Docking, ADMET prediction, DFT analysis, synthesis, cytotoxicity, antibacterial screening and QSAR analysis of diarylpyrimidine derivatives

•New diarylpyrimidine derivatives designed and synthesized as antibacterial agents.•The molecular docking studies were performed with in binding site of PDF enzyme receptor.•Docking simulation showed the stable ligand-protein complexes formed by all compounds.•TOPKAT analysis of all the diarylpyrimidine derivatives showed that all the compounds were less toxic.•Combination approach was used to determine the Fractional Inhibitory Concentration (FIC).•Cytotoxicity assay against HEK293 (Human embryonic kidney) cell lines proved that cytotoxicity of the active analogues was too low. A new series of 2, 4 disubstituted diarylpyrimidine derivatives has been designed, synthesized and screened for their antibacterial activity. QSAR studies followed by antibacterial screening using broth dilution technique showed excellent MIC values against four human pathogens, namely Escherichia coli, Pseudomonas aeruginosa, Bacillus cerus and Staphylococcus aureus. Some molecules were found to be highly active (MIC value up to 3.1 µg/mL) against different types of human pathogens, like P. aeruginosa, E. coli, S. aureus and B. cerus. All compounds having MIC values greater than reference drugs were subjected for combinatorial antibacterial screening with chloramphenicol, cycloheximide and paromomycin as standard references and fractional inhibitory concentration (FIC) values of compounds exhibited great synergistic effect as their MIC values were lowered by 1/33, 1/16 and 1/8 of the original MIC's. In vitro evaluation of cytotoxicity indicates that these molecules were less toxic against HEK293 (Human embryonic kidney) cell lines. Molecular docking assessment also revealed that all designed 2,4 disubstituted diarylpyrimidine derivatives showed good interaction within active site of PDF enzyme (PDB ID: 1G2A). 2, 4 disubstituted diarylpyrimidines formed H-bond with amino acid residue Leu91, Arg97, Ile44, Ile94, Gly89 and Glu95 at a distance of 2.78 - 3.20 Å. Molecules also showed π - + and π – π interaction with amino acid residues Arg97 and His132. In silico assessment of all molecules exhibited more than 88% of intestinal absorption, which was higher than the reference antibiotics viz. chloramphenicol (69.94%), cycloheximide (74.26%) and paromomycin (76.46%). [Display omitted]