Krátký Martin, Bősze Szilvia, Baranyai Zsuzsa, Stolaříková Jiřina, Vinšová Jarmila
Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
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.
Bioorg Med Chem Lett. 2017 Dec 1;27(23):5185-5189. doi: 10.1016/j.bmcl.2017.10.050. Epub 2017 Oct 21.
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.
鉴于基于异烟肼的腙类化合物已知的生物活性，由各种苯甲醛和脂肪族酮合成了17种4-(三氟甲基)苯甲酰肼腙作为其生物电子等排体。对这些化合物进行了体外抗结核分枝杆菌、非结核分枝杆菌（鸟分枝杆菌、堪萨斯分枝杆菌）、细菌和真菌菌株活性的筛选。还研究了最具抗菌活性的衍生物对三种细胞系的细胞生长抑制和细胞毒性特性。基于樟脑的分子4-(三氟甲基)-N'-(1,7,7-三甲基双环[2.2.1]庚烷-2-亚基)苯甲酰肼对结核分枝杆菌表现出最高的选择性抑制，最低抑菌浓度（MIC）为4 μM，而N'-(4-氯亚苄基)-4-(三氟甲基)苯甲酰肼对堪萨斯分枝杆菌表现出更强的活性（MIC = 16 μM）。N'-(5-氯-2-羟基亚苄基)-4-(三氟甲基)苯甲酰肼对包括耐甲氧西林金黄色葡萄球菌在内的革兰氏阳性菌以及光滑念珠菌和须癣毛癣菌两种真菌菌株的最低抑菌浓度值最低，范围在≤0.49 - 3.9 μM之间。在4位方便地取代亚苄基部分或存在5-氯-2-羟基亚苄基支架并同时具有足够的亲脂性对于显著的抗菌活性至关重要。这种5-氯水杨醛衍生物在浓度高达100 μM时对两种哺乳动物细胞培养物（HepG2、BMMΦ）没有任何细胞毒性，但它影响了单核细胞白血病细胞系MonoMac6的生长。
