Design, In Silico Studies, and Synthesis of Some Azole Derivatives as Antimicrobial Agents

Abstract

This work relates to the discovery of safer and more potent triazole-pyridazinone hybrid (TP) compounds as an inhibitor of sterol 14α-demethylase (SDM). The chemical structures of thirty-three TPs (TP1 to TP33) were designed. The docking scores (DS) of TPs were determined by molecular docking software utilizing three different proteins of SDM (PDB IDs: 3LD6, 5FSA, and 5TZ1). The ProTox II web server predicted TPs' oral LD50 and toxicity class (TC), whereas the Swiss-ADME database anticipated their pharmacokinetic parameters. Based on the in silico study data, four TPs (TP18, TP22, TP27, and TP33) were synthesized and evaluated for their in vitro antifungal activity against seven fungi. The DS (kcal/mol) of TP18 (3LD6 = -8.27; 5FSA = -9.07; 5TZ1 = -9.42), TP22 (3LD6 = -8.23; 5FSA = -8.93; 5TZ1 = -9.57), TP27 (3LD6 = -8.31; 5FSA = -9.12; 5TZ1 = -9.38), and TP33 (3LD6 = -8.19; 5FSA = -8.98; 5TZ1 = -9.94) were better than the DS of fluconazole (3LD6 = -8.18; 5FSA = -8.79; 5TZ1 = -9.18) and ketoconazole (3LD6 = -8.16; 5FSA = -8.86; 5TZ1 = -9.06) implying high potency of TP18, TP22, TP27 and TP33 than fluconazole and ketoconazole against SDM. The anticipated LD50 and toxicity class (TC) of TP18 (500 mg/kg; TC 4), TP22 (500 mg/kg; TC 4), TP27 (1000 mg/kg; TC 4), and TP33 (1000 mg/kg; TC 4) was better than ketoconazole (166 mg/kg; TC 3). The Swiss-ADME database results revealed that TP18, TP22, TP27, and TP33 passed Lipinski’s drug-likeliness rule and demonstrated high oral absorption and bioavailability comparable to ketoconazole and fluconazole. The synthesized compounds' spectral data (FTIR, 1H-NMR, 13C-NMR, and Mass) aligned to their designed chemical structure. The antifungal activity data implies that TP18, TP22, TP27, and TP33 were better antifungal agents than fluconazole and ketoconazole against tested fungi. These findings concurred with the DS of TP18, TP22, TP27, and TP33. In conclusion, TP18, TP22, TP27, and TP33 represent a new chemical template for developing safer and better SDM inhibitors as antifungal agents.