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).
Highlights
The development of novel drugs involves various medicinal chemistry approaches, including the widely used isostere/bioisostere strategy [1]
2k, 2l, 2p–2q) isocyanates were prepared commercially available, we prepared them in situ using the corresponding amines and triphosgene commercially available isocyanates and the hydrazide 1 in acetonitrile
Properties containing trifluoromethyl group has been known for their toxic action on eukaryotic cells and approved as anticancer drugs [19], we investigated cytostatic properties of the
Summary
A bioisostere is a molecule that results from the Molecules 2020, 25, 2268; doi:10.3390/molecules25102268 www.mdpi.com/journal/molecules. The development of novel drugs involves various medicinal chemistry approaches, including the widely used isostere/bioisostere strategy [1]. A bioisostere is a molecule that results from the exchange of an original atom or a group of atoms for an alternative, roughly similar atom or group of atoms. Based on physical and/or chemical similarity, isosteric compounds may share analogous. It is a way to ameliorate disadvantageous features of current drugs and drug candidates, e.g., low activity, drug resistance, toxicity, poor pharmacokinetic profile, exchange of an original or aan group of atoms for an[2,3]. Alternative, roughly similar atom or group etc. It is possible to atom establish original bioactivity of atoms
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