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

Abstract

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.

Fig. 1. Rationale design strategy of derivatives.

Fig. 2. Synthetic routes and the substituent for the derivatives. (a) KOH, H₂O; (b) SOCl₂, MeOH; (c) K₂CO₃, CH₃CN; (d) 3 N HCl; (e) NH₂OH·HCl, CH₃ONa; (f) EDCI, HOBT, TEA.

Fig. 3. The backbone (A) and stacked diagram (B).

Fig. 4. Calculated pMIC_C.al and experimental pMIC_C.al values for target compounds obtained by PLS analysis using CoMFA (A) and CoMSIA (B) models.

Fig. 5. CoMFA steric field (A) and electrostatic field (B); CoMSIA steric field (C), electrostatic field (D), hydrophobic field (E), hydrogen bond acceptor and donor field (F).

Fig. 6. The results of biofilm experiments.

Fig. 7. The histogram of biofilm formation rate.

Fig. 8. Binding pattern of compound 9j to amino acids in the active site of the 2QZX protein (A), 3D (B), 2D (C) and docking pocket of hydrogen bonding (D), hydrophobic (E), aromatic (F), SAS (G), ionization (H), and interpolated charge (I) interaction diagrams.

Fig. 9. Binding pattern of compound 10g to amino acids in the active site of the 2QZX protein (A), 3D (B), 2D (C) and docking pocket of hydrogen bonding (D), hydrophobic (E), aromatic (F), SAS (G), ionization (H), and interpolated charge (I) interaction diagrams.