Michael addition-based synthesis of lawsone-derived benzopyrans: antibacterial, CREST and ADMET studies.

Using the Michael addition reaction, we have developed a simple and facile method for the synthesis of novel lawsone-based highly substituted benzopyrans in good to excellent yields (62-94%) at room temperature. All the synthesized compounds were characterized by 1H NMR, 13C NMR, FTIR and HRMS. The relative configuration was assigned by ROESY spectrum, showing 1,3-syn interaction between H1 and H3 protons and further supported by CREST analysis. The Structure-E having SSR configuration possesses the lowest relative electronic energy among the eight possible structures. Following this, the in vitro antibacterial activity was evaluated for the synthesized compounds against two bacterial strains, E. coli (PDB ID: 1KZN) and S. aureus (PDB ID: 3G75), using DNA gyrase as the target. Among the tested compounds, 3p with 6,8-dichloro and -OMe appended phenyl group exhibited the highest bacterial inhibition potency with an MIC value of 6.25 µg mL-1 against E. coli and 12.5 µg mL-1 against S. aureus respectively. Additionally, in silico molecular docking results also revealed that 3p has an excellent binding free-energy estimate of -9.3 kcal mol-1 and -8.2 kcal mol-1 against E. coli and S. aureus. As well, the synthesized compounds with promising pharmacokinetic and drug-like properties were established by ADMET investigations. Consequently, the results of in vitro and in silico assays discovered the capabilities of these compounds as active antibacterial drugs.