Design, Synthesis, Drug-Likeness, anti-Inflammatory, Antimicrobial Activity, and Molecular Docking Studies of Pyrimidine Analogs

Abstract

Grounded on medicinal significances of pyrimidines, herein we are reporting initially the design and synthesis of 1-(2-benzylthiopyrimidin-4-yl)-benzimidazol-2-thioacetic acid/thioacetate 2(a, b), 1-(2-benzylthiopyrimidin-4-yl)-3,5 diaryl-2-pyrazoline (3) and 1-(2-benzylthiopyrimidin-4-yl)-3,5-dimethylpyrazole (4). In silico screening such as molecular docking studies of these compounds with inflammation-causing enzyme cyclooxagenase-2 (COX-2) suggests that only 2a has shown a strong affinity for the COX-2 (−9.0 kcal/mol) and forms three hydrogen bonds with active amino acid residues in comparison with standard anti-inflammatory drugs celecoxib (-8.8 kcal/mol) and indomethacin (-7.7 kcal/mol). However, in vitro, anti-inflammatory activity reveals that IC50 of compound 2a was 3.5 μM compared to celecoxib with IC50 of 0.65 μM. Also, 2a has displayed comparable activity of standard antibacterial drug gentamycin against E. coli with MIC 6.5 μM. Furthermore, the drug-likeness of potent compounds was studied using Swiss ADME and Mol inspiration software. All the compounds showed optimum drug-likeness without violating Lipinski’s rule of five. With our best observation and based on comparative SAR studies of these analogs with celecoxib and indomethacin, we conclude that compound 2a could develop as a therapeutically potent anti-inflammatory agent.