Novel Imine Derivatives of 1,2,4-Triazole-3-thione: Synthesis, Characterization, Antimicrobial Activities, and ADME Profile Investigation

Objective: A series of novel imine derivatives of 1,2,4-triazole-3-thione TAS-01–TAS-10 was synthesized from 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid via a multi-step sequence, culminating in acid-catalyzed condensation with various substituted benzaldehydes. Methods: The structures of the synthesized compounds were established using HRMS, FT-IR, and 1H and 13C NMR spectroscopy. In silico ADME profiling using the SwissADME platform revealed strict compliance with Lipinski’s rule of five; however, high topological polar surface area (TPSA >140 Å2) and low predicted gastrointestinal absorption suggested limited oral bioavailability. In vitro antimicrobial evaluation via the agar well diffusion method against Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Pseudomonas aeruginosa, Salmonella typhimurium) bacterial strains, using streptomycin as a positive reference, revealed distinct antibacterial profiles. Results and Discussion: Derivatives TAS-04, TAS-07, and TAS-09 exhibited pronounced inhibitory effects against Gram-positive bacteria, generating zones of inhibition (ZOI) of 20.0–22.0 mm (streptomycin: 36.0–44.7 mm). Conversely, compounds TAS-02, TAS-05, and TAS-08 demonstrated notable activity against Gram-negative strains, with ZOIs ranging from 10.3 to 13.3 mm (streptomycin: 32.3–41.3 mm). Although less potent than the standard antibiotic, these hybrids represent promising leads for further structural optimization aimed at enhancing membrane permeability and therapeutic efficacy. Conclusions: A novel series of 1,2,4-triazole-3-thione Schiff bases was synthesized, demonstrating substituent-modulated in vitro antibacterial activity against Gram-positive and Gram-negative pathogens. Although in silico profiling highlighted low oral bioavailability due to elevated TPSA, these triazole–thiazole hybrids establish a viable structural platform for further optimization via prodrug strategies or polarity reduction to enhance membrane permeability.