Substituted chalcones inhibit biofilm formation and efflux pumps of multidrug resistant Staphylococcus aureus: Antimicrobial, molecular docking, ADME and QSAR studies.

In this study, a library of 19 acetophenone-derived chalcones were synthesized via Claisen Schmidt Aldol condensation. Analytical and spectral instrumentation (FT-IR, 1H NMR, 13C NMR and HPLC-MS) were utilized for the structural elucidation. From the antibacterial evaluation against MRSA (clinical strain planktonic cells: ST152), compounds 3b and 3k were significantly active, demonstrating exceptional activity against the MRSA planktonic cells at an equipotent concentration of 3.9063 μg/ml, exceeding the efficacy of the reference drug clindamycin with MIC of 7.8125 μg/ml. Compound 3b demonstrated a remarkable inhibition of efflux pump at a sub-inhibitory concentration of 1.953 μg/ml out-performing the reference drug Verapamil. Notably, the most potent anti-biofilm compounds 3k and 3r bearing the indole moiety exhibited a percentage biofilm inhibition of 99.45 % and 96.70 % respectively. The molecular docking results showed compounds 3b, 3k, and 3r exhibited favorable binding energies and strong interactions with the SauPBP2a active site. From the ADME prediction using ADMETLAB 3.0, the compounds had good oral bioavailability, excellent membrane permeability according to the Caco-2 and PAMPA values, exhibited favorable safety profile and met drug-like features, however, further optimisation to improve toxicity is needed. The biological and in silico data available indicated 3k [(E)-3-(1H-indol-3-yl)-1-(4-methoxyphenyl) prop-2-en-1-one] and 3r [(E)-1-(4-chlorophenyl)-3-(1H-indol-3-yl) prop-2-en-1-one] as promising clinical candidates. The optimal QSAR model, generated via generic algorithm multiple linear regression (GA-MLR): -24.6553 + 2.9442GATs7m + 0.2937VE3_Dze+14.2926spMin2_Bhp demonstrated robust predictive performance with an R2 of 0.8926 and an adjusted R2 of 0.8604.