Design, Synthesis, and the Biological Evaluation of Some New Fused Thiazolotriazine Derivatives
Pharmaceutical sciences- Pharmaceutical Chemistry
DOI:
https://doi.org/10.22376/ijlpr.2024.14.3.P15-P26Keywords:
Thiazolotriazine, In silico studies,, 14-α-demethylase,, Synthesis,, Antifungal activity.Abstract
Thiazolotriazine is an essential medicinal chemistry molecule due to its biological properties, particularly antifungalactivity. Antifungal drug resistance is rising worldwide, necessitating the development of innovative, safer, and more effectiveantifungals. This study intended to uncover safer and more effective thiazolotriazine antifungals. ProTox II software was employedto forecast the toxicity of the designed thiazolotriazines. The pharmacokinetic parameters were calculated using the Swiss-ADMEdatabase. The Molecular Operating Environment software (2019.0102 version) was employed for the docking studies utilizing 14-α-demethylase protein (PDB ID: 3LD6). Compounds 4c, 4d, and 4e were prepared and evaluated for in vitro antifungal activity.The computational studies revealed compounds 4a, 4b, 5b, 5c, 6b, 6c and 6d as carcinogenic; 4a, 4b, 4c, 4d and 4e demonstratedbetter pharmacokinetic behaviour; and docking results of 4c, 4d, and 4e were superior than fluconazole (FLU). The moleculardocking studies establish 4c, 4d, and 4e as SDM inhibitors, suggesting a mechanism similar to FLU and ketoconazole (KET). Theantifungal activity evaluation revealed 4d (MIC = 6.25 μg/ml) as a more potent antifungal agent than KET (MIC = 12.5 μg/ml) andFLU (MIC = 12.5 μg/ml). Compounds 4c and 4e showed equal antifungal activity to KET (MIC = 12.5 μg/ml) and FLU (MIC = 12.5μg/ml). Compounds 4c, 4d, and 4e displayed encouraging antifungal activity with a favorable safety profile. Assessing the broadspectrum of 4c, 4d, and 4e against various pathogenic fungi, including resistant forms, is recommended.
References
Arshad MF, Alam A, Alshammari AA, Alhazza MB, Alzimam IM, Alam MA, Mustafa G, Ansari MS, Alotaibi AM, Alotaibi AA, Kumar S, Asdaq SMB, Imran M, Deb PK, Venugopala KN, Jomah S. Thiazole: A Versatile Standalone Moiety Contributing to the Development of Various Drugs and Biologically Active Agents. Molecules. 2022; 27(13):3994. doi: 10.3390/molecules27133994.
Maliszewski D, Drozdowska D. Recent Advances in the Biological Activity of s-Triazine Core Compounds. Pharmaceuticals (Basel). 2022; 15(2):221. doi: 10.3390/ph15020221.
Abd Elhameed AA, Ali AR, Ghabbour HA, Bayomi SM, El-Gohary NS. Design, synthesis, and antitumor screening of new thiazole, thiazolopyrimidine, and thiazolotriazine derivatives as potent inhibitors of VEGFR-2. Drug Dev Res. 2023; 84(8):1664-1698. doi: 10.1002/ddr.22109.
Hassan GS, Georgey HH, Mohammed EZ, Omar FA. Anti-hepatitis-C virus activity and QSAR study of certain thiazolidinone and thiazolotriazine derivatives as potential NS5B polymerase inhibitors. Eur J Med Chem. 2019; 184:111747. doi: 10.1016/j.ejmech.2019.111747.
Issartel V, Coudert P, Rubat C, Nhamias S, Couquelet J. Synthesis of thiazolotriazine derivatives and their antinociceptive effects in mice. J Pharm Pharmacol. 1998; 50(6):575-82. doi: 10.1111/j.2042-7158.1998.tb06890.x.
Rosam K, Monk BC, Lackner M. Sterol 14α-Demethylase Ligand-Binding Pocket-Mediated Acquired and Intrinsic Azole Resistance in Fungal Pathogens. J Fungi (Basel). 2020; 7(1):1. doi: 10.3390/jof7010001.
Monk BC, Keniya MV. Roles for Structural Biology in the Discovery of Drugs and Agrochemicals Targeting Sterol 14α-Demethylases. J Fungi (Basel). 2021; 7(2):67. doi: 10.3390/jof7020067.
Rakhshan A, Rahmati Kamel B, Saffaei A, Tavakoli-Ardakani M. Hepatotoxicity Induced by Azole Antifungal Agents: A Review Study. Iran J Pharm Res. 2023; 22(1):e130336. doi: 10.5812/ijpr-130336.
Carmo A, Rocha M, Pereirinha P, Tomé R, Costa E. Antifungals: From Pharmacokinetics to Clinical Practice. Antibiotics (Basel). 2023; 12(5):884. doi: 10.3390/antibiotics12050884.
Ubeid MT, Thabe HK, El-Feky SA. An efficient, one-pot, three-component synthesis of 4H-thiazolo[3,2-a][1,3,5]triazin-6-one derivatives. Het Comm. 2016; 22(1):43-47. Doi: https://doi.org/10.1515/hc-2015-0135.
Thabet HK, Al-Hossainy AF, Imran M. Synthesis, characterization, and DFT modeling of novel organic compound thin films derived from 2-amino-4-(2-hydroxy-3-methoxyphenyl)-4H-thiazolo[3,2-a][1,3,5]triazin-6(7H)-one. Opt Mater. 2020; 105:109915. Doi: https://doi.org/10.1016/j.optmat.2020.109915.
Mohd AA, Imran M, Alnaser NY, Altimyat SS, Al-Otaibi NM, Bawadekji A. Discovery of new isoniazid derivatives as anti-tubercular agents: In silico studies, synthesis, and in vitro activity evaluation. Orient J Chem. 2023; 39(6):1510-1520. Doi: http://dx.doi.org/10.13005/ojc/390610.
Imran M, Mohd AA, Nayeem N, Al-Otaibi NM, Homoud M, Alshammari MT. Synthesis and cyclooxygenase-2 inhibitory activity evaluation of some pyridazine derivatives. Orient J Chem. 2023; 39(5):1113-1119. Doi: http://dx.doi.org/10.13005/ojc/390504.
Zaidi SHH, Mohd AA, Imran M, Alshammari MK, Alfrah KF. Design, in silico studies, and synthesis of some azole derivatives as antimicrobial agents. Orient J Chem. 2023; 39(6):1579-1588. doi http://dx.doi.org/10.13005/ojc/390618.
Imran M. Ethionamide and prothionamide based coumarin-thiazole derivatives: Synthesis, antitubercular activity, toxicity investigations, and molecular docking studies. Pharm Chem J. 2022; 56(9):1215-1225. doi: 10.1007/s11094-022-02782-0.
Imran M, Mohd AA, Nayeem N, Alaqel SI. In silico studies-assisted design, synthesis, and discovery of biologically active isatin derivatives. Trop J Pharm Res. 2023; 22(6):1263-1269. doi: 10.4314/tjpr.v22i6.16.
Imran M, Bawadekji A, Alotaibi N. Synthesis and evaluation of antimicrobial properties of some azole derivatives. Trop J Pharm Res. 2020; 19(2):377-382. doi: 10.4314/tjpr.v19i2.21.
Abida, Diwan A, Thabet HK, Imran M. Synthesis of some pyridazine derivatives as antioxidants and antimicrobial agents. Trop J Pharm Res. 2019; 18(12):2633-2641. doi: 10.4314/tjpr.v18i12.24.
Behtash A, Nafisi S, Maibach HI. New Generation of Fluconazole: A Review on Existing Researches and Technologies. Curr Drug Deliv. 2017; 14(1):2-15. doi 10.2174/1567201813666160502125620.
Gupta AK, Lyons DC. The rise and fall of oral ketoconazole. J Cutan Med Surg. 2015; 19(4):352-357. doi: 10.1177/1203475415574970.
Tong W, Welsh WJ, Shi L, Fang H, Perkins R. Structure-activity relationship approaches and applications. Environ Toxicol Chem. 2003; 22(8):1680-95. doi: 10.1897/01-198.
Wu Y, Sun A, Chen F, Zhao Y, Zhu X, Zhang T, Ni G, Wang R. Synthesis, structure-activity relationship and biological evaluation of indole derivatives as anti-Candida albicans agents. Bioorg Chem. 2024; 146:107293. doi: 10.1016/j.bioorg.2024.107293.
Novič M. Quantitative Structure-Activity/Toxicity Relationship through Neural Networks for Drug Discovery or Regulatory Use. Curr Top Med Chem. 2023; 23(29):2792-2804. doi: 10.2174/0115680266251327231017053718.
Wang YL, Li JY, Shi XX, Wang Z, Hao GF, Yang GF. Web-Based Quantitative Structure-Activity Relationship Resources Facilitate Effective Drug Discovery. Top Curr Chem (Cham). 2021; 379(6):37. doi: 10.1007/s41061-021-00349-3.
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