N-Alkyl-2-4-(trifluoromethyl)benzoylhydrazine-1-carboxamides and Their Analogues: Synthesis and Multitarget Biological Activity

摘要

Based on the isosterism concept, we have designed and synthesized homologous -alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides (from C to C ) as potential antimicrobial agents and enzyme inhibitors. They were obtained from 4-(trifluoromethyl)benzohydrazide by three synthetic approaches and characterized by spectral methods. The derivatives were screened for their inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) via Ellman’s method. All the hydrazinecarboxamides revealed a moderate inhibition of both AChE and BuChE, with IC values of 27.04–106.75 µM and 58.01–277.48 µM, respectively. Some compounds exhibited lower IC for AChE than the clinically used drug rivastigmine. -Tridecyl/pentadecyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides were identified as the most potent and selective inhibitors of AChE. For inhibition of BuChE, alkyl chain lengths from C to C are optimal substituents. Based on molecular docking study, the compounds may work as non-covalent inhibitors that are placed in a close proximity to the active site triad. The compounds were evaluated against H Rv and nontuberculous mycobacteria ( , ). Reflecting these results, we prepared additional analogues of the most active carboxamide ( -hexyl derivative ). -Hexyl-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-amine ( ) exhibited the lowest minimum inhibitory concentrations within this study (MIC ≥ 62.5 µM), however, this activity is mild. All the compounds avoided cytostatic properties on two eukaryotic cell lines (HepG2, MonoMac6).