Abstract
Background:
There is an ongoing need for effective antimicrobial candidates with potential multi-target activities against resistant Gram-negative, Gram-positive, and fungal pathogens.
Objective:
To synthesize a new series of N-nicotinoyl amino acid-based Schiff bases (S1–S6), evaluate their antimicrobial potency, and investigate their molecular binding and pharmacokinetic properties through docking, molecular dynamics (MD) simulations, and ADME predictions.
Method:
Schiff bases (S1–S6) were synthesized via mixed anhydride and hydrazinolysis, followed by reaction with aromatic aldehydes, and structurally characterized using FTIR, 1H NMR, and 13C NMR spectroscopy. Antimicrobial activity against selected pathogens was evaluated, and in silico docking was performed against DNA gyrase (PDB ID: 2XCT) and lanosterol 14α-demethylase (CYP51, PDB ID: 4WMZ) alongside MD simulations and ADME predictions.
Results:
The synthesized compounds showed broad-spectrum antimicrobial activity with inhibition zones exceeding 20 mm. Compound S6 was the most effective antibacterial agent against E. coli (45 mm zone), while S4 showed the highest antifungal activity (41 mm zone). S1 and S6 demonstrated low MIC (125 µg/mL) against E. coli and P. mirabilis, while S2 showed lower MIC (125 µg/mL) against C. albicans. Docking revealed highest binding affinities for S6 with 2XCT (-8.564 kcal/mol) and S4 with 4WMZ (-7.848 kcal/mol), with MD simulations confirming dynamic stability for the S6-2XCT complex and ADME predicting favorable drug-likeness.
Conclusion:
These novel Schiff bases, particularly compounds S4 and S6, represent promising lead scaffolds for the development of potent, multi-target antimicrobial agents.
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