Alkyl Tail Variation on Chalcone-Based Quaternary Pyridinium Salts as Rule-of-Thumb for Antimicrobial Activity

Aiming at developing a new class of quaternary pyridinium salts, the lead compound 1, characterized by a pyridine-3-yl chalcone framework, was rationally modified by inserting alkyl functions varying from 6 to 18 carbon units. Among the set, some valuable lead compounds were identified. Derivatives 4–6 were primarily active against Staphylococcus aureus and Candida albicans, respectively (MIC = 1.56 and 3.125 μM). In comparison, analogs 4 and 5 showed significant activities against Escherichia coli (MIC = 6.25 μM). Interestingly, the antimicrobial property of compounds 4–6, as well as their antibiofilm activity, occurred at lower concentrations than their cyto- and erythrocyte toxicities, thus ensuring a favorable safety profile. Structure–activity relationship analysis highlighted the critical role of the alkyl tail length in the antimicrobial activity, and optimal results were observed for moieties ranging from 10 to 14 carbon units. Molecular dynamics studies performed on 2 and 5 by modeling them on Gram-positive and Gram-negative membranes showed that the derivatives, upon diffusing across periodic boundary conditions, were able to intercalate into the microbial membranes. The difference in diffusion rates provides useful information to support the diverse antimicrobial potencies of the newly designed quaternary pyridinium salt.