Synthesis and biological evolution of hydrazones derived from 4-(trifluoromethyl)benzohydrazide |
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Authors: | Martin Krátký Szilvia Bősze Zsuzsa Baranyai Jiřina Stolaříková Jarmila Vinšová |
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Affiliation: | 1. Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic;2. MTA-ELTE Research Group of Peptide Chemistry, Eötvös Loránd University, Pázmány Péter Sétány 1/A, Budapest, H-1117, P.O. Box 32, 1518 Budapest 112, Hungary;3. Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské náměstí 7, 702 00 Ostrava, Czech Republic |
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Abstract: | Reflecting the known biological activity of isoniazid-based hydrazones, seventeen hydrazones of 4-(trifluoromethyl)benzohydrazide as their bioisosters were synthesized from various benzaldehydes and aliphatic ketones. The compounds were screened for their in vitro activity against Mycobacterium tuberculosis, nontuberculous mycobacteria (M. avium, M. kansasii), bacterial and fungal strains. The most antimicrobial potent derivatives were also investigated for their cytostatic and cytotoxic properties against three cell lines. Camphor-based molecule, 4-(trifluoromethyl)-N′-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)benzohydrazide, exhibited the highest and selective inhibition of M. tuberculosis with the minimum inhibitory concentration (MIC) of 4?µM, while N′-(4-chlorobenzylidene)-4-(trifluoromethyl)benzohydrazide was found to be superior against M. kansasii (MIC?=?16?µM). N′-(5-Chloro-2-hydroxybenzylidene)-4-(trifluoromethyl)benzohydrazide showed the lowest MIC values for gram-positive bacteria including methicillin-resistant Staphylococcus aureus as well as against two fungal strains of Candida glabrata and Trichophyton mentagrophytes within the range of ≤0.49–3.9?µM. The convenient substitution of benzylidene moiety at the position 4 or the presence of 5-chloro-2-hydroxybenzylidene scaffold concomitantly with a sufficient lipophilicity are essential for the noticeable antimicrobial activity. This 5-chlorosalicylidene derivative avoided any cytotoxicity on two mammalian cell cultures (HepG2, BMMΦ) up to the concentration of 100?µM, but it affected the growth of MonoMac6 cells. |
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Keywords: | BAC bacitracin murine bone marrow culture-derived macrophages FLU fluconazole INH isoniazid MRSA NTM non-tuberculous (atypical) mycobacteria Antibacterial activity Antifungal activity Cytostasis Cytotoxicity Hydrazone Nontuberculous mycobacteria 4-(Trifluoromethyl)benzohydrazide |
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