Published: 2021-07-14

Page: 179-192


Department of Chemistry, Pioneer Kumaraswamy College, Nagercoil, Tamilnadu, India.


Department of Chemistry, Pioneer Kumaraswamy College, Nagercoil, Tamilnadu, India.


Department of Chemistry, Pioneer Kumaraswamy College, Nagercoil, Tamilnadu, India.


Department of Chemistry, M. S. University College, Govinthaperi, Tamilnadu, India.


Department of Chemistry, Pioneer Kumaraswamy College, Nagercoil, Tamilnadu, India.

*Author to whom correspondence should be addressed.


This study synthesized six pyrazole derivatives from the key intermediates 2,3-dihydrochromen-4-one and 3,4-dihydrobenzo[b]oxepin-5(2H)-one. We have characterized all pyrazole derivatives as well as conducted in silico anti-inflammatory studies. The DFT calculations were performed using Gaussian 09 software. The compound 9 has the lowest energy gap (∆E, 1.0698 eV), lowest hardness (0.5349 eV), highest softness (1.8695 eV), and highest electrophilicity (7.0809eV) among all pyrazole derivatives and standard Aspirin. Swiss ADME software was used to carry out the ADME analysis. The chloro-substituted pyrazole derivatives (5, 6, and 9) were non-toxic, however, the nitrogen-substituted pyrazole derivatives (10, 13 and 14) and Aspirin were toxic. The docking patterns of the pyrazole derivatives with COX-2 selective inhibitors proteins (5F19) have been studied. Compound 9 has the lower binding energy (-10.2Kcal/mol) as compared with that of other pyrazole derivatives and standard Aspirin drugs. As a result, the pyrazole derivatives compound 9 is a promising anti-inflammatory drug with selective COX-2 inhibition as compared to the Aspirin drugs physicochemical properties.

Keywords: Pyrazole derivatives, docking study, ADMET, DFT studies and anti-inflammatory activity

How to Cite



Download data is not yet available.


Ansari A, Ali A, Asif M. Biologically active pyrazole derivatives. New J. Chem. 2017;41: 16–41.

Fustero S, Sánchez-Roselló M, Barrio P, Simón-Fuentes A. From 2000 to Mid-2010: A fruitful decade for the synthesis of pyrazoles. Chem. Rev. 2011;111:6984–7034.

Steinbach G Lynch, Robin PM, Wallace KSP, Hawk MH, Gordon E, Wakabayashi GB, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N. Engl. J. Med. 2000; 342:1946–1952.

Uslaner JM, Parmentier-Batteur S, Flick RB, Surles NO, Lam JS. McNaughton C.H. Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus. Neuropharmacology. 2009;57: 531–538.

Ghaneya SH, Doaa EAR, Esraa AA, Rana H, Refaey MA, Yassin MN. New pyrazole derivatives: Synthesis, anti-inflammatory activity, cycloxygenase inhibition assay and evaluation of mPGES. Eur. J. Med. Chem. 2019;171:332-342.

Kamble RD, Meshram RJ, Hese SV, More RA, Kamble SS, Gacche RN, Dawane BS. Synthesis and in silico investigation of thiazoles bearing pyrazoles derivatives as anti-inflammatory agents. Comput. Biol. Chem. 2016;61:86–96.

Namera DL. Thakkar SS, Thakor P, Umed B, Shah A. Arylidene analogues as selective COX-2 inhibitors: Synthesis, characterization, in-silico and in vitro studies, Journal of Biomolecular Structure and Dynamics; 2020.

DOI: 10.1080/07391102.2020.1806109

Bekhit AA, Ashour HMA, Abdel Ghany YS, Bekhit AA, Baraka A. Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents. Eur. J. Med. Chem. 2008;43:456–463.

Girisha KS, Kalluraya B, Narayana V, Padmashree V. Synthesis and pharmacological study of 1-acetyl/propyl-3-aryl-5-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-pyrazoline. Eur. J. Med. Chem. 2010;45:4640–4644.

El-Moghazy SM, Barsoum FF, Abdel-Rahman HM, Marzouk AA. Synthesis and anti-inflammatory activity of some pyrazole derivatives. Med. Chem. Res. 2012;21:1722–1733.

Maggio B, Daidone G, Raffa D, Plescia S, Mantione L, Cutuli VMC, et al. Synthesis and pharmacological study of ethyl 1-methyl-5-(substituted 3,4-dihydro-4-oxoquinazolin-3-yl)-1H-pyrazole-4-acetates. Eur. J. Med. Chem. 2001;36:737–742.

Vijesh AM, Isloor AM, Shetty P, Sundershan S, Fun HK. New pyrazole derivatives containing 1,2,4-triazoles and benzoxazoles as potent antimicrobial and analgesic agents. Eur. J. Med. Chem. 2013;62:410–415.

Schneider G, Fechner U. Computer-based de novo design of druglike molecules. Nature Reviews Drug Discovery. 2005;4(8): 649-663.

Peerzade N, Jadhav A, Shravan Y, Bhikaji BR, Anantrao KA, Dnyandeo VB. Synthesis, Docking, in silico ADMET and Pharmacological Evaluation of Some N-acetyl Pyrazole and Quinoline Conjugates. Letters in Drug Design & Discovery. 2020;17(8):1015-1026.

Mallinson TE. A review of ketorolac as a prehospital analgesic. Journal of Paramedic Practice. 2017;9(12):522-526.

El-Shoukrofya Heba MS, El Razika Omaima AA, Wafaa Aida MA, El-Ashmawy EB. Pyrazoles containing thiophene, thienopyrimidine and thienotriazolopyrimidine as COX-2 selective inhibitors: Design, synthesis, in vivo anti-inflammatory activity, docking and in silico chemo-informatic studies Bioorganic Chemistry. 2019;85:541-557.

Bandgar BP, Adsul LK, Chavan HV, Jalde SS, Shringare SN. Synthesis, biological evaluation, and docking studies of 3-(substituted)- aryl-5-(9-methyl-3-carbazole)-1H-2-pyrazolines as potent antiinflammatory and antioxidant agents. Bioorganic & Medicinal Chemistry Letters. 2012;22(18):5839-5844.

Wiseman LR, Mc Tavish D. Formestane. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of breast cancer and prostatic cancer. Drugs. 1993;45(1):66-84.

Khaled RA, Abdellatifab Eman KA, Abdelalla Madlen B, Labiba Wael AA, Fadalya Taha HZ. Synthesis of novel halogenated triarylpyrazoles as selective COX-2 inhibitors: Anti-inflammatory activity, histopatholgical profile and in-silico studies. Bioorganic Chemistry. 2020;105:104418.

Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al. Gaussian 09, Revision A.02, Gaussian, Inc., Wallingford CT; 2009.

Bouanane X, Bounekhel M, Elkolli M, Abrigach F, Khoutoul M, Bouyala R, et al. Synthesis, structural, catecholase, tyrosinase and DFT studies of pyrazoloquinoxaline derivatives. Journal of Molecular Structure. 2017;1139:238–246.

Cheng F, Li W, Zhou Y, Shen J, Wu Z. admet SAR: A Comprehensive Source and Free Tool for Assessment of Chemical ADMET Properties. Journal of Chemical Information and Modeling. 2012;52(11):3099-3105.

Shilpa T, Varalakshmi Devi K. Molecular docking and synthesis of 5- acetylpyrimidine 2, 4, 6 trione based chalcones. World Journal of Pharmaceutical Research. 2017;7(03):664-673.

Seeliger D, De Groot BL. Conformational transitions upon ligand binding: holo-structure prediction from apo conformations. PLo Scomputational Biology. 2010;6:e1000634.

Lucido MJ, Orlando BJ, Vecchio AJ, Malkowski MG. Crystal Structure of Aspirin-Acetylated Human Cyclooxygenase-2: Insight into the Formation of Products with Reversed Stereochemistry. Biochemistry. 2016;55(8): 1226-1238.

Delano WL. The PyMOL Molecular Graphics System. De-Lano Scientific, San Carlos, CA, USA; 2002.

Moniruzzaman Mohammed JH, Mohammad NU, Amrin A, Tareq M. Quantum chemical, molecular docking, and ADMET predictions of ketorolac and its modified analogues. Biomed J Sci & Tech Res. 2018;11(5):8723-8729.

Bhuvaneswaria S, Umadevia M, Vanajothi R. Effects on anti-inflammatory, DNA binding and molecular docking properties of 2-chloroquinolin-3-yl-methylene-pyridine/pyrazole derivatives and their palladium (II) complexes. Bioorganic & Medicinal Chemistry Letters. 2020;30(21):127593.

Kohn W, Becke AD, Parr RG. Density functional theory of electronic structure. J. Phys. Chem. 1996;100:12974.

Parr RG, Pearson RG. Absolute hardness: companion parameter to absolute electronegativity. J. Am. Chem. Soc. 1983;105:7512.

Parr RG, Szentpaly LV, Liu S. Electrophilicity index. J. Am. Chem. Soc. 1999;121:1922.

Antoine D, Olivier M, Vincent Z. Swiss ADME: A free web tool to evaluate pharmacokinetics, druglikeness and medicinal chemistry friendliness of small molecules. Scientific Reports. 2017;7(1):42717.

Daina A, Zoete VA. BOILED-Egg to predict gastrointestinal absorption and brain penetration of small molecules. Chem Med Chem. 2016;11:1117–1121.

Testa B, Kraemer SD. The Biochemistry of Drug Metabolism – An Introduction. Chemistry & Biodiversity. 2007;4:257-405.

Van Waterschoot RAB, Schinkel AH. A critical analysis of the interplay between cytochrome P450 3A and P-glycoprotein: recent insights from knockout and transgenic mice. Pharmacological Reviews. 2011;63:390–410.

Wolf CR, Smith G, Smith RL. Pharmacogenetics. British Medical Journal. 2000;320:987.

Hollenberg PF. Characteristics and common properties of inhibitors, inducers, and activators of CYP enzymes. Drug Metab. Rev. 2002;34:17–35.

Huang SM. New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process. J. Clin. Pharmacol. 2008;48:662–670.

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug. Deliv. Rev. 2001;46:3–26.

Egan WJ, Merz KM, Baldwin JJ. Prediction of Drug Absorption Using Multivariate Statistics. J. Med. Chem. 2000;43:3867–3877.

Ghose AK, Viswanadhan VN,. Wendoloski JJ. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb. Chem. 1999;1:55–68.

Veber DF. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002;45:2615–2623.

Muegge I, Heald SL, Brittelli D. Simple selection criteria for drug-like chemical matter. J. Med. Chem. 2001;44:1841–1846.

Solis W. Minimization by random search techniques. Mathematics of Operations Research. 1981;6(1):19-30.

Moniruzzaman Hoque MJ, Ahsan A, Hossain MB. Molecular docking, pharmacokinetic, and DFT calculation of naproxen and its degradants. Biomedical Journal of Scientific & Technical Research. 2018;9:5.