raltegravir and Tuberculosis--Multidrug-Resistant

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.

Topics: Antitubercular Agents; Cytochrome P-450 Enzyme System; Drug Design; Drug Synergism; Glucuronosyltransferase; Half-Life; Humans; Microbial Sensitivity Tests; Microsomes, Liver; Mycobacterium tuberculosis; Nitroimidazoles; Piperazines; Pyridones; Tuberculosis, Multidrug-Resistant