Gezginci M H, Martin A R, Franzblau S G
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA.
J Med Chem. 2001 May 10;44(10):1560-3. doi: 10.1021/jm000350w.
Pyridines and pyrazines substituted with 1,2,4-oxadiazole-5-ones, 1,2,4-oxadiazole-5-thiones, and 1,3,4-oxathiazoline-2-ones were synthesized and tested against Mycobacterium tuberculosis. The two former ring systems were documented in the literature to act as carboxylic acid isosteres. The latter series was synthesized as possible synthetic intermediates to 1,2,4-thiadiazole-3-ones and was included in this study due to their interesting activity. Pivaloyloxymethyl derivatives of the isosteres were also prepared in order to increase their lipophilicity and therefore improve their cellular permeability. The derivatized isosteres were expected to be biotransformed by esterases to the active species after penetration of the mycobacterial cell wall. Biological properties of the compounds were compared with the unmodified polar isosteres of pyrazinoic and nicotinic acids. The majority of the compounds exhibited activities ranging from 0.5 to 16 times the potency of pyrazinamide.
合成了用1,2,4-恶二唑-5-酮、1,2,4-恶二唑-5-硫酮和1,3,4-恶噻唑啉-2-酮取代的吡啶和吡嗪，并对其进行了抗结核分枝杆菌测试。文献记载前两种环系可作为羧酸电子等排体。后一系列化合物作为1,2,4-噻二唑-3-酮的可能合成中间体进行合成，因其有趣的活性而被纳入本研究。还制备了电子等排体的新戊酰氧甲基衍生物，以增加其亲脂性，从而提高其细胞通透性。预期衍生化的电子等排体在穿透分枝杆菌细胞壁后会被酯酶生物转化为活性物质。将这些化合物的生物学特性与未修饰的吡嗪酸和烟酸极性电子等排体进行了比较。大多数化合物的活性是吡嗪酰胺的0.5至16倍。
