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Abstract <p><b>Objective:</b> A series of novel imine derivatives of 1,2,4-triazole-3-thione <b>TAS-01–TAS-10</b> was synthesized from 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid <i>via</i> a multi-step sequence, culminating in acid-catalyzed condensation with various substituted benzaldehydes. <b>Methods:</b> The structures of the synthesized compounds were established using HRMS, FT-IR, and <sup>1</sup>H and <sup>13</sup>C NMR spectroscopy. <i>In silico</i> ADME profiling using the SwissADME platform revealed strict compliance with Lipinski’s rule of five; however, high topological polar surface area (TPSA &gt;140 Å<sup>2</sup>) and low predicted gastrointestinal absorption suggested limited oral bioavailability. <i>In vitro</i> antimicrobial evaluation <i>via</i> the agar well diffusion method against Gram-positive (<i>Staphylococcus aureus</i>, <i>Bacillus subtilis</i>) and Gram-negative (<i>Pseudomonas aeruginosa</i>, <i>Salmonella typhimurium</i>) bacterial strains, using streptomycin as a positive reference, revealed distinct antibacterial profiles. <b>Results and Discussion:</b> Derivatives <b>TAS-04</b>, <b>TAS-07</b>, and <b>TAS-09</b> 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 <b>TAS-02</b>, <b>TAS-05</b>, and <b>TAS-08</b> 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. <b>Conclusions:</b> A novel series of 1,2,4-triazole-3-thione Schiff bases was synthesized, demonstrating substituent-modulated <i>in vitro</i> antibacterial activity against Gram-positive and Gram-negative pathogens. Although <i>in silico</i> profiling highlighted low oral bioavailability due to elevated TPSA, these triazole–thiazole hybrids establish a viable structural platform for further optimization <i>via</i> prodrug strategies or polarity reduction to enhance membrane permeability.</p>

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

  • 期刊论文

  • 发表日期：

    2026年6月3日

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  • Palak I. Vaja,
  • Mehul R. Chauhan,
  • Satish M. Ghelani

摘要

Abstract

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.