Discovery of novel 1,2,4-triazole tethered β-hydroxy sulfides as bacterial tyrosinase inhibitors: synthesis and biophysical evaluation through in vitro and in silico approaches

In this study, a series of 1,2,4-triazole-tethered beta-hydroxy sulfide scaffolds 11a-h was synthesized in good to remarkable yields (69-90%) through the thiolysis of oxiranes by the thiols in aqueous basic catalytic conditions. The synthesized 1,2,4-triazole-tethered beta-hydroxy sulfides were screened against bacterial tyrosinase enzyme, and Gram-positive and Gram-negative bacterial cultures i.e., (S. aureus) Staphylococcus aureus & (E. coli) Escherichia coli. Among the synthesized derivatives, the molecules 11a (IC50 = 7.67 +/- 1.00 mu M), 11c (IC50 = 4.52 +/- 0.09 mu M), 11d (IC50 = 6.60 +/- 1.25 mu M), and 11f (IC50 = 5.93 +/- 0.50 mu M) displayed the better tyrosinase inhibitory activity in comparison to reference drugs ascorbic acid (IC50 = 11.5 +/- 1.00 mu M) and kojic acid (IC50 = 30.34 +/- 0.75 mu M). The molecule benzofuran-triazol-propan-2-ol 11c proved to be the most potent bacterial tyrosinase inhibitory agent with a minimum IC50 of 4.52 +/- 0.09 mu M, as compared to other synthesized counterparts and both standards (kojic acid and ascorbic acid). The compound diphenyl-triazol-propan-2-ol 11a and benzofuran-triazole-propan-2-ol 11c showed comparable anti-bacterial chemotherapeutic efficacy with minimum inhibitory concentrations (MIC = 2.0 +/- 2.25 mg mL(-1) and 2.5 +/- 0.00 mg mL(-1), respectively) against S. aureus bacterial strain in comparison with standard antibiotic penicillin (MIC = 2.2 +/- 1.15 mg mL(-1)). Furthermore, among the synthesized derivatives, only compound 11c demonstrated better anti-bacterial activity (MIC = 10 +/- 0.40 mg mL(-1)) against E. coli, which was slightly less than the standard antibiotic i.e., penicillin (MIC = 2.4 +/- 1.00 mg mL(-1)). The compound 11c demonstrated a better binding score (-7.08 kcal mol(-1)) than ascorbic acid (-5.59 kcal mol(-1)) and kojic acid (-5.78 kcal mol(-1)). Molecular docking studies also validate the in vitro anti-tyrosinase assay results; therefore, the molecule 11c can be the lead bacterial tyrosinase inhibitor as well as the antibacterial agent against both types of bacterial strains after suitable structural modifications.