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Abstract <p><b>Objective:</b> The objective of this study was to design, synthesize, and evaluate the antibacterial efficacy of a novel library of hybrid heterocycles structuralized around a bio-sourced, <i>O</i>-alkylated vanillin framework to expand the chemical space of available antimicrobial agents. <b>Methods:</b> <i>O</i>-Alkylated vanillin (<b>I</b>) was functionalized through two divergent synthetic pathways. First, Knoevenagel condensation of <b>I</b> with diverse active methylene heterocycles yielded ylidene derivatives (<b>II–V</b>). Second, condensation of <b>I</b> with thiosemicarbazide afforded thiosemicarbazone (<b>VI</b>), which subsequently underwent regioselective cyclization with various active halo-compounds to generate thiazole derivatives (<b>VII–IXa–IXe</b>). Semicarbazone analogue (<b>X</b>) was synthesized using an optimized base-catalyzed method to evaluate comparative reactivity. All newly synthesized hybrids were evaluated <i>in vitro</i> for their antibacterial activity against Gram-positive (<i>Staphylococcus aureus</i>, <i>Bacillus cereus</i>) and Gram-negative (<i>Escherichia coli</i>, <i>Pseudomonas aeruginosa</i>) strains <i>via</i> the agar diffusion assay. <b>Results and Discussion:</b> A library of novel vanillin-centered hybrid heterocycles was successfully synthesized and structurally validated by IR and NMR spectroscopies. Chemical reactivity profiling revealed that while thiosemicarbazone <b>VI</b> readily underwent cyclization to form the corresponding thiazoles, the semicarbazone analogue <b>X</b> remained chemically refractory to cyclization under identical conditions. Antibacterial screening demonstrated potent, concentration-dependent inhibitory profiles across the synthesized derivatives. Notably, hybrid ylidene <b>V</b>, incorporating a thiazolo[3, 2-<i>a</i>]benzimidazol-3(2<i>H</i>)-one moiety, exhibited exceptional broad-spectrum antibacterial efficacy, consistently outperforming the other functionalized derivatives. <b>Conclusions:</b> Conjugating a bio-sourced vanillin core with tailored heterocyclic scaffolds provides a robust chemical strategy to enhance antimicrobial potency. The structurally optimized hybrid <b>V</b> represents a compelling lead candidate for the development of next-generation broad-spectrum antibacterial agents.</p>

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Synthesis and Antibacterial Evaluation of Hybrid Vanillin-Based Heterocycles via Knoevenagel Condensation and Thiosemicarbazone-Derived Thiazoles

  • 期刊论文

  • 发表日期：

    2026年8月4日

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  • Bahgat R. M. Hussein,
  • Hayam H. Mohammed,
  • Eman A. Ahmed,
  • Omran A. Omran

摘要

Abstract

Objective: The objective of this study was to design, synthesize, and evaluate the antibacterial efficacy of a novel library of hybrid heterocycles structuralized around a bio-sourced, O-alkylated vanillin framework to expand the chemical space of available antimicrobial agents. Methods: O-Alkylated vanillin (I) was functionalized through two divergent synthetic pathways. First, Knoevenagel condensation of I with diverse active methylene heterocycles yielded ylidene derivatives (II–V). Second, condensation of I with thiosemicarbazide afforded thiosemicarbazone (VI), which subsequently underwent regioselective cyclization with various active halo-compounds to generate thiazole derivatives (VII–IXa–IXe). Semicarbazone analogue (X) was synthesized using an optimized base-catalyzed method to evaluate comparative reactivity. All newly synthesized hybrids were evaluated in vitro for their antibacterial activity against Gram-positive (Staphylococcus aureus, Bacillus cereus) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) strains via the agar diffusion assay. Results and Discussion: A library of novel vanillin-centered hybrid heterocycles was successfully synthesized and structurally validated by IR and NMR spectroscopies. Chemical reactivity profiling revealed that while thiosemicarbazone VI readily underwent cyclization to form the corresponding thiazoles, the semicarbazone analogue X remained chemically refractory to cyclization under identical conditions. Antibacterial screening demonstrated potent, concentration-dependent inhibitory profiles across the synthesized derivatives. Notably, hybrid ylidene V, incorporating a thiazolo[3, 2-a]benzimidazol-3(2H)-one moiety, exhibited exceptional broad-spectrum antibacterial efficacy, consistently outperforming the other functionalized derivatives. Conclusions: Conjugating a bio-sourced vanillin core with tailored heterocyclic scaffolds provides a robust chemical strategy to enhance antimicrobial potency. The structurally optimized hybrid V represents a compelling lead candidate for the development of next-generation broad-spectrum antibacterial agents.