Design and Synthesis of (3′-Benzyloxy)-3-fluoro-5-(4-methylpiperazine-1-yl)-[1,1′-biphenyl] carbaldehyde and Indanone Derivatives and their Antibacterial Activity Close to Fab I Inhibitors

Abstract

Several bacterial targets are screened for the development of anti-infective medicines, but still finding new pharmacological targets and chemotherapeutics is still necessary in this field. Many anti-infective drugs and Fab I inhibitors with center cores like pyridines, pyridones, benzoxazole, benzothiazoles, quinolines, quinazolines and pyrazoles, etc. are in an advanced stage. In present work, we have designed an simple and efficient synthetic route of novel molecules based on the structure and binding modes of Fab I inhibitors with enzymes. The derivatives of (3′-benzyloxy-3-fluoro-5-(4-methylpiperazine-1-yl)-[1.1′-biphenyl]carbaldehyde (7a-j) and indanone (14a-f) were synthesized and characterized. Compared to earlier synthetic approaches, the derived synthetic routes are thought to be the shortest and most efficient. The reagent titanium isopropoxide was used for the nucleophilic aromatic substitution (SNAr) in the synthesis of carbaldehyde derivatives. The bacterial activity of synthesized novel molecules was evaluated against the Gram-positive bacteria (S. aureus and B. subtilis) and Gram-negative (E. coli and P. aeruginosa) bacteria. The synthesized compounds are found to be effective against S. aureus at 16 µg/mL and at 8 µg/mL concentration against B. subtilis. The molecular modeling study of these molecules has shown that the binding energies of some of the synthesized molecules are higher than the standard molecule triclosan. The binding interactions of the molecule with the protein with more hydrogen bonds prove that the synthesized molecules are well fit in the protein pocket.