Antifungal Activity of Novel 5,6,7,8-Tetrahydroquinazolin Derivatives against Plant Pathogenic Fungi by Targeting Sterol 14α-Demethylase (CYP51) and the Application on Rice

The emergence of severe resistance issues in plant pathogenic fungi poses a significant threat to the global quality and safety of crops. In this study, 36 novel derivatives featuring a 5,6,7,8-tetrahydroquinazolin structure were designed and synthesized for the first time. These 36 target compounds were subjected to <i>in vitro</i> tests against five fungal species. Specifically, compound <b>4r</b> demonstrated excellent efficacy against <i>R. solani</i>, with EC₅₀ values of 0.33 μg/mL, compared to the positive control value of 0.78 μg/mL. Additionally, the IC₅₀ values of compounds <b>4r</b> and Fluquinconazole were 0.34 and 0.62 μg/mL, respectively. The <i>in vivo</i> experiments further indicated that compound <b>4r</b> possessed a superior action effect compared to that of Fluquinconazole. The mechanism of action of compound <b>4r</b> was initially analyzed, revealing that it inhibits the production of fungal ergosterol, <b>4r</b> formed hydrophobic interactions with two more residues when compared with Fluquinconazole, and the binding energies of compound <b>4r</b> and Fluquinconazole were -57.2 and -39.7 kcal/mol. The studies presented above demonstrated that <b>4r</b> has a better mode of action than the positive control and could be a potential commercial fungicide candidate.