Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
J Med Chem. 2010 Jan 14;53(1):282-94. doi: 10.1021/jm901207n.
A series of biphenyl analogues of the new tuberculosis drug PA-824 was prepared, primarily by coupling the known (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol with iodobenzyl halides, followed by Suzuki coupling of these iodides with appropriate arylboronic acids or by assembly of the complete biaryl side chain prior to coupling with the above alcohol. Antitubercular activity was determined under both replicating (MABA) and nonreplicating (LORA) conditions. para-Linked biaryls were the most active, followed by meta-linked and then ortho-linked analogues. A more detailed study of a larger group of para-linked analogues showed a significant correlation between potency (MABA) and both lipophilicity (CLOGP) and the electron-withdrawing properties of terminal ring substituents ( summation operatorsigma). Selected compounds were evaluated for their efficacy in a mouse model of acute Mycobacterium tuberculosis infection. In vivo activity correlated well with the stability of compounds to microsomal metabolism. Three compounds bearing combinations of lipophilic, electron-withdrawing groups achieved >200-fold higher efficacies than the parent drug.
制备了一系列新型结核药物 PA-824 的联苯类似物，主要方法是将已知的（6S）-2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]恶嗪-6-醇与碘代苄基卤化物偶联，然后将这些碘化物与适当的芳基硼酸进行铃木偶联，或者在与上述醇偶联之前组装完整的联苯侧链。在复制（MABA）和非复制（LORA）条件下测定了抗结核活性。对位连接的联苯最活跃，其次是间位连接的，然后是邻位连接的类似物。对更大一组对位连接类似物的更详细研究表明，效力（MABA）与脂溶性（CLOGP）以及末端环取代基的吸电子性质（sigma 求和运算符）之间存在显著相关性。选择的化合物在急性结核分枝杆菌感染的小鼠模型中进行了疗效评估。体内活性与化合物对微粒体代谢的稳定性密切相关。三种具有亲脂性、吸电子基团组合的化合物的疗效比母体药物高 200 多倍。
