Department of Pharmacy, University of São Paulo, SP, Brazil.
Arch Pharm (Weinheim). 2010 Feb;343(2):91-7. doi: 10.1002/ardp.200900216.
Tuberculosis is an infection caused mainly by Mycobacterium tuberculosis. A first-line antimycobacterial drug is pyrazinamide (PZA), which acts partially as a prodrug activated by a pyrazinamidase releasing the active agent, pyrazinoic acid (POA). As pyrazinoic acid presents some difficulty to cross the mycobacterial cell wall, and also the pyrazinamide-resistant strains do not express the pyrazinamidase, a set of pyrazinoic acid esters have been evaluated as antimycobacterial agents. In this work, a QSAR approach was applied to a set of forty-three pyrazinoates against M. tuberculosis ATCC 27294, using genetic algorithm function and partial least squares regression (WOLF 5.5 program). The independent variables selected were the Balaban index (J), calculated n-octanol/water partition coefficient (ClogP), van-der-Waals surface area, dipole moment, and stretching-energy contribution. The final QSAR model (N = 32, r(2) = 0.68, q(2) = 0.59, LOF = 0.25, and LSE = 0.19) was fully validated employing leave-N-out cross-validation and y-scrambling techniques. The test set (N = 11) presented an external prediction power of 73%. In conclusion, the QSAR model generated can be used as a valuable tool to optimize the activity of future pyrazinoic acid esters in the designing of new antituberculosis agents.
结核病是一种主要由结核分枝杆菌引起的感染。一线抗分枝杆菌药物是吡嗪酰胺（PZA），它部分作为一种前药被吡嗪酰胺酶激活，释放出活性物质吡嗪酸（POA）。由于吡嗪酸穿过分枝杆菌细胞壁有一定的难度，而且吡嗪酰胺耐药株不表达吡嗪酰胺酶，因此已经评估了一组吡嗪酸酯作为抗分枝杆菌药物。在这项工作中，使用遗传算法函数和偏最小二乘回归（WOLF 5.5 程序），对一组 43 种吡嗪酸酯对结核分枝杆菌 ATCC 27294 的 QSAR 方法进行了应用。所选的自变量是 Balaban 指数（J）、计算的正辛醇/水分配系数（ClogP）、范德华表面积、偶极矩和拉伸能贡献。最终的 QSAR 模型（N = 32，r(2) = 0.68，q(2) = 0.59，LOF = 0.25，LSE = 0.19）通过留一法交叉验证和 y 打乱技术进行了全面验证。测试集（N = 11）具有 73%的外部预测能力。总之，生成的 QSAR 模型可用于优化未来吡嗪酸酯在新型抗结核药物设计中的活性，是一种有价值的工具。
