Novel 1,2,3-Thiadiazole-based Hydrazone and 1,3,4-Oxadiazole hybrids as promising agents against Streptococcus mutans: Synthesis, biological evaluation, and molecular modeling studies.

内容摘要

Tooth decay is a widespread chronic condition affecting nearly 50% of the global population, with Streptococcus mutans identified as the primary causative agent. The growing challenge of antimicrobial resistance highlights the need for new antibacterial agents. In this study, a series of novel 1,2,3-thiadiazole-based hydrazone (3a-f) and 1,3,4-oxadiazole (4a-f) hybrid compounds were designed, synthesized, and evaluated for their antimicrobial and antioxidant activities. All compounds were structurally characterized by FT-IR, 1H NMR, 13C NMR, and LC-MS analyses. An integrated in silico workflow combining molecular docking and binary QSAR analysis was applied to key S. mutans virulence-associated enzymes-glucosyltransferase B (GtfB), glucosyltransferase C (GtfC), and sortase A (SrtA)-to provide mechanistic insight into antibacterial activity. Docking studies revealed stable binding of the synthesized compounds within the catalytic domains of these targets, with compounds 3d and 4d showing favorable interaction patterns consistent with their strong in vitro antibacterial activity. Binary QSAR predictions further supported the antibacterial potential of the most active derivatives. Biological screening revealed selective antimicrobial activity against S. mutans, particularly for compounds 3d and 4d. Antioxidant activity assessed by DPPH• and ABTS•+ assays showed that compound 4d exhibited moderate ABTS•+ scavenging activity (IC50 = 24.21 ± 0.11 μg/mL). Overall, these findings indicate that thiadiazole-based hydrazone and 1,3,4-oxadiazole frameworks represent promising scaffolds for the development of multifunctional antibiofilm agents targeting oral pathogens.