COX inhibitory profiles of a series of thiadiazole-benzothiazole hybrids

Year 2024, Volume: 3 Issue: 1, 9 - 15, 30.04.2024

Ahmet Özdemir , Halide Edip Temel

https://doi.org/10.55971/EJLS.1443664

Abstract

In an endeavour to identify small molecule COX-1 inhibitors, a colorimetric assay protocol was applied for the in vitro evaluation of COX-1 and 2 inhibitory potential of a series of thiadiazole-benzothiazole hybrids. The most potent and selective COX-1 inhibitor in this series was found as 2-[(5-amino-1,3,4-thiadiazol-2-yl)thio]-N-(6-chlorobenzothiazol-2-yl)acetamide (7) (51.36 ± 3.32% at 100 µM) compared to SC-560 (83.64 ± 3.76% at 1 µM). Compound 7 exerted weaker inhibitory effect on COX-2 (11.05 ± 1.69% at 100 µM). To explore its binding interactions at the active site of human COX-1 (PDB ID: 6Y3C), molecular docking studies were conducted. Compound 7 could establish hydrogen bonds with proper residues thanks to its amide C=O group. In silico studies were employed to shed light on their pharmacokinetic properties. Taken together, compound 7 can be considered as a potential lead compound for the generation of selective COX-1 inhibitors with enhanced efficacy.

Keywords

Benzothiazole, cyclooxygenase, molecular docking, thiadiazole

References

• 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
• 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(15):7592-7641. https://doi.org/10.1021/acs.chemrev.0c00215
• Chahal S, Rani P, Kiran, Sindhu J, Joshi G, Ganesan A, Kalyaanamoorthy S, Mayank, Kumar P, Singh R, Negi A. Design and development of COX-II inhibitors: Current scenario and future perspective. ACS Omega. (2023); 8(20):17446-17498. https://doi.org/10.1021/acsomega.3c00692
• Ferrer MD, Busquets-Cortés C, Capó X, Tejada S, Tur JA, Pons A, Sureda A. Cyclooxygenase-2 inhibitors as a therapeutic target in inflammatory diseases. Curr Med Chem. (2019); 26(18):3225-3241. https://doi.org/10.2174/0929867325666180514112124
• 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
• 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
• Vanhoutte PM. COX-1 and vascular disease. Clin Pharmacol Ther. (2009); 86(2):212-215. https://doi.org/10.1038/clpt.2009.108
• Pairet M, van Ryn J. COX-2 inhibitors. Basel: Birkhäuser Verlag; (2004). ISBN:978-3-7643-6901-9
• Perrone MG, Scilimati A, Simone L, Vitale P. Selective COX-1 inhibition: A therapeutic target to be reconsidered. Curr Med Chem. (2010);17(32):3769-3805. https://doi.org/10.2174/092986710793205408
• Vitale P, Scilimati A, Perrone MG. Update on SAR studies toward new COX-1 selective inhibitors. Curr Med Chem. (2015); 22(37):4271-4292. https://doi.org/10.2174/0929867322666151029104717
• Sisa M, Konečný L, Temml V, Carazo A, Mladěnka P, Landa P. SC-560 and mofezolac isosteres as new potent COX-1 selective inhibitors with antiplatelet effect. Arch Pharm. (2023); 356(5):e2200549. https://doi.org/10.1002/ardp.202200549
• Li Y, Geng J, Liu Y, Yu S, Zhao G. Thiadiazole-A promising structure in medicinal chemistry. ChemMedChem. (2013); 8(1):27-41. https://doi.org/10.1002/cmdc.201200355
• Hu Y, Li CY, Wang XM, Yang YH, Zhu HL. 1,3,4-Thiadiazole: Synthesis, reactions, and applications in medicinal, agricultural, and materials chemistry. Chem Rev. (2014); 114(10):5572-5610. https://doi.org/10.1021/cr400131u
• Haider S, Alam MS, Hamid H. 1,3,4-Thiadiazoles: A potent multi targeted pharmacological scaffold. Eur J Med Chem. (2015); 92:156-77. https://doi.org/10.1016/j.ejmech.2014.12.035
• Matysiak J. Biological and pharmacological activities of 1,3,4-thiadiazole based compounds. Mini Rev Med Chem. (2015); 15(9):762-75. https://doi.org/10.2174/1389557515666150519104057
• Dawood KM, Farghaly TA. Thiadiazole inhibitors: A patent review. Expert Opin Ther Pat. (2017); 27(4):477-505. https://doi.org/10.1080/13543776.2017.1272575
• Bala M, Piplani P, Ankalgi A, Jain A, Chandel L. 1,3,4-Thiadiazole: A versatile pharmacophore of medicinal significance. Med Chem. (2023); 19(8):730-756. https://doi.org/10.2174/1573406419666230102104648
• Haroun M, Fesatidou M, Petrou A, et al. Identification of novel cyclooxygenase-1 selective inhibitors of thiadiazole-based scaffold as potent anti-inflammatory agents with safety gastric and cytotoxic profile. Molecules. (2023); 28(8):3416. https://doi.org/10.3390/molecules28083416
• Omar YM, Abdu-Allah HHM, Abdel-Moty SG. Synthesis, biological evaluation and docking study of 1,3,4-thiadiazole-thiazolidinone hybrids as anti-inflammatory agents with dual inhibition of COX-2 and 15-LOX. Bioorg Chem. (2018); 80:461-471. https://doi.org/10.1016/j.bioorg.2018.06.036
• Pathak P, Shukla PK, Naumovich V, Grishina M, Verma A, Potemkin V. 1,2,4-Triazole-conjugated 1,3,4-thiadiazole hybrid scaffolds: A potent ameliorant of carrageenan-induced inflammation by lessening proinflammatory mediators. Arch Pharm. (2020); 353(1):e1900233. https://doi.org/10.1002/ardp.201900233
• Keri RS, Patil MR, Patil SA, Budagumpi S. A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry. Eur J Med Chem. (2015); 89:207-251. https://doi.org/10.1016/j.ejmech.2014.10.059
• Kamal A, Syed MA, Mohammed SM. Therapeutic potential of benzothiazoles: A patent review (2010 - 2014). Expert Opin Ther Pat. (2015); 25(3):335-349. https://doi.org/10.1517/13543776.2014.999764
• Tariq S, Kamboj P, Amir M. Therapeutic advancement of benzothiazole derivatives in the last decennial period. Arch Pharm. (2019); 352(1):e1800170. https://doi.org/10.1002/ardp.201800170
• Sumit, Kumar A, Mishra AK. Advancement in pharmacological activities of benzothiazole and its derivatives: An up to date review. Mini-Rev Med Chem. (2021); 21(3):314-335. https://doi.org/10.2174/1389557520666200820133252
• Law CSW, Yeong KY. Current trends of benzothiazoles in drug discovery: A patent review (2015-2020). Expert Opin Ther Pat. (2022); 32(3):299-315. https://doi.org/10.1080/13543776.2022.2026327
• Yadav RK, Kumar R, Singh H, Mazumdar A, Salahuddin, Chauhan B, Abdullah MM. Recent insights on synthetic methods and pharmacological potential in relation with structure of benzothiazoles. Med Chem. (2023); 19(4):325-360. https://doi.org/10.2174/1573406418666220820110551
• Kumar G, Singh NP. Synthesis, anti-inflammatory and analgesic evaluation of thiazole/oxazole substituted benzothiazole derivatives. Bioorg Chem. (2021); 107:104608. https://doi.org/10.1016/j.bioorg.2020.104608
• Zheng XJ, Li CS, Cui MY, Song ZW, Bai XQ, Liang CW, Wang HY, Zhang TY. Synthesis, biological evaluation of benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety as potential anti-oxidant and anti-inflammatory agents. Bioorg Med Chem Lett. (2020); 30(13):127237. https://doi.org/10.1016/j.bmcl.2020.127237
• Altıntop MD, Temel HE, Özdemir A. Microwave-assisted synthesis of a series of 4,5-dihydro-1H-pyrazoles endowed with selective COX-1 inhibitory potency, J Serb Chem Soc. (2023); 88(4):355-365. https://doi.org/10.2298/JSC220907001A
• Altıntop MD, Akalın Çiftçi G, Yılmaz Savaş N, Ertorun İ, Can B, Sever B, Temel HE, Alataş Ö, Özdemir A. Discovery of small molecule COX-1 and Akt inhibitors as anti-NSCLC agents endowed with anti-inflammatory action. Int J Mol Sci. (2023); 24(3):2648. https://doi.org/10.3390/ijms24032648
• Altintop MD, Kaplancikli ZA, Ozdemir A, Turan-Zitouni G, Temel HE, Akalın G. Synthesis and anticholinesterase activity and cytotoxicity of novel amide derivatives. Arch Pharm. (2012); 345(2):112-116. https://doi.org/10.1002/ardp.201100124
• Altıntop MD, Sever B, Temel HE, Kaplancıklı ZA, Özdemir A. Design, synthesis and in vitro COX inhibitory profiles of a new series of tetrazole-based hydrazones. Eur J Life Sci. (2022); 1:20-27. https://doi.org/10.55971/EJLS.1095818
• Miciaccia M, Belviso BD, Iaselli M, Cingolani G, Ferorelli S, Cappellari M, Loguercio Polosa P, Perrone MG, Caliandro R, Scilimati A. Three-dimensional structure of human cyclooxygenase (hCOX)-1. Sci Rep. (2021); 11(1):4312. https://doi.org/10.1038/s41598-021-83438-z
• Al-Sanea MM, Hamdi A, Brogi S, S Tawfik S, Othman DIA, Elshal M, Ur Rahman H, Parambi DGT, M Elbargisy R, Selim S, Mostafa EM, Mohamed AAB. Design, synthesis, and biological investigation of oxadiazolyl, thiadiazolyl, and pyrimidinyl linked antipyrine derivatives as potential non-acidic anti-inflammatory agents. J Enzyme Inhib Med Chem. (2023); 38(1):2162511. https://doi.org/10.1080/14756366.2022.2162511
• Calvello R, Lofrumento DD, Perrone MG, Cianciulli A, Salvatore R, Vitale P, De Nuccio F, Giannotti L, Nicolardi G, Panaro MA, Scilimati A. Highly selective cyclooxygenase-1 inhibitors P6 and mofezolac counteract inflammatory state both in vitro and in vivo models of neuroinflammation. Front Neurol. (2017); 8:251. https://doi.org/10.3389/fneur.2017.00251
• Wang Y, Xing J, Xu Y, Zhou N, Peng J, Xiong Z, Liu X, Luo X, Luo C, Chen K, Zheng M, Jiang H. In silico ADME/T modelling for rational drug design. Q Rev Biophys. 2015; 48(4):488-515. https://doi.org/10.1017/S0033583515000190