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Article

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

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Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
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MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös Loránd University, Pázmány Péter Sétány 1/A, H-1117, 1518 Budapest, Hungary
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Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
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Department of Chemistry, Faculty of Science, J. E. Purkinje University, České mládeže 8, 400 96 Ústí nad Labem, Czech Republic
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Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské námĕstí 7, 702 00 Ostrava, Czech Republic
*
Author to whom correspondence should be addressed.
Academic Editors: Diego Muñoz-Torrero and Beatriz De Pascual-Teresa
Molecules 2020, 25(10), 2268; https://doi.org/10.3390/molecules25102268
Received: 21 April 2020 / Revised: 7 May 2020 / Accepted: 9 May 2020 / Published: 12 May 2020
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). View Full-Text
Keywords: antimycobacterial activity; acetylcholinesterase inhibition; butyrylcholinesterase inhibition; cytostatic properties; hydrazides; 4-(trifluoromethyl)benzohydrazide antimycobacterial activity; acetylcholinesterase inhibition; butyrylcholinesterase inhibition; cytostatic properties; hydrazides; 4-(trifluoromethyl)benzohydrazide
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MDPI and ACS Style

Krátký, M.; Baranyai, Z.; Štěpánková, Š.; Svrčková, K.; Švarcová, M.; Stolaříková, J.; Horváth, L.; Bősze, S.; Vinšová, J. N-Alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides and Their Analogues: Synthesis and Multitarget Biological Activity. Molecules 2020, 25, 2268. https://doi.org/10.3390/molecules25102268

AMA Style

Krátký M, Baranyai Z, Štěpánková Š, Svrčková K, Švarcová M, Stolaříková J, Horváth L, Bősze S, Vinšová J. N-Alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides and Their Analogues: Synthesis and Multitarget Biological Activity. Molecules. 2020; 25(10):2268. https://doi.org/10.3390/molecules25102268

Chicago/Turabian Style

Krátký, Martin, Zsuzsa Baranyai, Šárka Štěpánková, Katarína Svrčková, Markéta Švarcová, Jiřina Stolaříková, Lilla Horváth, Szilvia Bősze, and Jarmila Vinšová. 2020. "N-Alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides and Their Analogues: Synthesis and Multitarget Biological Activity" Molecules 25, no. 10: 2268. https://doi.org/10.3390/molecules25102268

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