Synthesis, structure-activity relationships (SAR) and in silico studies of coumarin derivatives with antifungal activity

Abstract

The increased incidence of opportunistic fungal infections, associated with greater resistance to the antifungal drugs currently in use has highlighted the need for new solutions. In this study twenty four coumarin derivatives were screened in vitro for antifungal activity against strains of Aspergillus. Some of the compounds exhibited significant antifungal activity with MICs values ranging between 16 and 32 µg/mL. The structure-activity relationships (SAR) study demonstrated that O-substitutions are essential for antifungal activity. It also showed that the presence of a short aliphatic chain and/or electron withdrawing groups (NO(2) and/or acetate) favor activity. These findings were confirmed using density functional theory (DFT), when calculating the LUMO density. In Principal Component Analysis (PCA), two significant principal components (PCs) explained more than 60% of the total variance. The best Partial Least Squares Regression (PLS) model showed an r2 of 0.86 and q2(cv) of 0.64 corroborating the SAR observations as well as demonstrating a greater probe N1 interaction for active compounds. Descriptors generated by TIP correlogram demonstrated the importance of the molecular shape for antifungal activity.

Figure 1

Representation of LUMO density surfaces for active (22–24) and inactive (3–5) compounds. Red regions represent lower electronic concentrations.

Figure 2

Scores plot from PCA. Red triangle represents less active and blue triangle represents more active compounds.

Figure 3

Best fit model obtained in PLS.

Figure 4

Examples of important structural features for antifungal activity, highlighted by the PLS analysis: (A) and (B) 12 and 15, respectively—active compounds; (C) and (D) 3 and 4—inactive compounds, respectively. N1–TIP interactions (orange), N1–N1 (green) interactions.

Scheme 1

Synthesis of alkyl-, acetyl- and nitro-coumarin derivatives. Reagents and Conditions: (a) Acetic Anhydride, Pyridine, rt., ultrasound irradiation; (b) Allyl Bromide, Geranyl Bromide, Prenyl Bromide, or Ethyl Chloroacetate, K₂CO₃, Acetonitrile, reflux; (c) HNO₃/AcOH, 0–5 °C for 30 min, then 90 min at rt.