title: Synthesis, screening for antitubercular activity and 3D-QSAR studies of substituted N-phenyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxamides.
abstract: Multi-drug resistance to commonly used antitubercular drugs has propelled the development of new structural classes of antitubercular agents. This paper reports the synthesis, evaluation and 3D-QSAR analysis of a set of substituted N-phenyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamides as antitubercular agents. Substituted acetoacetanilides were reacted with various aromatic aldehydes and urea which yielded the tetrahydropyrimidine derivatives with a phenyl carbamoyl group at C5 position, and with various substitutions on the 4-phenyl and the N-phenyl aromatic rings. All compounds were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain. The QSAR models were generated on a training set of 23 molecules. The molecules were aligned using the atom-fit and field-fit techniques. The CoMFA and CoMSIA models generated on the molecules aligned by the atom-fit method show a correlation coefficient (r2) of 0.98 and 0.95 with cross-validated r2(q2) of 0.68 and 0.58, respectively. The 3D-QSAR models were externally validated against a test set of 7 molecules for which the predictive r2 (r(pred)2) is recorded as 0.41 and 0.32 for the CoMFA and CoMSIA models, respectively. The CoMFA and CoMSIA contours helped to design some new molecules with improved activity.
authors.affiliation: Department of Chemistry, Saurashtra University, Rajkot 360 005, Gujarat, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Virsodia
authors.forename: Raghuvir R S
authors.initials: RR
authors.lastname: Pissurlenkar
authors.forename: Dinesh
authors.initials: D
authors.lastname: Manvar
authors.forename: Chintan
authors.initials: C
authors.lastname: Dholakia
authors.forename: Priti
authors.initials: P
authors.lastname: Adlakha
authors.forename: Anamik
authors.initials: A
authors.lastname: Shah
authors.forename: Evans C
authors.initials: EC
authors.lastname: Coutinho
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011743:Pyrimidines / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000577:Amides; D000995:Antitubercular Agents; D008024:Ligands; D011743:Pyrimidines; C030986:pyrimidine