Cyrhetrenyl and cymantrenyl N-acylhydrazone complexes based on isoniazid: Synthesis, characterization, X-ray crystal structures and antitubercular activity evaluation

Mario Mallea, Alejandra Acuña, A. Hugo Klahn, Vania Artigas, Fernando Rogério Pavan, Fernanda Manaia Demarqui, Luis Lemus, Danilo H. Jara, Patricia M. Toro

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

Resumen

Four organometallic N-acylhydrazones of the general formulae [M{(η5-C5H4)-CH[dbnd]N[sbnd]NH[sbnd]C(O)-(C5H4[sbnd]N)}(CO)3] [(with M = Re (5a) or Mn (6a)] and [M{(η5-C5H4)-C(Me)=N[sbnd]NH[sbnd]C(O)-(C5H4[sbnd]N)}(CO)3] [(with M = Re (5b) or Mn (6b)] were prepared by reaction of aldehyde/methyl ketone organometallic precursors with isoniazid (INH). All compounds were fully characterized using conventional spectroscopic techniques (FT-IR, 1H and 13C{1H} NMR, mass spectrometry, and high-resolution mass spectrometry). The X-ray crystal structures of cyrhetrenyl compounds (5a and 5b) are also reported. This structural analysis indicated that both compounds exhibited an E-configuration of the substituents on the -C(R1)=N- (R1 = H or Me). The biological activity of the four analogous organometallic compounds (5 and 6) to INH and their organics counterpart {[(C6H5)-C(R)=N[sbnd]NH[sbnd]C(O)-(C5H4[sbnd]N)] where R = H (NAH[sbnd]H) or R = Me (NAH-Me)} were evaluated on Mycobacterium tuberculosis (M. tuberculosis) in the standard strain H37Rv ATCC 27,294. The replacement of a hydrogen atom by a methyl group on the acylhydrazone moiety led to a significant increase in antitubercular properties. The compounds 5b and 6b (R1 = Me) were at least 36- and 18-fold more effective than 5a and 6a (R1 = H), respectively. The cyrhetrenyl derivative (5b) was the most active complex against M. tuberculosis. This compound was shown to be about 2-times more effective than its organic analog (NAH-Me) and showed activity comparable to antitubercular drug INH. In vitro toxicity assays against murine macrophage cells J774A.1 (ATCC TIB-67) were also conducted, and selectivity indexes were determined for the most promising compounds. All N-acylhydrazones showed a moderated cytotoxic profile, similar to the isoniazid and rifampicin (RIF) control drugs, while 5b exhibited better selectivity index (SI) concerning the organic counterpart NAH-Me. Based on the anti-TB activity, cytotoxicity, and selectivity index, compound 5b has more potential for evolution as a new antitubercular agent.

Idioma originalInglés
Número de artículo122299
PublicaciónJournal of Organometallic Chemistry
Volumen964
DOI
EstadoPublicada - 15 abr. 2022
Publicado de forma externa

Áreas temáticas de ASJC Scopus

  • Bioquímica
  • Química física y teórica
  • Química orgánica
  • Química inorgánica
  • Química de los materiales

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