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

Abstract

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.