Design, Synthesis, and Antimicrobial Evaluation of Novel Thiazolyl-Based Compounds Incorporating Bioactive Amide and Hydrazide Groups

In recent years, the hydrazide skeleton, as a pivotal class of nitrogen-containing structures, has garnered considerable attention in medicinal chemistry and organic synthesis owing to its unique chemical versatility and broad-spectrum biological activities. In this study, a series of thiazole-containing benzoylhydrazine derivatives <b>A1</b>-<b>A19</b>, <b>B1</b>-<b>B19</b>, and <b>C1</b>-<b>C8</b> with structural divergence from conventional hydrazide-based molecular frameworks were designed, synthesized, and evaluated for their antifungal/antioomycete activities. The <i>in vitro</i> antifungal/antioomycete assay showed that some of the targeted compounds exhibited remarkable and broad-spectrum antifungal activities. Notably, compounds <b>B10</b> and <b>C2</b> exhibited remarkable antifungal activity against <i>Valsa mali</i> (EC₅₀ = 0.790 mg/L for <b>B10</b>; 0.280 mg/L for <b>C2</b>), <i>Sclerotinia sclerotiorum</i> (EC₅₀ = 0.350 mg/L for <b>B10</b>; 1.11 mg/L for <b>C2</b>), and <i>Phytophthora capsici</i> (EC₅₀ = 0.460 mg/L for <b>B10</b>; 0.130 mg/L for <b>C2</b>). The <i>in vivo</i> experiments revealed that compound <b>C2</b> exhibited excellent control efficacy against <i>P. capsici</i> and <i>V. mali</i>, showing protective and curative activities comparable to those of <b>tebuconazole</b> at an equivalent dose of 40.0 mg/L. Integrated ultrastructural analyses using SEM, TEM, and CLSM revealed that compound <b>C2</b> compromised hyphal structural integrity in <i>P. capsici</i> and <i>V. mali</i>. <i>In vitro</i> succinate dehydrogenase (SDH) inhibition assays and molecular docking analyses suggest that compound <b>C2</b> may effectively suppress SDH activity through significant interactions with key amino acid residues at the enzyme's active site. Furthermore, toxicity tests on <i>Apis Mellifera</i> Ligustica revealed low acute toxicity of <b>B10</b> and <b>C2</b> toward <i>A. mellifera</i> L. These results indicate that compound <b>C2</b> holds potential as a novel antifungal for further investigation.