title: A novel molecule with notable activity against multi-drug resistant tuberculosis.
abstract: 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.
authors: UGA Center for Drug Discovery and the College of Pharmacy, University of Georgia, R.C. Wilson Pharmacy, Room 320A, Athens, GA 30602, USA. Electronic address: vnair@uga.edu.
authors: Vasu
authors: V
authors: Nair
authors: UGA Center for Drug Discovery and the College of Pharmacy, University of Georgia, R.C. Wilson Pharmacy, Room 320A, Athens, GA 30602, USA.
authors: Maurice O
authors: MO
authors: Okello
authors: UGA Center for Drug Discovery and the College of Pharmacy, University of Georgia, R.C. Wilson Pharmacy, Room 320A, Athens, GA 30602, USA.
authors: Naveen K
authors: NK
authors: Mangu
authors: UGA Center for Drug Discovery and the College of Pharmacy, University of Georgia, R.C. Wilson Pharmacy, Room 320A, Athens, GA 30602, USA.
authors: Byung I
authors: BI
authors: Seo
authors: UGA Center for Drug Discovery and the College of Pharmacy, University of Georgia, R.C. Wilson Pharmacy, Room 320A, Athens, GA 30602, USA.
authors: Machhindra G
authors: MG
authors: Gund
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004357:Drug Synergism; D014453:Glucuronosyltransferase / Q000737:chemistry / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009593:Nitroimidazoles / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018088:Tuberculosis, Multidrug-Resistant
chemical_list: C000603771:1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-hydroxybut-2-ene-1,4-dione; D000995:Antitubercular Agents; D009593:Nitroimidazoles; D010879:Piperazines; D011728:Pyridones; C410767:pretomanid; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase
keywords: Anti-MDR TB; CYP and UGT profiles; Drug discovery; Synergism