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 β-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 β-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 μM), 11c (IC₅₀ = 4.52 ± 0.09 μM), 11d (IC₅₀ = 6.60 ± 1.25 μM), and 11f (IC₅₀ = 5.93 ± 0.50 μM) displayed the better Tyrosinase inhibitory activity in comparison to reference drugs ascorbic acid (IC₅₀ = 11.5 ± 1.00 μM) and kojic acid (IC₅₀ = 30.34 ± 0.75 μM). 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 μM, 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.