Pharmacophore Modeling, Synthesis, and Antibacterial Evaluation of Chalcones and Derivatives.

A series of novel chalcone and thiol-Michael addition analogues was synthesized and tested against and other clinically significant bacterial pathogens. Previously reported chalcone-like antibacterials (- and ) were used as a training set to generate a pharmacophore model. The chalcone derivative hit compound was subsequently identified through a pharmacophore-based virtual screen of the Specs library of >200 000 compounds. Among the newly synthesized chalcones and thiol-Michael addition analogues, chalcones and were active (minimum inhibitory concentrations (MICs) = 1.56-6.25 μg/mL) against Gram-positive pathogens and [methicillin-susceptible (MSSA) and methicillin-resistant (MRSA)]. The chalcone thiol-Michael addition derivatives - showed good to excellent antibacterial activities (MICs = 0.78-6.25 μg/mL) against , , and . Interestingly, the amine-Michael addition analogue showed promising anti-MRSA activity (MIC = 1.56 μg/mL) with a selectivity index of 14 toward mammalian Vero cells. In addition, evaluation of selected compounds against biofilm and planktonic (MSSA and MRSA) revealed that exhibited bactericidal activities in these assays, which was overall superior to vancomycin. These properties may result from the compounds dissipating the proton motive force of bacterial membranes.