The escalating global health crisis of Antimicrobial Resistance (AMR) necessitates the rapid discovery of agents with novel structures and multi-targeted mechanisms of action. This study utilizes the Pharmacophore Hybridization Approach (PHA) to address this challenge by designing novel conjugates targeting essential bacterial pathways, specifically the Peptide Deformylase (PDF) enzyme. A virtual library of over 40 compounds, integrating the triazole linker with four established heterocyclic scaffolds (indoline-2,3‑dione, 4‑hydroxy-2H-chromen-2-one, 2-phenyl-1H-indole, and 2-hydroxybenzaldehyde), was generated. Eighteen lead molecules were rationally selected following in silico screening for drug-likeness (Lipinski’s Rule of Five) and preliminary ADMET profiles. These 18 leads were successfully synthesized via an optimized Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC) reaction, utilizing a high-yield 1:1 THF/Water solvent system. The structures of all synthesized triazole derivatives were confirmed by a rigorous spectral assessment including 1H NMR, 13C-NMR and HRMS analyses. Molecular docking studies against Escherichia coli PDF (PDB ID: 1G2A) revealed potent binding affinities for several synthesized derivatives, significantly exceeding those of standard antibiotics. Structure-activity relationship (SAR) analysis highlighted the crucial role of specific substituents, particularly electron-withdrawing groups at R1 and a -NHCOCH3 group at R3, in enhancing binding affinity and predicted activity. Molecular dynamics simulations comparing a representative compound (Compound 3) to sulphamethoxazole indicated differences in dynamic behavior, with Compound 3 showing less conformational stability and higher flexibility, despite similar overall compactness. Experimental validation confirmed the successful synthesis of the target compounds and demonstrated promising antibacterial activity against a panel of Gram-positive and Gram-negative bacterial strains, correlating well with the predicted SAR. Cytotoxicity assessment in HEK293 cells showed dose-dependent, generally moderate effects. These integrated computational and experimental findings identify several triazole-based conjugates as promising lead candidates for further development in the fight against AMR.
扫码关注我们
求助内容:
应助结果提醒方式:
