title: Preparation, biological evaluation and molecular docking study of imidazolyl dihydropyrimidines as potential Mycobacterium tuberculosis dihydrofolate reductase inhibitors.
abstract: 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, (1)H NMR, (13)C NMR and Mass spectroscopy. In vitro antitubercular evaluation of all the newly synthesized compounds 4a-p against Mycobacterium tuberculosis (Mtb) H37Rv showed, 4j (MIC: 0.39μg/mL; SI: >25.64), 4m (MIC: 0.78μg/mL; SI: >12.82) and 4p (MIC: 0.39μg/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.
authors.affiliation: Division of Medicinal Chemistry, Department of Chemistry (DST-FIST Sponsored), Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar 364 002, Gujarat, India. Electronic address: dnisheeth@rediffmail.com.
authors.forename: N C
authors.initials: NC
authors.lastname: Desai
authors.affiliation: Division of Medicinal Chemistry, Department of Chemistry (DST-FIST Sponsored), Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar 364 002, Gujarat, India.
authors.forename: A R
authors.initials: AR
authors.lastname: Trivedi
authors.affiliation: School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban 4000, South Africa.
authors.forename: Vijay M
authors.initials: VM
authors.lastname: Khedkar
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007093:Imidazoles / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000995:Antitubercular Agents; D005493:Folic Acid Antagonists; D007093:Imidazoles; D011743:Pyrimidines; C029899:imidazole; D013762:Tetrahydrofolate Dehydrogenase
keywords: Antitubercular activity; Cytotoxicity; Dihydropyrimidines; Imidazoles; Molecular docking; Mycobacterium tuberculosis dihydrofolate reductase inhibitors