Abstract
In the process of research and development of new drugs, in silico analyzes are widely used. They address the pharmacokinetics of the molecules in study and can predict the binding mode and affinity, using a docking software. This approach can optimize the development of new drugs, reducing costs, time, and resources. In this study, a library of 300 pyrazole–chalcone derivatives were designed, the in silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties were evaluated, and a structure-based virtual screening was performed using AutoDock Vina. The docking results exhibited that the derivatives binding mode at the COX-2 active site is similar to celecoxib, the reference drug, and presented similar binding energy. Six compounds were synthetized and tested for in vitro inhibition of the COX-1 and COX-2 isoenzymes and the selectivity index (SI) was calculated. The compound 2a11 showed the best activity for COX-2 (IC50COX-2 = 0.73 μM) whereas the control, celecoxib, resulted IC50COX-2 = 0.88 μM. All the other compounds synthetized presented better potency for COX-2 inhibition than the control. Compound 2a23 exhibited the higher SI, of 280.17 (IC50COX-1 = 210.13 μM/ IC50COX-2 = 0.75 μM), while celecoxib was 246.88 (IC50COX-1 = 217.26 μM/ IC50COX-2 = 0.88 μM). These results corroborate with a possible anti-inflammatory activity and COX-2 selectivity of the new compounds synthetized.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baell JB, Holloway GA (2010) New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem 53:2719–2740. https://doi.org/10.1021/jm901137j
Bandgar BP, Patil SA, Gacche RN, Korbad BL, Hote BS, Kinkar SN, Jalde SS (2010) Synthesis and biological evaluation of nitrogen-containing chalcones as possible anti-inflammatory and antioxidant agents. Bioorg Med Chem Lett 20:730–733. https://doi.org/10.1016/j.bmcl.2009.11.068
Berman HM (2000) The protein data bank. Nucleic Acids Res 28:235–242. https://doi.org/10.1093/nar/28.1.235
Brenk R, Schipani A, James D, Krasowski A, Gilbert IH, Frearson J, Wyatt PG (2008) Lessons learnt from assembling screening libraries for drug discovery for neglected diseases. ChemMedChem 3:435–444. https://doi.org/10.1002/cmdc.200700139
Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:1–13. https://doi.org/10.1038/srep42717
Daly AK, Rettie AE, Fowler DM, Miners JO (2018) Pharmacogenomics of CYP2C9: functional and clinical considerations. J Pers Med 8:1–31. https://doi.org/10.3390/jpm8010001
Danielson, ML, Hu, B, Shen, J, Desai, PV (2017) In silico ADME techniques used in early-phase drug discovery. In: Bhattachar, SN, Morrison, JS, Mudra, DR, Bender, DM (eds) Translating Molecules into Medicines. Springer Nature, Cham, Switzerland, p 81–117
de Pedro M, Baeza S, Escudero M-T, Dierssen-Sotos T, Gómez-Acebo I, Pollán M, Llorca J (2015) Effect of COX-2 inhibitors and other non-steroidal inflammatory drugs on breast cancer risk: a meta-analysis. Breast Cancer Res Treat 149:525–536. https://doi.org/10.1007/s10549-015-3267-9
Egan WJ, Merz KM, Baldwin JJ (2000) Prediction of drug absorption using multivariate statistics. J Med Chem 43:3867–3877. https://doi.org/10.1021/jm000292e
Enchev V, Mehandzhiyski AY (2017) Computational insight on the chalcone formation mechanism by the Claisen–Schmidt reaction. Int J Quantum Chem 117:1–8. https://doi.org/10.1002/qua.25365
Faria JV, Vegi PF, Miguita AGC, dos Santos MS, Boechat N, Bernardino AMR (2017) Recently reported biological activities of pyrazole compounds. Bioorganic Med Chem 25:5891–5903. https://doi.org/10.1016/j.bmc.2017.09.035
Gaonkar SL, Vignesh UN (2017) Synthesis and pharmacological properties of chalcones: a review. Res Chem Intermed 43:6043–6077. https://doi.org/10.1007/s11164-017-2977-5
Ghose AK, Viswanadhan VN, Wendoloski JJ (1999) A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery: a qualitative and quantitative characterization of known drug databases. J Comb Chem 1:55–68. https://doi.org/10.1021/cc9800071
Gomes, MN, Muratov, EN, Pereira, M, Peixoto, JC, Rosseto, LP, Cravo, PVL, Andrade, CH, Neves, BJ (2017) Chalcone derivatives: promising starting points for drug design. Molecules. https://doi.org/10.3390/molecules22081210
Hawkey C (1999) COX-2 inhibitors. Lancet 353:307–314. https://doi.org/10.1016/S0140-6736(98)12154-2
Karrouchi, K, Radi, S, Ramli, Y, Taoufik, J, Mabkhot, YN, Al-Aizari, FA, Ansar, M (2018) Synthesis and pharmacological activities of Pyrazole derivatives: a review, Molecules. https://doi.org/10.3390/molecules23010134
Khalaf N, Yuan C, Hamada T, Cao Y, Babic A, Morales-Oyarvide V, Kraft P, Ng K, Giovannucci E, Ogino S, Stampfer M, Cochrane BB, Manson JE, Clish CB, Chan AT, Fuchs CS, Wolpin BM (2018) Regular use of aspirin or non-aspirin nonsteroidal anti-inflammatory drugs is not associated with risk of incident pancreatic cancer in two large cohort studies. Gastroenterology 154:1380–1390.e5. https://doi.org/10.1053/j.gastro.2017.12.001
Khan MF, Alam MM, Verma G, Akhtar W, Akhter M, Shaquiquzzaman M (2016) The therapeutic voyage of pyrazole and its analogs: a review. Eur J Med Chem 120:170–201. https://doi.org/10.1016/j.ejmech.2016.04.077
Kim HS, Sharma A, Ren WX, Han J, Kim JS (2018) COX-2 Inhibition mediated anti-angiogenic activatable prodrug potentiates cancer therapy in preclinical models. Biomaterials 185:63–72. https://doi.org/10.1016/j.biomaterials.2018.09.006
Li J, Li D, Xu Y, Guo Z, Liu X, Yang H, Wu L, Wang L (2017) Design, synthesis, biological evaluation, and molecular docking of chalcone derivatives as anti-inflammatory agents. Bioorg Med Chem Lett 27:602–606. https://doi.org/10.1016/j.bmcl.2016.12.008
Li M, Zhao BX (2014) Progress of the synthesis of condensed pyrazole derivatives (from 2010 to mid-2013). Eur J Med Chem 85:311–340. https://doi.org/10.1016/j.ejmech.2014.07.102
Lipinski CA (2016) Rule of five in 2015 and beyond: target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions. Adv Drug Deliv Rev 101:34–41. https://doi.org/10.1016/j.addr.2016.04.029
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25. https://doi.org/10.1016/S0169-409X(00)00129-0
Martin YC (2005) A bioavailability score. J Med Chem 48:3164–3170. https://doi.org/10.1021/jm0492002
Moroy G, Martiny VY, Vayer P, Villoutreix BO, Miteva MA (2012) Toward in silico structure-based ADMET prediction in drug discovery. Drug Discov Today 17:44–55. https://doi.org/10.1016/j.drudis.2011.10.023
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791. https://doi.org/10.1002/jcc.21256
Muegge I, Heald SL, Brittelli D (2001) Simple selection criteria for drug-like chemical matter J Med Chem 44:1841–1846. https://doi.org/10.1021/jm015507e
Mukarram S, Bandgar BP, Shaikh RU, Ganapure SD, Chavan HV (2017) Synthesis of novel α,α-difluoro-β-hydroxycarbonyl pyrazole derivatives as antioxidant, anti-inflammatory and anticancer agents. Med Chem Res 26:262–273. https://doi.org/10.1007/s00044-016-1744-2
Özdemir A, Altıntop MD, Sever B, Gençer HK, Kapkaç HA, Atlı Ö, Baysal M (2017) A new series of pyrrole-based chalcones: synthesis and evaluation of antimicrobial activity, cytotoxicity, and genotoxicity. Molecules 22:2112. https://doi.org/10.3390/molecules22122112
Patrono C, Baigent C (2017) Coxibs, traditional NSAIDs, and cardiovascular safety post-PRECISION: what we thought we knew then and what we think we know now. Clin Pharmacol Ther 102:238–245. https://doi.org/10.1002/cpt.696
Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera: a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612. https://doi.org/10.1002/jcc.20084
Rayar A-M, Lagarde N, Ferroud C, Zagury J-F, Montes M, Sylla-Iyarreta Veitia M (2017) Update on COX-2 selective inhibitors: chemical classification, side effects and their use in cancers and neuronal diseases. Curr Top Med Chem 17:2935–2956. https://doi.org/10.2174/1568026617666170821124947
Richter L (2017) Topliss Batchwise Schemes reviewed in the era of open data reveal significant differences between enzymes and membrane receptors. J Chem Inf Model 57:2575–2583. https://doi.org/10.1021/acs.jcim.7b00195
Schmidt M, Lamberts M, Olsen AMS, Fosbøll E, Niessner A, Tamargo J, Rosano G, Agewall S, Kaski JC, Kjeldsen K, Lewis BS, Torp-Pedersen C (2016) Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs: Review and position paper by the working group for Cardiovascular Pharmacotherapy of the European Society of Cardiology. Eur Hear J Cardiovasc Pharmacother 2:108–118. https://doi.org/10.1093/ehjcvp/pvv054
Serhan CN, Savill J (2005) Resolution of inflammation: the beginning programs the end. Nat Immunol 6:1191–1197. https://doi.org/10.1038/ni1276
Shen FQ, Wang ZC, Wu SY, Ren SZ, Man RJ, Wang BZ, Zhu HL (2017) Synthesis of novel hybrids of pyrazole and coumarin as dual inhibitors of COX-2 and 5-LOX. Bioorganic Med Chem Lett 27:3653–3660. https://doi.org/10.1016/j.bmcl.2017.07.020
Singh P, Anand A, Kumar V (2014) Recent developments in biological activities of chalcones: a mini review. Eur J Med Chem 85:758–777. https://doi.org/10.1016/j.ejmech.2014.08.033
Sugimoto, MA, Sousa, LP, Pinho, V, Perretti, M, Teixeira, MM (2016) Resolution of inflammation: what controls its onset? Front Immunol. https://doi.org/10.3389/fimmu.2016.00160
Teague SJ, Davis AA, Leeson PD, Oprea T (1999) The design of leadlike combinatorial libraries. Angew Chemie Int Ed 38:3743–3748. https://doi.org/10.1002/(SICI)1521-3773(19991216)38:24<3743::AID-ANIE3743>3.0.CO;2-U
Tian S, Wang J, Li Y, Li D, Xu L, Hou T (2015) The application of in silico drug-likeness predictions in pharmaceutical research. Adv Drug Deliv Rev 86:2–10. https://doi.org/10.1016/j.addr.2015.01.009
Topliss JG (1972) Utilization of operational schemes for analog synthesis in drug design. J Med Chem 15:1006–1011. https://doi.org/10.1021/jm00280a002
Trott O, Olson AJ (2009) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 8:NA–NA. https://doi.org/10.1002/jcc.21334
Umamaheswaran S, Dasari SK, Yang P, Lutgendorf SK, Sood AK (2018) Stress, inflammation, and eicosanoids: an emerging perspective. Cancer Metastasis Rev 37:203–211. https://doi.org/10.1007/s10555-018-9741-1
Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:2615–2623. https://doi.org/10.1021/jm020017n
Viveka S, Dinesha, Nagaraja GK, Shama P, Basavarajaswamy G, Rao KP, Yanjarappa Sreenivasa M (2018) One pot synthesis of thiazolo[2,3-b]dihydropyrimidinone possessing pyrazole moiety and evaluation of their anti-inflammatory and antimicrobial activities. Med Chem Res 27:171–185. https://doi.org/10.1007/s00044-017-2058-8
Wang JL, Limburg D, Graneto MJ, Springer J, Hamper JRB, Liao S, Pawlitz JL, Kurumbail RG, Maziasz T, Talley JJ, Kiefer JR, Carter J (2010) The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: the second clinical candidate having a shorter and favorable human half-life. Bioorg Med Chem Lett 20:7159–7163. https://doi.org/10.1016/j.bmcl.2010.07.054
Wang Z, Sun H, Yao X, Li D, Xu L, Li Y, Tian S, Hou T (2016) Comprehensive evaluation of ten docking programs on a diverse set of protein–ligand complexes: the prediction accuracy of sampling power and scoring power. Phys Chem Chem Phys 18:12964–12975. https://doi.org/10.1039/C6CP01555G
van de Waterbeemd H, Gifford E (2003) ADMET in silico modelling: towards prediction paradise? Nat Rev Drug Discov 2:192–204. https://doi.org/10.1038/nrd1032
Zhuang C, Zhang W, Sheng C, Zhang W, Xing C, Miao Z (2017) Chalcone: a privileged structure in medicinal chemistry. Chem Rev 117:7762–7810. https://doi.org/10.1021/acs.chemrev.7b00020
Acknowledgements
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001, and, research support fund (FAP-UNIVALI).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Macarini, A.F., Sobrinho, T.U.C., Rizzi, G.W. et al. Pyrazole–chalcone derivatives as selective COX-2 inhibitors: design, virtual screening, and in vitro analysis. Med Chem Res 28, 1235–1245 (2019). https://doi.org/10.1007/s00044-019-02368-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-019-02368-8