Potent antimicrobial pyridyl-imine derivatives: experimental and computational insights into their biological...

Dermatophytic infections remain a persistent therapeutic challenge, particularly due to the increasing resistance to conventional antifungal agents. In search of alternative antifungal scaffolds, a series of 2-pyridyl-imine derivatives (PYE1-PYE11) was synthesized and evaluated for antimicrobial, cytotoxic, and biomolecular interaction properties. All compounds exhibited antimicrobial activity, with the ortho-vanillin derivative PYE10 showing the highest potency, including remarkable activity against Proteus mirabilis (MIC = 0.01 mg/mL) and Trichophyton mentagrophytes (MIC = 0.05 mg/mL). Fluorescence displacement assays provided evidence for PYE10-DNA interactions involving both intercalative and minor-groove-associated binding modes, while human serum albumin binding studies revealed 1:1 complex formation, indicating appreciable interaction with HSA. Molecular docking and molecular dynamics simulations identified favorable and stable binding of the most active compounds within the CYP51B active site, supporting the experimentally observed antifungal activity. Computational thermodynamic analysis indicated that Fe²⁺ chelation is protonation-dependent under physiological conditions. Structure-activity relationship analysis revealed that antimicrobial activity is influenced by the electronic nature of substituents, aromatic planarity, molecular flexibility, and the ability to establish multiple intermolecular interactions. In silico ADMET evaluation demonstrated favorable drug-likeness and pharmacokinetic profiles, highlighting these pyridyl-imine derivatives as promising candidates for further antimicrobial development.