N-Alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides and Their Analogues: Synthesis and Multitarget Biological Activity

Abstract

Based on the isosterism concept, we have designed and synthesized homologous N-alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides (from C1 to C18) 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 IC50 values of 27.04–106.75 µM and 58.01–277.48 µM, respectively. Some compounds exhibited lower IC50 for AChE than the clinically used drug rivastigmine. N-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 C5 to C7 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 Mycobacterium tuberculosis H37Rv and nontuberculous mycobacteria (M. avium, M. kansasii). Reflecting these results, we prepared additional analogues of the most active carboxamide (n-hexyl derivative 2f). N-Hexyl-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-amine (4) 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).

Hydrazones of 4-(Trifluoromethyl)benzohydrazide as New Inhibitors of Acetyl- and Butyrylcholinesterase

“…The hydrazide–hydrazones 2 and 3 as well as the parent compound 1 were screened for their potential to affect the function of AChE isolated from electric eel ( Ee AChE) and BuChE obtained from equine serum (EqBuChE) using Ellman’s spectrophotometric method ( Table 1 ). These enzymes of nonhuman origin were used to screen inhibitory activity and to compare the results with our previous compounds sharing a certain degree of a chemical similarity [ 23 , 24 ]. Their efficacy is expressed as the concentration leading to 50% inhibition of the enzymatic activity (IC 50 ).…”

“…The relationship between 4-hydroxybenzohydrazide-hydrazones and laccase from Trametes versicolor was studied and a competitive type of inhibition was identified [ 22 ]. In our previous study [ 23 ], N -alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides were identified as inhibitors of both AChE and BuChE. Based on here presented findings, we investigated our trifluoromethylated hydrazide–hydrazones 2 – 3 ( Table 1 ) [ 12 ] as potential inhibitors of AChE a BuChE together with their newly prepared analogues 2n – 2u .…”

Novel Inhibitors of Acetyl- and Butyrylcholinesterase Derived from Benzohydrazides: Synthesis, Evaluation and Docking Study

“…2-Acylhydrazine-1-carboxamides are a group of compounds with interesting and potentially useful biological properties utilized in drug design. They have been reported as antimycobacterial [ 1 , 2 ], antibacterial [ 3 , 4 ], antifungal [ 4 ], anticancer [ 5 ], anticonvulsant [ 6 ] and anti-inflammatory [ 3 ] agents. Importantly, hydrazine-1-carboxamides have also been reported as inhibitors of cholinesterases [ 2 , 7 ].…”

“…They have been reported as antimycobacterial [ 1 , 2 ], antibacterial [ 3 , 4 ], antifungal [ 4 ], anticancer [ 5 ], anticonvulsant [ 6 ] and anti-inflammatory [ 3 ] agents. Importantly, hydrazine-1-carboxamides have also been reported as inhibitors of cholinesterases [ 2 , 7 ].…”

“…Krátký et al [ 2 ] reported a series of N -alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides (I, Figure 1 ; n -alkyl chain R from C 1 to C 18 ) as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). All hydrazinecarboxamides exhibited dual inhibition of both AChE and BChE, with IC 50 values of 27.0–106.8 μM and 58.0–277.5 μM, respectively.…”