Nair Vasu, Okello Maurice O, Mangu Naveen K, Seo Byung I, Gund Machhindra G
UGA Center for Drug Discovery and the College of Pharmacy, University of Georgia, R.C. Wilson Pharmacy, Room 320A, Athens, GA 30602, USA.
UGA Center for Drug Discovery and the College of Pharmacy, University of Georgia, R.C. Wilson Pharmacy, Room 320A, Athens, GA 30602, USA.
Bioorg Med Chem Lett. 2015 Mar 15;25(6):1269-73. doi: 10.1016/j.bmcl.2015.01.050. Epub 2015 Jan 28.
Multi-drug resistant tuberculosis (MDR-TB) is emerging as a serious global health problem, which has been elevated through co-infection involving HIV and MDR-Mtb. The discovery of new compounds with anti-MDR TB efficacy and favorable metabolism profiles is an important scientific challenge. Using computational biology and ligand docking data, we have conceived a multifunctional molecule, 2, as a potential anti-MDR TB agent. This compound was produced through a multi-step synthesis. It exhibited significant in vitro activity against MDR-TB (MIC 1.56μg/mL) and its half-life (t1/2) in human liver microsomes was 14.4h. The metabolic profiles of compound 2 with respect to human cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) isozymes were favorable. Compound 2 also had relatively low in vitro cytotoxicity in uninfected macrophages. It displayed synergistic behavior against MDR-TB in combination with PA-824. Interestingly, compound 2 also displayed in vitro anti-HIV activity.
耐多药结核病（MDR-TB）正成为一个严重的全球健康问题，通过HIV和耐多药结核分枝杆菌（MDR-Mtb）的合并感染，这一问题愈发严重。发现具有抗耐多药结核病疗效且代谢特征良好的新化合物是一项重要的科学挑战。利用计算生物学和配体对接数据，我们构想了一种多功能分子2，作为一种潜在的抗耐多药结核病药物。该化合物通过多步合成制备。它对耐多药结核病表现出显著的体外活性（MIC 1.56μg/mL），在人肝微粒体中的半衰期（t1/2）为14.4小时。化合物2相对于人细胞色素P450（CYP）和尿苷5'-二磷酸葡萄糖醛酸转移酶（UGT）同工酶的代谢特征良好。化合物2在未感染的巨噬细胞中体外细胞毒性也相对较低。它与PA-824联合使用时对耐多药结核病表现出协同作用。有趣的是，化合物2还表现出体外抗HIV活性。
