Antibacterial Bioevaluation of Novel Chalcone, Dihydropyrazoline, and 1,2,3-Triazole Derivatives and Identification of Broad-Spectrum Antibacterial Leads

Abstract

The rapid emergence of antimicrobial resistance has created an urgent need for new antibacterial agents capable of overcoming the limitations of existing antibiotics. In the present study, a series of structurally related aromatic aldehyde intermediates, chalcones, dihydropyrazoline derivatives, and 1,2,3-triazole analogues were evaluated for their in vitro antibacterial activity against three clinically relevant bacterial strains: Escherichia coli, Staphylococcus aureus, and Klebsiella pneumoniae. Antibacterial potency was expressed as IC₅₀ values in µg/mL. The early aminoalkyl-substituted benzaldehyde derivatives (2a–3) were essentially inactive against all tested organisms, with IC₅₀ values greater than 50 µg/mL. Transformation of these intermediates into chalcone derivatives (5a–5d) resulted in moderate antibacterial activity, particularly against S. aureus and K. pneumoniae, with compound 5b displaying the most favorable activity in this series. Cyclization of chalcones into dihydropyrazoline analogues (8a–8d) produced a substantial enhancement in antibacterial potency. Among them, compound 8c demonstrated pronounced activity against S. aureus, while compound 8d exhibited a broader spectrum of inhibition against both Gram-positive and Gram-negative organisms. The most significant improvement was observed following conversion of the propargyl-containing precursor into 1,2,3-triazole derivatives (10a and 10b), both of which showed excellent broad-spectrum activity, including strong inhibition of E. coli with IC₅₀ values of approximately 1.25 µg/mL. Structure–activity relationship analysis revealed a clear stepwise evolution in antibacterial potency from inactive aromatic precursors to highly active triazole-based leads. The results indicate that incorporation of the chalcone pharmacophore, pyrazoline ring, and triazole nucleus progressively optimized physicochemical properties, target affinity, and membrane permeability. Compounds 10a and 10b emerged as the most promising antibacterial leads and warrant further mechanistic, toxicity, and in vivo investigations.