Synthesis, structural characterization, and antimicrobial activity of novel ferrocene-N-acyl hydrazones designed by means of molecular simplification strategy Celebrating the 100th anniversary of the birth of Professor Paulo Freire

Abstract

• A new series of ferrocenyl- N -acyl hydrazone (Fc-NAH) derivatives has been planned by means of a molecular simplification strategy. • The CeCl 3 -catalyzed synthesis of the N -acyl hydrazone moiety has led to the stereoselectivity of the E -isomers . • The new more structurally simple compounds Fc-NAH have disclosed an interesting antimicrobial profile, while the starting model molecules were inactive. • Compounds Fc-NAH have been evaluated for their antimicrobial activity and exhibited especially good outcomes against Gram-positive bacteria. The pursuit of new biological active and structurally diverse molecules is the main core of medicinal chemistry, which can be achieved by means of different theoretical and experimental strategies, including molecular simplification. Starting from a structural model of more complexity, it is possible to design new molecules with easier synthetical requirements, improved physicochemical properties, and even new biological profiles. Based on this strategy, 36 ferrocenyl- N -acyl hydrazone (Fc-NAH) hybrids have been planned, synthesized, and screened for their antimicrobial activity. The applied synthetical method has led to the stereoselectivity of the E -isomers, avoiding diastereomeric mixtures that can affect biological studies. In opposition to the starting structural model, the Fc-NAH derivatives have disclosed significant antimicrobial activity. Compounds SintMed(75-110) were especially active against the gram-positive bacterial strains B. subtilis and S. aureus , and the nitro-substituted derivatives must be highlighted due to their best results. In fact, derivatives SintMed77 (3,5-dinitrophenyl) and SintMed93 (4-nitrophenyl) were the most active in the series, with inhibitory zones of 20.1 ± 0.52 and 21.4 ± 0.83, respectively. General structural features could be established from the analysis of the in vitro antimicrobial activity and minimum inhibitory concentration (MIC) studies, such as the importance of the electron-withdrawing substituents, as well as the role of the formation of hydrogen bonds in the biological responses. Besides, a clear tendency of low activity or even inactivity was observed for the derivatives bearing nonpolar groups, a piece of crucial information for further studies of structural modifications. By means of molecular simplification strategy, a new series of ferrocenyl- N -acyl hydrazones (Fc-NAH) was planned, synthesized, and found to be active as antimicrobials, in opposition to the inactive starting more complex model.