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 Mycobacterium tuberculosis and other clinically significant bacterial pathogens. Previously
reported chalcone-like antibacterials (1a–c and 2) were used as a training set to generate
a pharmacophore model. The chalcone derivative hit compound 3 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 6r and 6s were active (minimum
inhibitory concentrations (MICs) = 1.56–6.25 μg/mL) against
Gram-positive pathogens Bacillus anthracis and Staphylococcus aureus [methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA)]. The chalcone thiol-Michael addition
derivatives 7j–m showed good to excellent
antibacterial activities (MICs = 0.78–6.25 μg/mL) against Enterococcus faecalis, B. anthracis, and S. aureus. Interestingly, the
amine-Michael addition analogue 12a 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 S. aureus (MSSA and MRSA) revealed that 12a 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.