Design, synthesis and in-vitro COX inhibitory profiles of a new series of tetrazole-based hydrazones

Year 2022, Volume: 1 Issue: 1, 20 - 27, 29.04.2022

Mehlika Dilek Altıntop , Belgin Sever , Halide Edip Temel , Zafer Asım Kaplancıklı , Ahmet Özdemir

https://doi.org/10.55971/EJLS.1095818

https://izlik.org/JA94KW57TL

Abstract

Inhibition of cyclooxygenases (COXs), by selective and nonselective inhibitors, is a favorable approach for pharmacologic intervention in a variety of disorders such as cancer. For this purpose, a new class of tetrazole-hydrazone hybrids (1-12) was designed. A facile and efficient procedure was applied for the preparation of compounds 1-12, which were tested for their inhibitory activities towards cyclooxygenases (COXs) by means of an in vitro colorimetric method. The most potent and selective COX-1 inhibitors were determined as 2-[(1-methyl-1H-tetrazol-5-yl)thio]-N'-(4-(piperidin-1-yl)benzylidene)acetohydrazide (1) (40.88±2.79%) and 2-[(1-methyl-1H-tetrazol-5-yl)thio]-N'-(4-(morpholin-4-yl)benzylidene)acetohydrazide (2) (39.80±2.78%), whereas the most potent and selective COX-2 inhibitor was found as 2-[(1-phenyl-1H-tetrazol-5-yl)thio]-N'-(4-(pyrrolidin-1-yl)benzylidene)acetohydrazide (10) (42.38±1.16%). In general, 1-methyl-1H-tetrazole moiety resulted in selective COX-1 inhibition, whereas 1-phenyl-1H-tetrazole moiety gave rise to preferential COX-2 inhibition.

Keywords

Cyclooxygenase , hydrazone , synthesis , tetrazole

Supporting Institution

Anadolu University

Project Number

2005S019

References

• 1. Rouzer CA, Marnett LJ. Structural and chemical biology of the interaction of cyclooxygenase with substrates and non-steroidal anti-inflammatory drugs. Chem Rev. (2020);120:7592-7641. https://dx.doi.org/10.1021/acs.chemrev.0c00215
• 2. Brock TG, McNish RW, Peters-Golden M. Arachidonic acid is preferentially metabolized by cyclooxygenase-2 to prostacyclin and prostaglandin E2. J Biol Chem. (1999);274(17):11660-6. https://doi.org/10.1074/jbc.274.17.11660
• 3. Mazaleuskaya, LL, Ricciotti E. Druggable prostanoid pathway. Adv Exp Med Biol. (2020);1274:29-54. https://doi.org/10.1007/978-3-030-50621-6_3
• 4. Pannunzio A, Coluccia M. Cyclooxygenase-1 (COX-1) and COX-1 inhibitors in cancer: A review of oncology and medicinal chemistry literature. Pharmaceuticals (2018);11:101. https://doi.org/10.3390/ph11040101
• 5. Sharma V, Bhatia P, Alam O, Javed Naim M, Nawaz F, Ahmad Sheikh A, Jha M. Recent advancement in the discovery and development of COX-2 inhibitors: Insight into biological activities and SAR studies (2008-2019). Bioorg Chem. (2019);89:103007. https://doi.org/10.1016/j.bioorg.2019.103007
• 6. Zidar N, Odar K, Glavac D, Jerse M, Zupanc T, Stajer D. Cyclooxygenase in normal human tissues – is COX-1 really a constitutive isoform, and COX-2 an inducible isoform? J Cell Mol Med. (2009);13:3753-3763. https://doi.org/10.1111/j.1582-4934.2008.00430.x
• 7. Yu T, Lao X, Zheng H. Influencing COX-2 activity by COX related pathways in inflammation and cancer. Mini Rev Med Chem. (2016);16:1230-1243. https://doi.org/10.2174/1389557516666160505115743
• 8. Gandhi J, Khera L, Gaur N, Paul C, Kaul R. Role of modulator of inflammation cyclooxygenase-2 in gammaherpesvirus mediated tumorigenesis. Front Microbiol. (2017);8:538. https://doi.org/10.3389/fmicb.2017.00538
• 9. Caiazzo E, Ialenti A, Cicala C. The relatively selective cyclooxygenase-2 inhibitor nimesulide: What's going on? Eur J Pharmacol. (2019);848:105-111. https://doi.org/10.1016/j.ejphar.2019.01.044
• 10. Vitale P, Tacconelli S, Perrone MG, Malerba P, Simone L, Scilimati A, Lavecchia A, Dovizio M, Marcantoni E, Bruno A, Patrignani P. Synthesis, pharmacological characterization, and docking analysis of a novel family of diarylisoxazoles as highly selective cyclooxygenase-1 (COX-1) inhibitors. J Med Chem. (2013);56(11):4277-4299. https://doi.org/10.1021/jm301905a
• 11. Perrone MG, Scilimati A, Simone L, Vitale P. Selective COX-1 inhibition: A therapeutic target to be reconsidered. Curr Med Chem. (2010);17(32):3769-805. https://doi.org/10.2174/092986710793205408
• 12. Carullo G, Galligano F, Aiello F. Structure-activity relationships for the synthesis of selective cyclooxygenase 2 inhibitors: An overview (2009-2016). Medchemcomm. (2016);8(3):492-500. https://doi.org/10.1039/c6md00569a
• 13. Kumar P, Narasimhan B. Hydrazides/hydrazones as antimicrobial and anticancer agents in the new millennium. Mini-Rev Med Chem. (2013);13:971-987. https://doi.org/10.2174/1389557511313070003
• 14. Rollas S, Küçükgüzel SG. Biological activities of hydrazone derivatives. Molecules (2007);12(8):1910-1939. https://doi.org/10.3390/12081910
• 15. Narang R, Narasimhan B, Sharma S. A review on biological activities and chemical synthesis of hydrazide derivatives. Curr Med Chem. 2012;19(4):569-612. https://10.2174/092986712798918789
• 16. Mali SN, Thorat BR, Gupta DR, Pandey A. Mini-review of the importance of hydrazides and their derivatives—Synthesis and biological activity. Eng. Proc. (2021);11:21. https://doi.org/10.3390/ASEC2021-11157
• 17. Ju Z, Su M, Hong J, La Kim E, Moon HR, Chung HY, Kim S, Jung JH. Design of balanced COX inhibitors based on anti-inflammatory and/or COX-2 inhibitory ascidian metabolites. Eur J Med Chem. (2019);180:86-98. https://doi.org/10.1016/j.ejmech.2019.07.016
• 18. Abdelgawad MA, Labib MB, Abdel-Latif M. Pyrazole-hydrazone derivatives as anti-inflammatory agents: Design, synthesis, biological evaluation, COX-1,2/5-LOX inhibition and docking study. Bioorg Chem. (2017);74:212-220. http://dx.doi.org/10.1016/j.bioorg.2017.08.014
• 19. Gorantla V, Gundla R, Jadav SS, Anugu SR, Chimakurthy J, Nidasanametla SK, Korupolu R. Molecular hybrid design, synthesis and biological evaluation of N-phenyl sulfonamide linked N-acyl hydrazone derivatives functioning as COX-2 inhibitors: new anti-inflammatory, anti-oxidant and anti-bacterial agents. New J Chem. (2017);41:13516-13532. https://doi.org/10.1039/c7nj03332j
• 20. Mohammed KO, Nissan YM. Synthesis, molecular docking, and biological evaluation of some novel hydrazones and pyrazole derivatives as anti-inflammatory agents. Chem Biol Drug Des. (2014);84(4):473-488. https://doi.org/10.1111/cbdd.12336
• 21. El-Sayed MA-A, Abdel-Aziz NI, Abdel-Aziz AA-M, El-Azab AS, Asiri YA, ElTahir KEH. Design, synthesis, and biological evaluation of substituted hydrazone and pyrazole derivatives as selective COX-2 inhibitors: Molecular docking study. Bioorg Med Chem. (2011);19:3416-3424. https://doi.org/10.1016/j.bmc.2011.04.027
• 22. Xiong Q, Dong S, Chen Y, Liu X, Feng X. Asymmetric synthesis of tetrazole and dihydroisoquinoline derivatives by isocyanide-based multicomponent reactions. Nat Commun. (2019);10:2116. https://doi.org/10.1038/s41467-019-09904-5
• 23. Lamie PF, Philoppes JN, Azouz AA, Safwat NM. Novel tetrazole and cyanamide derivatives as inhibitors of cyclooxygenase-2 enzyme: design, synthesis, anti-inflammatory evaluation, ulcerogenic liability and docking study. J Enzyme Inhib Med Chem. (2017);32:805-820. https://doi.org/10.1080/14756366.2017.1326110
• 24. Labib MB, Fayez AM, El-Nahass ES, Awadallah M, Halim PA. Novel tetrazole-based selective COX-2 inhibitors: Design, synthesis, anti-inflammatory activity, evaluation of PGE2, TNF-α, IL-6 and histopathological study. Bioorg Chem. (2020);104:104308. https://doi.org/10.1016/j.bioorg.2020.104308
• 25. Wei C-X, Bian M, Gong G-H. Tetrazolium compounds: synthesis and applications in medicine. Molecules (2015);20:5528-5553. https://doi.org/10.3390/molecules20045528
• 26. Altıntop MD, Kaplancıklı ZA, Akalın Çiftçi G, Demirel R. Synthesis and biological evaluation of thiazoline derivatives as new antimicrobial and anticancer agents. Eur J Med Chem. (2014);74:264-277. https://doi.org/10.1016/j.ejmech.2013.12.060
• 27. Altıntop MD, Özdemir A, Turan-Zitouni G, Ilgın S, Atlı Ö, İşcan G, Kaplancıklı ZA. Synthesis and biological evaluation of some hydrazone derivatives as new anticandidal and anticancer agents. Eur J Med Chem. (2012);58:299-307. https://doi.org/10.1016/j.ejmech.2012.10.011