Design, synthesis and antifungal activity of novel matrine-hydroxamic acid derivatives containing benzene sulfonamide†

To address the urgent need for novel antibacterial drugs, herein, a series of 27 novel matrine derivatives incorporating hydroxamic acid and benzene sulfonamide moieties were designed and synthesized. Antimicrobial testing demonstrated exceptional inhibitory activity against Candida albicans, with the most potent compound (10g) showing a MIC value of 0.062 mg mL⁻¹, which was significantly lower than that of the clinical antibiotic fluconazole (8.590 mg mL⁻¹). 3D-QSAR analysis identified the phenylsulfonyl group as crucial for activity, particularly when substituted with a 4-(CH₃)₃ group. The hydroxamic acid moiety was also found to contribute positively to the antifungal effects. Mechanistic studies indicated that these compounds act by both preventing biofilm formation and disrupting established biofilms. Furthermore, molecular docking studies of compounds 9j and 10g with fungal proteins (PDB: 2QZX) revealed that their antifungal activity involves multiple interactions, including hydrogen bonding, hydrophobic interactions, and van der Waals forces. These findings position compound 10g as a particularly promising lead candidate for the development of new antifungal agents.