Wächter G A, Davis M C, 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. 1998 Jun 18;41(13):2436-8. doi: 10.1021/jm9708745.
Pyrazines and pyridines substituted with alkylated tetrazoles, esterified vinylogous carboxylic acids, and ketosulfides were synthesized as precursors of antimycobacterial agents which, after penetration of the mycobacterial cell wall, could be biotransformed by esterases or peroxidase-catalases. The expected products are tetrazoles, a vinylogous carboxylic acid, and CH-acidic ketosulfoxides, isosteres of pyrazinoic and nicotinic acids, which should inhibit mycobacterial growth when released inside the bacterial cell. The growth inhibitory activity of the synthesized compounds against the H37Rv strain of Mycobacterium tuberculosis was determined to assess the viability of this concept. It was shown that all of the compounds designed as lipophilic precursors were more active than the unmodified polar isosteres of pyrazinoic and nicotinic acids.
合成了用烷基化四氮唑、酯化的乙烯型羧酸和酮硫醚取代的吡嗪和吡啶，作为抗分枝杆菌剂的前体，这些前体在穿透分枝杆菌细胞壁后，可被酯酶或过氧化物酶-过氧化氢酶进行生物转化。预期产物为四氮唑、乙烯型羧酸和CH-酸性酮亚砜，它们是吡嗪酸和烟酸的电子等排体，当在细菌细胞内释放时应能抑制分枝杆菌生长。测定了合成化合物对结核分枝杆菌H37Rv菌株的生长抑制活性，以评估这一概念的可行性。结果表明，所有设计为亲脂性前体的化合物都比未修饰的吡嗪酸和烟酸的极性电子等排体更具活性。
