gram pos- and evaluated them for antimicrobial activity. Among the com-
itive strains of bacteria [240]. Amongst the various pyrazole de- pounds synthesized, compound 162 was recorded to be the most
rivatives developed by Kalaria et al., compound 146 elicited active molecule against S. aureus with 6.25 mg/mL [257]. Amongst
maximum antibacterial activity with an inhibitory effect with MIC the series of pyrazolopyrimidines synthesized by Sayed et al.,
of 62.5 mg/mL against B. subtilis [241]. Nasr et al. synthesized a se- compound 163 demonstrated best antibacterial activity with MIC
ries of pyrazole based compounds and evaluated their antimicro- value of 110 mg/mL against S. aureus with zone of inhibition of
bial activity. Compound 147 was reported to be the most active 2.5e3.5 cm [258]. Desai et al. synthesized various pyrazole based
antifungal agent against Aspergillus fumigates (A. fumigates) with a compounds and evaluated their antimicrobial potential. Compound
MIC value of 0.03 mg/mL [242]. In another series of pyrazole de- 164 containing nitro group at ortho-position was found to be the
rivatives developed by Mehta et al., compound 148 was reported to most active molecule against E. coli with MIC value of 12.5 mg/mL
exhibit excellent potency with MIC 62.5 mg/mL against B. subtilis [259].
and was found to be superior to Ampicillin [243]. Prakash et al.
synthesized a series of amine linked bis- and tris-heterocycles and 2.11. Antiparkinsonian activity
evaluated their antimicrobial activity. Amongst the synthesized
compounds, compounds 149a and 149c depicted remarkable Parkinson’s disease (PD) is a progressive movement disorder of
antibacterial activity whereas 149b and 149c exhibited excellent the nervous system marked by tremor, muscular rigidity and slow
antifungal activity [244]. A pyrazole based series of 2- imprecise movements. Approximately 1% of the global population
Chloroquinoline derivatives was synthesized by Miniyar et al. and over the age of 65 years is found to be affected by PD [260]. Around
was screened for antimicrobial activity. Compound 150a was found 103,000 deaths were reported as a result of PD in 2013 which has
to be active against A. fumigatus, Penicillium notatum (P. notatum) increased from 44,000 deaths in 1990. Although there is no cure to
and B. subtilis having a MIC 48, 46 and 44 mg/mL, respectively. the disease yet, but symptomatic relief can be achieved by medi-
Compound 150b was found active against P. notatum, B. subtilis and cations, surgery and multidisciplinary management [261]. Some of
Escherichia coli (E. coli) with MIC value of 57, 54 and 43 mg/mL [245]. the pyrazole based antiparkinson compounds developed by
Several pyrimidine pyrazoles were developed by Kumar et al. and chemists have been documented below (Fig. 12).
screened for antimicrobial activity. Amongst the synthesized mol- Estrada et al. discovered two of the highly potent, selective and
ecules, compound 151 showed best antibacterial activity with MIC brain penetrant aminopyrazole Leucine-rich repeat kinase 2
of 31.2544 mg/mL against S. aureus and Bacillus cereus (B. cereus) (LRRK2) small molecule inhibitors, compounds 165a and 165b via
[246]. Amongst the pyrazole derivatives developed by Desai et al., the disciplined application of established central nervous system
compounds 152a-f were reported to be highly potent, when eval- (CNS) design parameters. The IC50 values of the two compounds
uated against different bacterial strains at non cytotoxic concen- mentioned above were found to be 3 nM and 19 nM respectively.
trations [247]. Amongst the compounds synthesized by Renuka and The compounds also exhibited metabolic stability, brain penetra-
Kumar, compound 153 having chloro substitution showed tion, and selectivity, which support their use in preclinical efficacy
remarkable antibacterial and antifungal activity against the and safety studies as well [262]. Chan et al. utilized aminopyrazole
different microbial tested strains [248]. A number of pyrazole based as a bioisostere of aniline and discovered a novel series of LRRK2
derivatives were synthesized and assessed for antibacterial po- inhibitors. Henceforth, the authors succeeded in identification of a
tential by Malladi et al. Upon evaluation, compound 154 was re- highly potent, brain-penetrant aminopyrazole LRRK2 inhibitor, 166
ported as the most potent compound of the series with MIC of that exhibited good brain exposure and hence, a promising anti-
1.612 mg/mL against S. aureus, B. subtilis, E. coli and Pseudomonas parkinson agent [263]. A novel, selective and brain penetrant 4-(1-
aeruginosa (P. aeruginosa) [249]. Song et al. synthesized a series of Phenyl-1H-pyrazol-4-yl)quinolone (167) was identified by Jimenez
5-aryloxypyrazole and rhodamine analogues and evaluated them et al. and characterized for having metabotropic glutamate (mGlu)
for antimicrobial action. Consequently, compound 155 demon- receptor 4 positive allosteric modulator properties. Compound 167
strated highest antimicrobial activity with MIC value 1 and 2 mg/mL was found to posess excellent antiparkinson activity, as the mole-
against selected Mehicillin resistant S. aureus (MRSA) and Quino- cule was also found selective over other mGlu receptors and a panel
lone resistant S. aureus (QRSA) strains [250]. Among the com- of G-protein coupled receptors (GPCRs), ion channels and enzymes.
pounds synthesized by Vijesh et al., compound 156 was found to be compound 167 depicted an EC50 value of 220 nM along with a
the most remarkable antimicrobial agent with MIC value between ramarkable ligand efficacy (LE) of 0.43 [264]. A pyrazole based
1.6125 and 3.125 mg/mL [251]. In a one step synthesis reaction analogue of curcumin called CNB-001 (compound 168) was syn-
Jardosh et al. designed a series of pyrido[1,2-a]benzimidazole de- thesized by Maher et al. and was assessed for its ability to enhance
rivatives and evaluated their antimicrobial potential. As a result, the activity of Ca2þ/calmodulin dependent protein kinase II (CaM-
compound 157 was found to be the most potent antimicrobial KII). The compound also appeared to be a good facilitator of the
agent [252]. Kendre et al. synthesized 1H-pyrazole derivatives induction of long term potentiation (LTP) in rat hippocampal slices
containing an aryl sulphonate moiety and tested them for antimi- and memory enhancement in rat object recognition test [265].
crobial activity. Compound 158 was found to be one of the most Niswender et al. discovered a novel series of pyrazolo [3,4-d]
 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201 189

Fig. 11. Antimicrobial activity of pyrazole derivatives.

pyrimidines as mGluR4 positive allosteric modulators through an 2.13. Antitubercular activity

iterative analogue library approach. Resultantly, compound 169
exhibited a notable antiparkinson activity by being a remarkable Tuberculosis (TB) is an infectious disease caused by bacteria
positive allosteric modulator of mGluR4 [266]. Mycobacterium tuberculosis (M. tuberculosis) that mainly affects the
lungs [270,271]. According to a report by World Health Organiza-
tion, around 9 million people get affected by TB every year
[272,273]. In another report it was stated that about 1/3rd of the
2.12. Antipsychotic activity world’s population is believed to be suffering from latent TB
[274,275]. Amongst which, around 10% cases are liable to be con-
Psychosis, an abnormal mental condition is mainly character- verted into active TB [276,277]. Emergence of resistance to
ized by loss of contact with the reality, as the patient goes through currently available antitubercular drugs has become another
hallucinations, delusions and disorganized speech and behaviour. trouble to the researchers, and has paved the way for the devel-
The primarily used medications for the management of psychosis opment of newer, potent and effective antimycobacterial agents
are neuroleptics or antipsychotic drugs, especially the atypical [278]. In this regard, various pyrazole based antitubercular com-
antipsychotic agents. However, atypical antipsychotic drugs are pounds have also been designed by chemists (Fig. 14).
associated with several harmful adverse effects as compared to the Silva et al. developed a series of pyrazole based compounds and
typical ones. Hence, there is an immediate requirement for the determined their antimycobacterial activity. Compound 173 was
development of new safe and effective antipsychotic agents. In this proved to be the best molecule of the series with MIC of
regard, several pyrazole containing antipsychotic agents have also 7.61 ± 2.18 mM [279]. Amongst the imidazopyrazole derivatives
been developed by researchers (Fig. 13). developed by Kalaria et al., compound 174 was found to be most
In a series of compounds developed by Hoveyda et al., com- active in-vitro agent (96%) with MIC of 250 mg/mL against
pound 170 exhibited highest antipsychotic activity with an IC50 M. tuberculosis H37Rv [280]. Amongst the compounds synthesized
value of 180 nM against G-protein coupled human tachykinin NK3 by Karad et al., compound 175 displayed highest antimycobacterial
(hNK3) receptor [267]. Neves et al. designed a novel series of pyr- activity with 96% inhibition at 250 mg/mL concentration against
azole based N-phenylpiperazine ligands of D2-like and 5-HT1A re- H37 Rv strain of M. tuberculosis [281]. Mehta et al. developed pyr-
ceptors. Upon evaluating compounds for antipsychotic activity, azole substituted quinazolinine derivatives. These compounds
compounds 171a and 171b were found to be the most active anti- were screened for in-vitro antimycobacterial activity against H37Rv
psychotic compounds [268]. A series of pyrazole and isoxazole strain. Of the developed compounds, compound 176 was found to
derivatives were synthesized by Barcelo et al. and tested for their be most active with MIC of 12.5 mg/mL [282]. Kalaria et al. devel-
binding affinities against D2, 5-HT2A and 5-HT2C receptors. Conse- oped polyhydroquinoline derivatives as antimycobacterial agents.
quently, compound 172 was found to possess highest antipsychotic Compound 177, was reported as most active with 94% inhibition at
activity [269].
190 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201

Fig. 12. Antiparkinsonian acitvity of pyrazole derivatives.

concentration of 250 and 100 mg/mL against M. tuberculosis H37Rv 2.14. Antiviral activity
[283]. Several pyrazole derivatives developed by Maurya et al. were
evaluated for antimycobacterial activity against M. tuberculosis Viruses, kind of tiny capsules containing genetic material inside
H37Rv. Following evaluation, compound 178 was reported as the [291] are capable of causing infectious disease called as viral
most active compound of the series with MIC of 25 mM [284]. infection [292,293]. Certain viral infections like the one caused by
Anand et al. developed pyrazole substituted derivatives and hepatitis C virus (HCV) are so grievous that they may even cause
screened them for antimycobacterial activity. Compound 179 was chronic liver disease leading to cirrhosis and HCC [294,295]. Due to
reported as the most active compound with MIC of 0.61 mg/mL the emergence of drug resistant strains due to rapid mutability of
against H37Rv strain [285]. Amongst the 3-(4-chlorophenyl)-4- the virus, the treatment of viral infections is still an important
substituted pyrazole derivatives developed by Pathak et al., 2-OH challenge for the researchers [296,297]. Some of the pyrazole based
substituted azetidinone derivative (180) was found to be most antiviral molecules designed by chemists have been documented
active in-vitro with MIC of 0.35 mg/mL against M. tuberculosis H37Rv below (Fig. 15).
[286]. A series of N-phenyl-3-(4-fluorophenyl)-4-substituted pyr- Compounds synthesized by Dawood et al. were evaluated for
azole derivatives was designed and developed by Khunt et al. and antiviral activity. Compound 185 was reported as the most potent
was evaluated for antitubercular activity. Among the synthesized anti-hepatitis C virus agent [298]. In a series of compounds devel-
molecules, compound 181 was found to be the most potent agent oped by Fioravanti et al., compounds 186a-186c were found to be
having an IC50 of 0.47 mM against M. tuberculosis H37Rv [287]. active against Bovine Viral Diarrhea Virus, Yellow Fever Virus and
Amongst the pyrazole analogues developed by Shelke et al., com- Respiratory Synctial Virus [299]. Manvar et al. reported compound
pound 182 displayed significant antitubercular activity. The com- 187 as a potent inhibitor of hepatitis C virus replication [300].
pound elicited MIC of 6.25 mg/mL against H37Rv strain of Manvar et al. developed a series of pyrazolecarboxamide and
M. tuberculosis [288]. Among the pyrazole derivatives synthesized evaluated them for antiviral activity. Among the synthesized mol-
by Trivedi et al., compound 183 demonstrated an excellent anti- ecules, compound 188 displayed most remarkable antiviral activity
tubercular activity with 100% at 6.25 mg/mL inhibition and MIC with an EC50 value of 6.7 mM and a SI of 23 against HCV 1b [301].
value 0.02 mg/mL against H37Rv strain of M. tuberculosis [289]. Several pyrazole fused heterocyclic analogues were designed by
Various pyrazole analogues were synthesized by Castagnolo et al. Han et al. and tested for antiviral activity. Consequently, compound
and were tested for antimycobactrial activity. As a result, com- 189 showed best antiviral activity with EC50 of 0.12 mM, which is ten
pound 184 depicted good antitubercular activity against MTB with times better than the standard drug ribavirin (EC50 ¼ 1.3 mmol/l)
MIC value of 4 mg/mL [290]. [302]. In a series based on phenylpyrazole synthesized by Mizuhara

Fig. 13. Antipsychotic activity of pyrazole derivatives.

 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201 191

Fig. 14. Antitubercular activity of pyrazole derivatives.

et al., a highly potent anti HIV agent (190) was discovered, which 0.2 nM [307]. A series of potent biaryl ethers were reported by Su
was found to possess an EC50 value of 0.047 ± 0.011 mM [303]. In an et al. as NNRTIs. As per the biological evauation of the synthesized
another research, Hwang et al. reported a series of 1,3,4- trisub- compounds, molecule 195 was found to be the most potent anti-
stituted pyrazoles and tested them as (HCV) inhibitors. Amongst viral agent possessing an intrinsic activity in nanomolar concen-
the synthesized compounds, compound 191 displayed significant tration against infected cells [308]. In a two step synthesis process,
antiviral activity with an EC50 value of 0.11 mM [304]. Moreau et al. Riyadh et al. prepared a series of new pyrazole derivatives and
designed and developed several complex pyrazole based de- evaluated their anti-HCV activity. Compound 196 expressed a very
rivatives and tested them for their antiviral action against HCV NS3- good antiviral activity against HCV with a MIC value 0.144 mg/mL
4A protease. Compound 192 was recorded to be a promising anti- [309]. Mowbray et al. synthesized three novel pyrazole containing
viral agent, as it displayed significant potency against the key NNRTIs, which exhibited noteworthy in vitro anti HIV activity. Out
resistant variants with a favourable liver distribution [305]. Ndungu of the three compounds, molecule 197 (lersivirine) got selected as a
et al. discovered a non nucleoside inhibitor of the measles virus candidate for further clinical development [310]. Sidique et al. re-
(MeV) RNA-dependent RNA polymerase (193a) and further opti- ported several pyrazole derivatives as allosteric inhibitors of west
mised it to form 193b, another potent MeV inhibitor. Both the nile virus (WNS) NS2B-NS3 proteinase. Compound 198 was found
molecules were found to be good antiviral agents having EC50 to be the most potent anti-WNS agent having an IC50 value of
values of 14 nM and 60 nM respectively [306]. A series of phenyl- 1.96 mM and the compound also demonstrated significantly good
aminopyridine analogues were synthesized by Kim et al. and were stability in pH 8 buffer [311]. Mowbray et al. developed various
tested for antiviral activity against HIV-1 non-nucleoside reverse compounds containing pyrazole as their basic moiety, and evalu-
transcriptase inhibitors (NNRTIs). Compound 194 showed an ated them as NNRTIs. Compound 199 was found to be a promising
excellent inhibition against wild type HIV-1 with an EC50 value of antiviral candidate as it inhibited eight different viral strains with
192 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201

Fig. 15. Antiviral activity of pyrazol derivatives.

an IC50 of nanomolar concentration range [312]. Pyrazole analogues reported as the most active compounds of the series as the com-
synthesized by Rashad et al. were evaluated for anti-Herpes Sim- pounds revealed higher anti Hepatitis A Virus (HAV) activity [315].
plex Virus 1 (HSV-1) activity. Amongst all the synthesized com- Several pyrazole analogues containing an oxime moiety were
pounds, compounds 200a and 200b were found to be most potent developed by Ouyang et al. and were investigated for antiviral ac-
agents at concentrations of 10 mg/105 cells and 20 mg/105 cells tivity. Compound 203 was found to possess excellent antiviral ac-
respectively [313]. Amongst the compounds developed by Zeng tivity amongst the synthesized compounds with an EC50 of 58.7 mg/
et al. compound 201 displayed considerable antiviral activity by mL [316]. Sun et al. identified 1-methyl-3-(trifluoromethyl)-N-[4-
inhibiting HIV-1 integrase with an EC50 value of 3.6 mM [314]. (pyrrolidinylsulfonyl)phenyl]-1H-pyrazole-5-carboxamide (204a)
Rashad et al. synthesized some new pyrazole and pyrazolopyr- as a significant (IC50 ¼ 35e145 nM) inhibitor of diverse genotypes
imidine analoges and evaluated them for antiviral activity. of MV. Compound 204b, an analogue of 204a also displayed good
Following evaluation, compounds 202a, 202b and 202c were activity against MV and its replication [317].

Fig. 16. Neuroprotective activity of pyrazole derivatives.

 M.F. Khan et al. / European Journal of Medicinal Chemistry 120 (2016) 170e201 193

2.15. Neuroprotective activity [9] I. Koca, A. Ozgur, K.A. Coskun, Y. Tutar, Synthesis and anticancer activity of
acyl thioureas bearing pyrazole moiety, Bioorg. Med. Chem. 21 (2013)
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