Abstract

Four organometallic N-acylhydrazones of the general formulae [M{(eta(5)-C5H4)-CH= N -NH -C(O)-(C5H4-N)}(CO)(3)] [(with M = Re ( 5a ) or Mn ( 6a )] and [M{(eta(5)-C5H4)-C(Me)=N -NH -C(O)-(C5H4-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, H-1 and C-13{ H-1} 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(R-1) = N (R-1 = 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 -NH -C(O)-(C5H4-N)] where R = H (NAH -H ) or R = Me (NAH-Me)} were evaluated on Mycobacterium tuberculosis ( M. tuberculosis ) in the standard strain H(37)Rv 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 (R-1 = Me) were at least 36-and 18-fold more effective than 5a and 6a (R-1 = 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. (c) 2022 Published by Elsevier B.V.