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).

• Keywords
• 4-(trifluoromethyl)benzohydrazide, acetylcholinesterase inhibition, antimycobacterial activity, butyrylcholinesterase inhibition, cytostatic properties, hydrazides,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Anti-Infective Agents * chemical synthesis   chemistry   pharmacology   MeSH
• Hep G2 Cells MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors * chemical synthesis   chemistry   pharmacology   MeSH
• GPI-Linked Proteins metabolism   MeSH
• Imidazoles * chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Mycobacterium avium growth & development   MeSH
• Mycobacterium kansasii growth & development   MeSH
• Mycobacterium tuberculosis growth & development   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• ACHE protein, human MeSH Browser
• Anti-Infective Agents * MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors * MeSH
• GPI-Linked Proteins MeSH
• Imidazoles * MeSH

This report presents a new modification of the isoniazid (INH) structure linked with different anilines via a carbonyl group obtained by two synthetic procedures and with N-substituted 5-(pyridine-4-yl)-1,3,4-oxadiazole-2-amines prepared by their cyclisation. All synthesised derivatives were characterised by IR, NMR, MS and elemental analyses and were evaluated in vitro for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium avium 330/88, Mycobacterium kansasii 235/80 and one clinical isolated strain of M. kansasii 6509/96. 2-Isonicotinoyl-N-(4-octylphenyl)hydrazinecarboxamide displayed an in vitro efficacy comparable to that of INH for M. tuberculosis with minimum inhibitory concentrations (MICs) of 1-2 μM. Among the halogenated derivatives, the best anti-tuberculosis activity was found for 2-isonicotinoyl-N-(2,4,6-trichlorophenyl)hydrazinecarboxamide (MIC=4 μM). In silico modelling on the enoyl-acyl carrier protein reductase InhA confirmed that longer alkyl substituents are advantageous for the interactions and affinity to InhA. Most of the hydrazinecarboxamides, especially those derived from 4-alkylanilines, exhibited significant activity against INH-resistant nontuberculous mycobacteria.

• MeSH
• Amines chemistry   MeSH
• Aniline Compounds chemistry   MeSH
• Antitubercular Agents chemical synthesis   pharmacology   MeSH
• Mycobacterium Infections, Nontuberculous microbiology   MeSH
• Azoles chemistry   MeSH
• Drug Resistance, Bacterial MeSH
• Bacterial Proteins antagonists & inhibitors   chemistry   MeSH
• Cyclization MeSH
• Isoniazid analogs & derivatives   chemical synthesis   pharmacology   MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium avium drug effects   enzymology   growth & development   MeSH
• Mycobacterium kansasii drug effects   enzymology   growth & development   isolation & purification   MeSH
• Mycobacterium tuberculosis drug effects   enzymology   growth & development   MeSH
• Oxidoreductases antagonists & inhibitors   chemistry   MeSH
• Pyridines chemistry   MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Amines MeSH
• aniline MeSH Browser
• Aniline Compounds MeSH
• Antitubercular Agents MeSH
• Azoles MeSH
• Bacterial Proteins MeSH
• InhA protein, Mycobacterium MeSH Browser
• Isoniazid MeSH
• Oxidoreductases MeSH
• Pyridines MeSH