title: Additional synthesis on thiophene-containing trisubstituted methanes (TRSMs) as inhibitors of M. tuberculosis and 3D-QSAR studies.
abstract: We earlier reported thiophene-containing trisubstituted methanes (TRSMs) as novel cores carrying anti-tubercular activity, and identified S006-830 as the phenotypic lead with potent bactericidal activity against single- and multi-drug resistant clinical isolates of Mycobacterium tuberculosis (M. tb). In this work, we carried out additional synthesis of several TRSMs. The reaction scheme essentially followed the Grignard reaction and Friedel-Crafts alkylation, followed by insertion of a dialkylaminoethyl chain. We also performed microbiological evaluations including in vitro screening against the virulent strain M. tb H37Rv, cytotoxicity assessment in the Vero C-1008 cell line, and 3D-QSAR studies with comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). CoMFA and CoMSIA models yielded good statistical results in terms of q2and r2values, suggesting the validity of the models. It was concluded that a para-substituted benzene ring with bulkier electron-donating groups and aminoalkyl chains are required for higher inhibitory capacity against M. tuberculosis. We believe that these insights will rationally guide the design of newer, optimal, TRSMs.
authors.affiliation: a Institut des Biomolécules Max Mousseron , Montpellier , France.|b Medicinal and Process Chemistry Division , CSIR-Central Drug Research Institute , Lucknow , India.
authors.forename: P
authors.initials: P
authors.lastname: Singh
authors.affiliation: b Medicinal and Process Chemistry Division , CSIR-Central Drug Research Institute , Lucknow , India.
authors.forename: T
authors.initials: T
authors.lastname: Saha
authors.affiliation: b Medicinal and Process Chemistry Division , CSIR-Central Drug Research Institute , Lucknow , India.
authors.forename: P
authors.initials: P
authors.lastname: Mishra
authors.affiliation: b Medicinal and Process Chemistry Division , CSIR-Central Drug Research Institute , Lucknow , India.
authors.forename: M K
authors.initials: MK
authors.lastname: Parai
authors.affiliation: b Medicinal and Process Chemistry Division , CSIR-Central Drug Research Institute , Lucknow , India.
authors.forename: S
authors.initials: S
authors.lastname: Ireddy
authors.affiliation: b Medicinal and Process Chemistry Division , CSIR-Central Drug Research Institute , Lucknow , India.
authors.forename: S
authors.initials: S
authors.lastname: Lavanya Kumar M
authors.affiliation: c Molecular and Structural Biology Division , CSIR-Central Drug Research Institute , Lucknow , India.
authors.forename: S
authors.initials: S
authors.lastname: Krishna
authors.affiliation: d Biochemistry Division , CSIR-Central Drug Research Institute , Lucknow , India.
authors.forename: S K
authors.initials: SK
authors.lastname: Kumar
authors.affiliation: d Biochemistry Division , CSIR-Central Drug Research Institute , Lucknow , India.
authors.forename: V
authors.initials: V
authors.lastname: Chaturvedi
authors.affiliation: d Biochemistry Division , CSIR-Central Drug Research Institute , Lucknow , India.
authors.forename: S
authors.initials: S
authors.lastname: Sinha
authors.affiliation: c Molecular and Structural Biology Division , CSIR-Central Drug Research Institute , Lucknow , India.
authors.forename: M I
authors.initials: MI
authors.lastname: Siddiqi
authors.affiliation: b Medicinal and Process Chemistry Division , CSIR-Central Drug Research Institute , Lucknow , India.
authors.forename: G
authors.initials: G
authors.lastname: Panda
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial; D008697:Methane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014376:Tuberculosis / Q000188:drug therapy; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D013876:Thiophenes; D008697:Methane
keywords: 3D-QSAR; CoMFA; CoMSIA; M. Tb H37Rv; Mycobacterium tuberculosis; anti-tuberculosis; trisubstituted methanes