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).

• Klíčová slova
• 4-(trifluoromethyl)benzohydrazide, acetylcholinesterase inhibition, antimycobacterial activity, butyrylcholinesterase inhibition, cytostatic properties, hydrazides,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antiinfekční látky * chemická syntéza   chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory * chemická syntéza   chemie   farmakologie   MeSH
• GPI-vázané proteiny metabolismus   MeSH
• imidazoly * chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• Mycobacterium avium růst a vývoj   MeSH
• Mycobacterium kansasii růst a vývoj   MeSH
• Mycobacterium tuberculosis růst a vývoj   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• ACHE protein, human MeSH Prohlížeč
• antiinfekční látky * MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory * MeSH
• GPI-vázané proteiny MeSH
• imidazoly * MeSH

The development of novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) represents a viable approach to alleviate Alzheimer's disease. Thirty-six halogenated 2-hydroxy-N-phenylbenzamides (salicylanilides) with various substitution patterns and their esters with phosphorus-based acids were synthesized in yields of 72% to 92% and characterized. They were evaluated for in vitro inhibition of AChE from electric eel and BuChE from equine serum using modified Ellman's spectrophotometric method. The benzamides exhibited a moderate inhibition of AChE with IC50 values in a narrow concentration range from 33.1 to 85.8 µM. IC50 values for BuChE were higher (53.5-228.4 µM). The majority of derivatives inhibit AChE more efficiently than BuChE and are comparable or superior to rivastigmine-an established cholinesterases inhibitor used in the treatment of Alzheimer's disease. Phosphorus-based esters especially improved the activity against BuChE with 5-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl diethyl phosphite 5c superiority (IC50 = 2.4 µM). This derivative was also the most selective inhibitor of BuChE. It caused a mixed inhibition of both cholinesterases and acted as a pseudo-irreversible inhibitor. Several structure-activity relationships were identified, e.g., favouring esters and benzamides obtained from 5-halogenosalicylic acids and polyhalogenated anilines. Both 2-hydroxy-N-phenylbenzamides and esters share convenient physicochemical properties for blood-brain-barrier penetration and thus central nervous system delivery.

• Klíčová slova
• acetylcholinesterase, benzamides, butyrylcholinesterase, enzyme inhibition, esters, in vitro inhibition, phosphorus derivatives, salicylanilides,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• benzamidy chemie   farmakologie   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• Electrophorus MeSH
• estery chemie   farmakologie   MeSH
• fosfor chemie   MeSH
• inhibiční koncentrace 50 MeSH
• koně MeSH
• molekulární struktura MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• benzamidy MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• estery MeSH
• fosfor MeSH