Synthesis, Biochemical Characterization, and Theoretical Studies of Novel β-Keto-enol Pyridine and Furan Derivatives as Potent Antifungal Agents

Abstract

In the present study, we report the design and synthesis of new derivatives of the β-keto-enol grafted on pyridine and furan moieties (L ₁ -L ₁₁ ). Structures of compounds were fully confirmed by Fourier transform infrared spectroscopy (FT-IR), ¹H NMR, ¹³C NMR, electrospray ionization/liquid chromatography-mass spectrometry (ESI/LC-MS), and elemental analysis. The compounds were screened for antifungal and antibacterial activities (Escherichia coli, Bacillus subtilis, and Micrococcus luteus). In vitro evaluation showed significant fungicidal activity for L ₁ , L ₄ , and L ₅ against fungal strains (Fusarium oxysporum f.sp albedinis) compared to the reference standard. Especially, the exceptional activity has been demonstrated for L ₁ with IC₅₀ = 12.83 μg/mL. This compound and the reference benomyl molecule also showed a correlation between experimental antifungal activity and theoretical predictions by Petra/Osiris/Molinspiration (POM) calculations and molecular coupling against the Fgb1 protein. The highest inhibition of bacterial growth for L ₁ is due to its strongest binding to the target protein. This report may stimulate the further synthesis of examples of this substance class for the development of new drugs.

Figure 1

Molecular structures of some drugs containing keto-enol functionality.

Scheme 1. Synthetic Route for the Compounds L₁–L₁₁

Figure 2

R substituent for L₁, L₄, and L₅.

Figure 3

Antibacterial and antifungal pharmacophore sites for L₁.

Figure 4

Binding conformations predicted from the ADVina runs for benomyl (a), L₁ (b), and L₄ (c) bound to β-tubulin of F. oxysporum. The protein (Fgb1) binding site is shown by the molecular surface and colored according to the protein atomic composition. All protein residues are drawn as ball-and-stick models. Hydrogen bonds are visualized as dashed lines. The ligand molecules are depicted in sticks, and hydrogen atoms were removed to enhance clarity.