title: Anti-tuberculosis evaluation and conformational study of N-acylhydrazones containing the thiophene nucleus.
abstract: A series of N-acylhydrazonyl-thienyl derivatives (compounds 2 and 3), mainly of the type 2-(aryl-CH=N-NHCOCH2 )-thiene (2: aryl = substituted-phenyl; 3: aryl = heteroaryl) were evaluated against Mycobacterium tuberculosis. Particularly active compound was 3 (heteroaryl = 5-nitrothien-2-yl or 5-nitrofuran-2-yl) with MIC values of 8.5 and 9.0 μM, respectively. Moderately active compounds were compound 3 (heteroaryl = pyridin-2-yl) and compound 2 containing aryl = 2- or 4-hydroxyphenyl groups, with MIC values between 170 and 408 μM. Compound 2 containing OMe, H, F, Cl, Br, CN, and NO2 substituents and compound 3 (heteroaryl = furan-2-yl, thien-2-yl, pyrrol-2-yl, imidazol-2-yl, pyridin-3-yl, and pyridin-4-yl) were all inactive. Clearly, there is no correlation of activity with the electronic effects of the substituents. The activities suggest different modes of biological action of the compounds having nitro-heteroaryl groups, on the one hand, and the 2-hydroxyphenyl or pyridin-2-yl substituents, on the other hand. Compounds having 2- or 4-hydroxyphenyl, 2-hydroxy-5-nitrophenyl, or 4-hydroxy-3-chlorophenyl were less cytotoxic than ethambutol. It is important to notice that compound 3 (aryl = 5-NO2 -furan-2-yl) exhibited a promising therapeutic index (TI = 1093.90), with a value 4.4 less than that of ethambutol. Compounds 2 and 3 exist in DMSO or MeOD solutions as mixtures of EC(O)N /EC=N and ZC(O)N /EC=N conformers.
authors.affiliation: Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-Far Manguinhos, Manguinhos, Rio de Janeiro, Brazil; Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil.
authors.forename: Laura N F
authors.initials: LN
authors.lastname: Cardoso
authors.forename: Marcelle L F
authors.initials: ML
authors.lastname: Bispo
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Kaiser
authors.forename: James L
authors.initials: JL
authors.lastname: Wardell
authors.forename: Solange M S V
authors.initials: SM
authors.lastname: Wardell
authors.forename: Maria C S
authors.initials: MC
authors.lastname: Lourenço
authors.forename: Flávio A F M
authors.initials: FA
authors.lastname: Bezerra
authors.forename: Rodrigo P P
authors.initials: RP
authors.lastname: Soares
authors.forename: Marcele N
authors.initials: MN
authors.lastname: Rocha
authors.forename: Marcus V N
authors.initials: MV
authors.lastname: de Souza
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D006835:Hydrazones; D013876:Thiophenes
keywords: Antimycobacterial activity; Conformational study; N-Acylhydrazones; Thiophene; Tuberculosis