Exploring Quinoline-linked Chalcones as broad-Spectrum antimicrobial agents: Synthesis, antibacterial, antifungal,...

The present study focuses on the synthesis, spectral characterization, and antimicrobial evaluation of a series of (E)-3-(2-morpholinoquinolin-3-yl)-1-(substituted aryl/heteroaryl)prop-2-en-1-one chalcone derivatives (5a-5j). A multistep synthetic strategy was employed, starting from acetanilide through a Vilsmeier-Haack reaction, followed by replacement of chloro group by morpholine and Claisen-Schmidt condensation. Structural confirmation was accomplished through FT-IR, ¹H NMR, and ¹³C NMR spectroscopy. FT-IR spectra showed characteristic α,β-unsaturated carbonyl stretching with confirmation of other functional groups. The ¹H NMR spectra displayed characteristic trans-alkene proton doublets (J = 15.6-15.8 Hz), morpholine multiplets at δ 3.37-3.97, and distinct aromatic signals. ¹³C NMR confirmed carbon skeleton with enone CO carbon atoms between δ 177.90-190.24, and consistent morpholine signals. Antimicrobial activities were assessed against four bacterial (Gram-positive and Gram-negative) and two fungal strains. Compound 5b showed the highest antibacterial activity with a 32 mm inhibition zone against S.typhi and compound 5a exhibited the highest antifungal activity (15 mm) against C. albicans. A comparative ADME analysis of chalcone derivatives 5a and 5b revealed good pharmacokinetic profiles. The molecular docking analysis revealed that compounds 5a and 5b exhibits favorable molecular interactions with microbial targets. Compound 5b was docked against DNA GyraseA C-terminal domain of of S. typhi, showing a binding affinity of -9.8 kcal/mol whereas compound 5a exhibited binding interaction of - 7.7 kcal/mol against sterol 14-α demethylase (CYP51) of C. albicans. DFT analysis of chalcone derivatives 5a and 5b revealed optimized geometries, electronic structures, and electrostatic potential surfaces.