Preparation, biological evaluation and molecular docking study of imidazolyl dihydropyrimidines as potential Mycobacterium tuberculosis dihydrofolate reductase inhibitors

A series of novel dihydropyrimidine derivatives bearing an imidazole nucleus at C-4 position were synthesized in excellent yields via Biginelli multi-component reaction. The newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR and Mass spectroscopy. In vitro antitubercular evaluation of all the newly synthesized compounds 4a–p against Mycobacterium tuberculosis (Mtb) H37Rv showed, 4j (MIC: 0.39 μg/mL; SI: >25.64), 4m (MIC: 0.78 μg/mL; SI: >12.82) and 4p (MIC: 0.39 μg/mL; SI: 24.10) as the most promising lead analogues. Compounds 4j, 4m and 4p displayed effective reduction in residual Mtb growth within the tuberculosis-infected macrophage model. Further, molecular docking study of active molecules 4j, 4m and 4p against Mycobacterium tuberculosis dihydrofolate reductase (Mtb DHFR) proved their potency as Mtb DHFR inhibitors acting as potential leads for further development. Pharmacokinetic properties leading to drug-likeness were also predicted for most active molecules 4j, 4m and 4p.

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