title: Microwave-assisted synthesis, molecular docking and antitubercular activity of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives.
abstract: Based on bioisosteric similarities with isoniazid, a series of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives has been designed. The target compounds have been synthesized by multicomponent reaction which involves one-pot organic reactions using ethylcyanoacetate, urea/thiourea and arylaldehydes in presence of ethanolic K(2)CO(3). Two methodologies, conventional and microwave-assisted, have been adopted for the synthesis. The later strategy gave high yields in less than 10 min as compared to long hours using the former approach. Molecular docking of the target compounds into the enzyme Mycobacterium tuberculosis enoyl reductase (InhA) revealed important structural information on the plausible binding interactions. Major binding interactions were found to be of dispersion type (residues Tyr158, Ile215, Met103 and Met199) and a hydrogen bond with Tyr158. Binding poses of the all the compounds were energetically favorable and showed good interactions with the active site residues. Few selected compounds were also evaluated for antitubercular activity in vitro against drug-sensitive M. tuberculosis H37Rv strain and clinically isolated S, H, R and E resistant M. tuberculosis by luciferase reporter phage (LRP) assay method. Some compounds displayed promising antimycobacterial activity comparable or less than the standard drugs isoniazid and rifampicin.
authors.affiliation: Department of Pharmaceutical Chemistry, Roland Institute of Pharmaceutical Sciences, Khodasinghi, Berhampur 760 010, India. biswamohan81@gmail.com
authors.forename: Sahoo Biswa
authors.initials: SB
authors.lastname: Mohan
authors.forename: B V V
authors.initials: BV
authors.lastname: Ravi Kumar
authors.forename: S C
authors.initials: SC
authors.lastname: Dinda
authors.forename: D
authors.initials: D
authors.lastname: Naik
authors.forename: S
authors.initials: S
authors.lastname: Prabu Seenivasan
authors.forename: Vanaja
authors.initials: V
authors.lastname: Kumar
authors.forename: Dharmarajsinh N
authors.initials: DN
authors.lastname: Rana
authors.forename: Pathik S
authors.initials: PS
authors.lastname: Brahmkshatriya
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D008872:Microwaves; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C581076:1,2,3,4-tetrahydropyrimidine-5-carbonitrile; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D009570:Nitriles; D011743:Pyrimidines; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium