Design, synthesis and molecular dynamic studies of novel imidazo/pyrido-pyrimidine clubbed ethyl-1,2,3,4-tetrahydro-4-phenylpyrimidine-5-carboxylate derivatives as potent anti-tubercular agents

Abstract

A small library of substituted ethyl-1,2,3,4-tetrahydro-4-phenylpyrimidine-5-carboxylate was designed and synthesized. All the characterized molecules were screened for their anti-tubercular activity using the H37Rv strain of Mycobacterium tuberculosis (Mtb). The compounds 5c, 5d, 5f, 5h, and 5k showed equipotent activity (MIC 3.12 µg/mL), compounds 5b, 5e, 5g, 5i, and 5j were more potent (MIC 1.6 µg/mL), whereas, 5a and 5l shown moderate activity (MIC 6.25 µg/mL). The potent inhibitory activity of screened compounds was rationalized with in-silico molecular modeling studies against the Mtb-dihydrofolate reductase (DHFR) enzyme. Compound 5i displayed a good docking score of −8.56 Kcal/mole with H-bond and hydrophobic interactions. These interactions revealed the stability of the complex which in turn determined the potent inhibitory effect. To get in-depth mechanistic insight into the inhibitory effect and to assess the stability of the ligand–protein complex, a molecular dynamics (MD) simulation study was performed. The RMSD and RMSF values obtained by the MD simulation study were 2.39 Å and 0.92 Å, respectively. The obtained values suggested that the drug–ligand complex maintained the stability over entire 100 ns run and the molecule did not fluctuate. The H-bond and hydrophobic interactions displayed in molecular docking studies were found to be retained in the MD simulation run. The obtained MD simulation values indicate that the complex was stable and rationalize the potent inhibitory effect. The drug-likeliness properties of potent compounds were calculated and the values thus obtained suggested that the molecule 5i has drug-likeliness properties and complies with Lipinski's rule of five/Ro3. Hence, the identified compounds can be taken into further stages of drug discovery processes.