Pyrazoles as Anti-inflammatory and Analgesic Agents: In-vivo and In-silico Studies


Дәйексөз келтіру

Толық мәтін

Аннотация

Background::Pyrazole is a well-known nucleus in the pharmacy field with a wide range of other activities in addition to anti-inflammatory and analgesic, i.e., anticonvulsant, antiviral, and anticancer activities. There are well-known marketed drugs having pyrazole moi-ety as celecoxib, and lonazolac as COX-II inhibitors.

Aims::We aim to synthesize better anti-inflammatory than existing ones. Thiophene is also known for its analgesic and anti-inflammatory action. Thus, the fusion of both gives better anti-inflammatory agents. In the present studies, derivatives from two series of pyrazole were prepared by reacting substituted chalcone (3a-3f) derivatives prepared from 2-acetyl thiophene. They substituted aromatic aldehydes with phenyl hydrazine to form (5a-5f) and with 2, 4-dinitro phenyl hydrazine giving compounds (6a-6f) separately.

Methods::Purified and characterized pyrazoles have been analyzed for in-vivo analgesic and anti-inflammatory activities by using standard methods. Compounds 5e, 5f, and 6d were proved to be potent analgesics and series (5a-5f) was found to have anti-inflammatory action, which was further validated using docking and ADME studies.

Results::The ADME profile of synthesized compounds was found to be satisfactory.

Conclusion::The synthesized compounds can serve as lead for further drug designing.

Авторлар туралы

Geeta Chahal

Institute of Pharmaceutical Sciences, Kurukshetra University

Email: info@benthamscience.net

Jyoti Monga

, Ch. Devi Lal College of Pharmacy

Email: info@benthamscience.net

Isha Rani

, Spurthy College of Pharmacy

Email: info@benthamscience.net

Shubham Saini

Institute of Pharmaceutical Sciences, Kurukshetra University

Email: info@benthamscience.net

Manish Devgun

Institute of Pharmaceutical Sciences, Kurukshetra University

Email: info@benthamscience.net

Asif Husain

Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research,, Jamia Hamdard

Email: info@benthamscience.net

Sukhbir Lal Khokra

Institute of Pharmaceutical Sciences, Kurukshetra University

Хат алмасуға жауапты Автор.
Email: info@benthamscience.net

Әдебиет тізімі

  1. Omar, F.A.; Mahfouz, N.M.; Rahman, M.A. Design, synthesis and antiinflammatory activity of some 1,3,4-oxadiazole derivatives. Eur. J. Med. Chem., 1996, 31(10), 819-825. doi: 10.1016/0223-5234(96)83976-6 PMID: 22026938
  2. Sandhu, J.S. 2006. Renal effects of selective cyclooxygenase-2 (COX- 2) inhibitors. J. Indian Acad. Clin. Med., 2003, 4(1), 18-20.
  3. Ostad, S.N. Mohsen Amini; Zahra Haghipour; Leila Karimi; Latifeh Navidpour; Ghahremani, M.H.; Shafiee, A. Inhibitory activities of new series of 4, 5-diaryl thiadiazoles derivaties on lipopolysaccharide-induced Cox-2 expression. Int. J. Pharmacol., 2004, 1(1), 79-84. doi: 10.3923/ijp.2005.79.84
  4. Rahme, E.; Nedjar, H. Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: Does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. Rheumatology (Oxford), 2007, 46(3), 435-438. doi: 10.1093/rheumatology/kel428 PMID: 17255138
  5. Hawkey, C.J. COX-2 inhibitors The Lancet, 1999, 23;353(9149), 307-314.
  6. Khanna, I.K.; Weier, R.M.; Yu, Y.; Collins, P.W.; Miyashiro, J.M.; Koboldt, C.M.; Veenhuizen, A.W.; Currie, J.L.; Seibert, K.; Isakson, P.C. 1,2-Diarylpyrroles as potent and selective inhibitors of cyclooxygenase-2. J. Med. Chem., 1997, 40(11), 1619-1633. doi: 10.1021/jm970036a PMID: 9171872
  7. Boehm, J.C.; Smietana, J.M.; Sorenson, M.E.; Garigipati, R.S.; Gallagher, T.F.; Sheldrake, P.L.; Bradbeer, J.; Badger, A.M.; Laydon, J.T.; Lee, J.C.; Hillegass, L.M.; Griswold, D.E.; Breton, J.J.; Chabot-Fletcher, M.C.; Adams, J.L. 1-substituted 4-aryl-5-pyridinylimidazoles: A new class of cytokine suppressive drugs with low 5-lipoxygenase and cyclooxygenase inhibitory potency. J. Med. Chem., 1996, 39(20), 3929-3937. doi: 10.1021/jm960415o PMID: 8831759
  8. Li, J.J.; Anderson, G.D.; Burton, E.G.; Cogburn, J.N.; Collins, J.T.; Garland, D.J.; Gregory, S.A.; Huang, H.C.; Isakson, P.C.; Koboldt, C.M. 1,2-Diarylcyclopentenes as selective cyclooxygenase-2 inhibitors and orally active anti-inflammatory agents. J. Med. Chem., 1995, 38(22), 4570-4578. doi: 10.1021/jm00022a023 PMID: 7473585
  9. Manivannan, E.; Prasanna, S.; Chaturvedi, S.C. Rationalization of physico-chemical properties of 5, 6-diarylthiazolo 3, 2-b-1, 2, 4-triazoles towards cyclooxygenase-2 (COX-2) inhibition: A QSAR approach. Indian J. Biochem. Biophys., 2004, 41(4), 179-183.
  10. Stiller, C.O.; Hjemdahl, P. Lessons from 20 years with COX-2 inhibitors: Importance of dose-response considerations and fair play in comparative trials. J. Intern. Med., 2022, 292(4), 557-574. doi: 10.1111/joim.13505 PMID: 35585779
  11. El-Malah, A.A.; Gineinah, M.M.; Deb, P.K.; Khayyat, A.N.; Bansal, M.; Venugopala, K.N.; Aljahdali, A.S. Selective COX-2 inhibitors: Road from success to controversy and the quest for repurposing. Pharmaceuticals (Basel), 2022, 15(7), 827. doi: 10.3390/ph15070827 PMID: 35890126
  12. Wang, D.; Dubois, R.N. Prostaglandins and cancer. Gut, 2006, 55(1), 115-122. doi: 10.1136/gut.2004.047100 PMID: 16118353
  13. Laine, L. The gastrointestinal effects of nonselective NSAIDs and COX-2-selective inhibitors. Semin. Arthritis Rheum., 2002, 32(3)(Suppl. 1), 25-32. doi: 10.1053/sarh.2002.37217 PMID: 12528071
  14. Hawkey, C.J. The gastroenterologist’s caseloadcontribution of the rheumatologist. Semin. Arthritis Rheum., 1997, 26(6)(Suppl. 1), 11-15. doi: 10.1016/S0049-0172(97)80047-9 PMID: 9219314
  15. Laine, L.; Smith, R.; Min, K.; Chen, C.; Dubois, R.W. Systematic review: The lower gastrointestinal adverse effects of non-steroidal anti-inflammatory drugs. Aliment. Pharmacol. Ther., 2006, 24(5), 751-767. doi: 10.1111/j.1365-2036.2006.03043.x PMID: 16918879
  16. Deeks, J.J.; Smith, L.A.; Bradley, M.D. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: Systematic review of randomised controlled trials. BMJ, 2002, 325(7365), 619. doi: 10.1136/bmj.325.7365.619 PMID: 12242171
  17. Wober, W. Comparative efficacy and safety of nimesulide and diclofenac in patients with acute shoulder, and a meta-analysis of controlled studies with nimesulide. Br. J. Rheumatol., 1999, 38(90001)(Suppl. 1), 33-38. doi: 10.1093/rheumatology/38.suppl_1.33 PMID: 10369404
  18. Lücker, P.W.; Pawlowski, C.; Friedrich, I.; Faiella, F.; Magni, E. Double-blind, randomised, multi-centre clinical study evaluating the efficacy and tolerability of nimesulide in comparison with etodalac in patients suffering from osteoarthritis of the knee. Eur. J. Rheumatol. Inflamm., 1994, 14(2), 29-38. PMID: 7744131
  19. Schnitzer, T.J.; Constantine, G. Etodolac (Lodine) in the treatment of osteoarthritis: Recent studies. J. Rheumatol. Suppl., 1997, 47, 23-31. PMID: 9035017
  20. Neustadt, D.H. Double blind evaluation of the long-term effects of etodolac versus ibuprofen in patients with rheumatoid arthritis. J. Rheumatol. Suppl., 1997, 47, 17-22. PMID: 9035016
  21. Silverstein, F.E.; Faich, G.; Goldstein, J.L.; Simon, L.S.; Pincus, T.; Whelton, A.; Makuch, R.; Eisen, G.; Agrawal, N.M.; Stenson, W.F.; Burr, A.M.; Zhao, W.W.; Kent, J.D.; Lefkowith, J.B.; Verburg, K.M.; Geis, G.S. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA, 2000, 284(10), 1247-1255. doi: 10.1001/jama.284.10.1247 PMID: 10979111
  22. Bombardier, C.; Laine, L.; Reicin, A.; Shapiro, D.; Burgos-Vargas, R.; Davis, B.; Day, R.; Ferraz, M.B.; Hawkey, C.J.; Hochberg, M.C.; Kvien, T.K.; Schnitzer, T.J. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N. Engl. J. Med, 2000, 343(21), 1520-1528. 2, 1528. doi: 10.1056/NEJM200011233432103 PMID: 11087881
  23. Schnitzer, T.J.; Burmester, G.R.; Mysler, E.; Hochberg, M.C.; Doherty, M.; Ehrsam, E.; Gitton, X.; Krammer, G.; Mellein, B.; Matchaba, P.; Gimona, A.; Hawkey, C.J. comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (aff), reduction in ulcer complications: Randomised controlled trial. Lancet, 2004, 364(9435), 665-674. doi: 10.1016/S0140-6736(04)16893-1 PMID: 15325831
  24. Farag, A.A.; Khalifa, E.M.; Sadik, N.A.; Abbas, S.Y.; Al-Sehemi, A.G.; Ammar, Y.A. Synthesis, characterization, and evaluation of some novel 4(3H)-quinazolinone derivatives as anti-inflammatory and analgesic agents. Med. Chem. Res., 2013, 22(1), 440-452. doi: 10.1007/s00044-012-0046-6
  25. Sharma, S.; Srivastava, V.K.; Kumar, A. Newer N-substituted anthranilic acid derivatives as potent anti-inflammatory agents. Eur. J. Med. Chem., 2002, 37(8), 689-697. doi: 10.1016/S0223-5234(02)01340-5 PMID: 12161066
  26. Shoman, M.E.; Abdel-Aziz, M.; Aly, O.M.; Farag, H.H.; Morsy, M.A. Synthesis and investigation of anti-inflammatory activity and gastric ulcerogenicity of novel nitric oxide-donating pyrazoline derivatives. Eur. J. Med. Chem., 2009, 44(7), 3068-3076. doi: 10.1016/j.ejmech.2008.07.008 PMID: 18722034
  27. Rani, I.; Khokra, S.L.; Kaur, G.; Sharma, P. Anti-inflammatory, analgesic and antimicrobial activities of some synthetic furanones and their pyrrolone derivatives. Int. J. Pharm. Sci. Res., 2021, 12(12), 3339-3348.
  28. Aggarwal, R.; Bansal, A.; Rozas, I.; Kelly, B.; Kaushik, P.; Kaushik, D. Synthesis, biological evaluation and molecular modeling study of 5-trifluoromethyl-Δ2-pyrazoline and isomeric 5/3-trifluoromethylpyrazole derivatives as anti-inflammatory agents. Eur. J. Med. Chem., 2013, 70, 350-357. doi: 10.1016/j.ejmech.2013.09.052 PMID: 24177361
  29. Ahsan, M.J. Anticonvulsant activity and neuroprotection assay of 3-substituted-N-aryl-6,7-dimethoxy-3a,4-dihydro-3H-indeno1,2-cpyrazole-2-carboxamide analogues. Arab. J. Chem., 2017, 10, S2762-S2766. doi: 10.1016/j.arabjc.2013.10.023
  30. Abdel-Aziz, M.; Abuo-Rahma, G.E.D.A.; Hassan, A.A. Synthesis of novel pyrazole derivatives and evaluation of their antidepressant and anticonvulsant activities. Eur. J. Med. Chem., 2009, 44(9), 3480-3487. doi: 10.1016/j.ejmech.2009.01.032 PMID: 19268406
  31. El-Sabbagh, O.I.; Baraka, M.M.; Ibrahim, S.M.; Pannecouque, C.; Andrei, G.; Snoeck, R.; Balzarini, J.; Rashad, A.A. Synthesis and antiviral activity of new pyrazole and thiazole derivatives. Eur. J. Med. Chem., 2009, 44(9), 3746-3753. doi: 10.1016/j.ejmech.2009.03.038 PMID: 19419804
  32. Ouyang, G.; Chen, Z.; Cai, X.J.; Song, B.A.; Bhadury, P.S.; Yang, S.; Jin, L.H.; Xue, W.; Hu, D.Y.; Zeng, S. Synthesis and antiviral activity of novel pyrazole derivatives containing oxime esters group. Bioorg. Med. Chem., 2008, 16(22), 9699-9707. doi: 10.1016/j.bmc.2008.09.070 PMID: 18945621
  33. Cankara Pirol, Ş.; Çalışkan, B.; Durmaz, İ.; Atalay, R.; Banoglu, E. Synthesis and preliminary mechanistic evaluation of 5-(p-tolyl)-1- (quinolin-2-yl)pyrazole-3-carboxylic acid amides with potent antiproliferative activity on human cancer cell lines. Eur. J. Med. Chem., 2014, 87, 140-149. doi: 10.1016/j.ejmech.2014.09.056 PMID: 25247770
  34. Kumari, S.; Paliwal, S.; Chauhan, R. Synthesis of pyrazole derivatives possessing anticancer activity: Current status. synthetic communications, 2014, 44(11), 1521-1578.
  35. David, S.; Perkins, R.S.; Fronczek, F.R.; Kasiri, S.; Mandal, S.S.; Srivastava, R.S. Synthesis, characterization, and anticancer activity of ruthenium-pyrazole complexes. J. Inorg. Biochem., 2012, 111, 33-39. doi: 10.1016/j.jinorgbio.2012.02.022 PMID: 22484498
  36. Penning, T.D.; Talley, J.J.; Bertenshaw, S.R.; Carter, J.S.; Collins, P.W.; Docter, S.; Graneto, M.J.; Lee, L.F.; Malecha, J.W.; Miyashiro, J.M.; Rogers, R.S.; Rogier, D.J.; Yu, S.S.; Anderson, G.D.; Burton, E.G.; Cogburn, J.N.; Gregory, S.A.; Koboldt, C.M.; Perkins, W.E.; Seibert, K.; Veenhuizen, A.W.; Zhang, Y.Y.; Isakson, P.C. Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-ylbenze nesulfonamide (SC-58635, celecoxib). J. Med. Chem., 1997, 40(9), 1347-1365. doi: 10.1021/jm960803q PMID: 9135032
  37. O’Connor, J.P.; Lysz, T. Celecoxib, NSAIDs and the skeleton. Drugs Today (Barc), 2008, 44(9), 693-709. doi: 10.1358/dot.2008.44.9.1251573 PMID: 19137124
  38. Riedel, R. Lonazolac-Ca= calcium (3-(p-chlorophenyl)-1- phenylpyrazole-4)-acetate/pharmacological properties of a new antiinflammatory/antirheumatic drug various animals. In: Arzneimittelforschung-Drug Research; (Germany, FR). 1981.
  39. da Cruz, R.M.D.; Mendonça-Junior, F.J.B.; de Mélo, N.B.; Scotti, L.; de Araújo, R.S.A.; de Almeida, R.N.; de Moura, R.O. Thiophene-based compounds with potential anti-inflammatory activity. Pharmaceuticals, 2021, 14(7), 692.
  40. Lahsasni, S.; Al-Hemyari, D.A.; Ghabbour, H.A.; Mabkhoot, Y.N.; Aleanizy, F.S.; Alothman, A.A.; Almarhoon, Z.M. Synthesis, characterization, and antibacterial and anti-inflammatory activities of new pyrimidine and thiophene derivatives. Journal of Chemistry, 2018.
  41. Metwally, H.M.; Khalaf, N.A.; Abdel-Latif, E.; Ismail, M.A. Synthesis, DFT investigations, antioxidant, antibacterial activity and SAR-study of novel thiophene-2-carboxamide derivatives. BMC Chem., 2023, 17(1), 1-21.
  42. Chan, P.F.; Germe, T.; Bax, B.D.; Huang, J.; Thalji, R.K.; Bacqué, E.; Checchia, A.; Chen, D.; Cui, H.; Ding, X.; Ingraham, K.; McCloskey, L.; Raha, K.; Srikannathasan, V.; Maxwell, A.; Stavenger, R.A. Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase. Proc. Natl. Acad. Sci. USA, 2017, 114(22), E4492-E4500.
  43. Bitew, H.; Mammo, W.; Hymete, A.; Yeshak, M.Y. Antimalarial activity of acetylenic thiophenes from Echinops hoehnelii Schweinf. Molecules, 2017, 22(11), 1965.
  44. Zani, C.L.; Chiari, E.; Krettli, A.U.; Murta, S.M.; Cunningham, M.L.; Fairlamb, A.H.; Romanha, A.J. Anti-plasmodial and anti-trypanosomal activity of synthetic naphtho 2, 3-b thiophen-4, 9-quinones. Bioorg. Med. Chem., 1997, 5(12), 2185-2192.
  45. W. A. G. N. A. T., Abdel-Salam, O. M., & Elmegeed, G. A. Screening for antidepressant, sedative and analgesic activities of novel fused thiophene derivatives. Acta Pharm., 2008, 58(1), 1-14.
  46. Sondhi, S.M.; Jain, S.; Dinodia, M.; Kumar, A. Synthesis of some thiophene, imidazole and pyridine derivatives exhibiting good anti-inflammatory and analgesic activities. Med. Chem., 2008, 4(2), 146-154.
  47. Mikhail, D.S. El‐Nassan, H. B., Mahmoud, S. T., & Fahim, S. H. Nonacidic thiophene‐based derivatives as potential analgesic and design, synthesis, biological evaluation, and metabolic stability study. Drug Dev. Res., 2022, 83(8), 1739-1757.
  48. Dos Santos, F. A.; Pereira, M. C.; de Oliveira, T. B.; Mendonça, F. J. B., Junior; de Lima, M. D. C. A.; Pitta, M. G. D. R. Anticancer Drugs, 2018, 29(2), 157-166.
  49. Wickham, A.M.; Islam, M.M.; Mondal, D.; Phopase, J.; Sadhu, V.; Tamás, É.; Polisetti, N.; Richter-Dahlfors, A.; Liedberg, B.; Griffith, M. Polycaprolactone–thiophene‐conjugated carbon nanotube meshes as scaffolds for cardiac progenitor cells. J. Biomed. Mater. Res. B Appl. Biomater., 2014, 102(7), 1553-1561.
  50. Vinh, N.B.; Devine, S.M.; Munoz, L.; Ryan, R.M.; Wang, B.H.; Krum, H.; Chalmers, D.K.; Simpson, J.S.; Scammells, P.J. Design, Synthesis, and Biological Evaluation of Tetra‐Substituted Thiophenes as Inhibitors of p38α MAPK. ChemistryOpen, 2015, 4(1), 56-64.
  51. Sibbald, B. Rofecoxib (Vioxx) voluntarily withdrawn from market. CMAJ, 2004, 171(9), 1027-1028. doi: 10.1503/cmaj.1041606 PMID: 15505253
  52. Sun, S.X.; Lee, K.Y.; Bertram, C.T.; Goldstein, J.L. Withdrawal of COX-2 selective inhibitors rofecoxib and valdecoxib: Impact on NSAID and gastroprotective drug prescribing and utilization. Curr. Med. Res. Opin., 2007, 23(8), 1859-1866. doi: 10.1185/030079907X210561 PMID: 17605893
  53. Ramesh, B.; Rao, B.S. Synthesis, spectral studies and anti-inflammatory activity of 2-acetyl thiophene. E-J. Chem., 2010, 7(2), 433-436. doi: 10.1155/2010/404715
  54. Ganapathi, M. A facile synthesis & characterization of biologically active halogen substituted 1-Acetyl -3,5-diphenyl pyrazole derivatives. SOJ Mater. Sci. Eng. Symbiosis., 2015, 3(3), 145-158.
  55. Choudhary, A.N.; Juyal, V. Synthesis of chalcone and their derivatives as antimicrobial agents. Int. J. Pharm. Pharm. Sci., 2011, 3(3), 125-128.
  56. Ingle, A.V.; Doshi, A.G.; Raut, A.W.; Kadu, N.S. Synthesis of 3, 5-disubstituted pyrazoles and their derivatives. Orient. J. Chem., 2011, 27(4), 1691.
  57. Sharshira, E.M.; Hamada, N.M.M. Synthesis and antimicrobial evaluation of some pyrazole derivatives. Molecules, 2012, 17(5), 4962-4971. doi: 10.3390/molecules17054962 PMID: 22547318
  58. Winter, C.A.; Risley, E.A.; Nuss, G.W. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Exp. Biol. Med., 1962, 111(3), 544-547. doi: 10.3181/00379727-111-27849 PMID: 14001233
  59. Eddy, N.B.; Leimbach, D. Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. J. Pharmacol. Exp. Ther., 1953, 107(3), 385-393. PMID: 13035677
  60. Umar, A.B.; Uzairu, A.; Shallangwa, G.A.; Uba, S. Design of potential anti-melanoma agents against SK-MEL-5 cell line using QSAR modeling and molecular docking methods. SN Applied Sciences, 2020, 2(5), 815. doi: 10.1007/s42452-020-2620-8
  61. Monga, J.; Ghosh, N.S.; Mujwar, S.; Rani, I. In silico studies of some newly designed benzimidazolethiazolidinone based antagonists of human estrogen receptor. India Drugs, 2023, 60(8), 15-30. doi: 10.53879/id.60.08.14087
  62. Rani, I.; Goyal, A.; Sharma, M. Computational design of phosphatidylinositol 3-kinase inhibitors. Assay Drug Dev. Technol., 2022, 20(7), 317-337. doi: 10.1089/adt.2022.057 PMID: 36269231
  63. Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1pii of original article: s0169-409x(96)00423-1. The article was originally published in advanced drug delivery reviews 23 (1997) 3-25. 1. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26. doi: 10.1016/S0169-409X(00)00129-0 PMID: 11259830
  64. Kumar, M.; Rani, I.; Mujwar, S.; Narang, R.; Devgun, M.; Khokra, S. In-Silico design, synthesis, and pharmacological evaluation of oxadiazole-based selective cyclo-oxygenase-2 inhibitors. Assay Drug Dev. Technol., 2023, 21(4), 166-179. doi: 10.1089/adt.2022.090 PMID: 37318837
  65. Egan, W.J.; Merz, K.M., Jr; Baldwin, J.J. Prediction of drug absorption using multivariate statistics. J. Med. Chem., 2000, 43(21), 3867-3877. doi: 10.1021/jm000292e PMID: 11052792
  66. Muegge, I.; Heald, S.L.; Brittelli, D. Simple selection criteria for drug-like chemical matter. J. Med. Chem., 2001, 44(12), 1841-1846. doi: 10.1021/jm015507e PMID: 11384230
  67. Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623. doi: 10.1021/jm020017n PMID: 12036371
  68. Desai Optimized synthesis of novel pyrazole based thiazole derivatives and their antimicrobial evaluation. International Letters of Chemistry. Physics and Astronomy, 2016, 66, 109-118. doi: 10.56431/p-i63g13
  69. Özdemir, Z.; Kandilci, H.B. Gümüşel, B.; Çalış Ü.; Bilgin, A.A. Synthesis and studies on antidepressant and anticonvulsant activities of some 3-(2-furyl)-pyrazoline derivatives. Eur. J. Med. Chem., 2007, 42(3), 373-379. doi: 10.1016/j.ejmech.2006.09.006 PMID: 17069933
  70. Saravanan, G.; Alagarsamy, V.; Prakash, C.R.; Kumar, P.D.; Selvam, T.P. Synthesis of novel thiazole derivatives as analgesic agents. Asian Journal of Pharmaceutical Research, 2011, 1(4), 134-138.

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