Strong In Vitro Activities of Two New Rifabutin Analogs against Multidrug-Resistant Mycobacterium tuberculosis

Abstract

Two new rifabutin analogs, RFA-1 and RFA-2, show high in vitro antimycobacterial activities against Mycobacterium tuberculosis. MIC values of RFA-1 and RFA-2 were <0.02 g/ml against rifamycin-susceptible strains and 0.5 g/ml against a wide selection of multidrug-resistant strains, compared to >50 g/ml for rifampin and 10 g/ml for rifabutin. Molecular dynamic studies indicate that the compounds may exert tighter binding to mutants of RNA polymerase that have adapted to the rifamycins.

Structure-Based Design of Novel Benzoxazinorifamycins with Potent Binding Affinity to Wild-Type and Rifampin-Resistant Mutant Mycobacterium tuberculosis RNA Polymerases

“…The solution was concentrated, and the residue was distributed between dichloromethane and 5% aqueous sodium carbonate. The organic phase was dried and concentrated to an orange oil that was purified by flash silica gel chromatography, eluting with dichloromethane: methanol/NH 4 150.8, 137.4, 135.6, 132.8, 130.9, 129.2, 128.7, 128.2, 127.0, 119.3, 105.8, 105.6, 70.9, 69.3, 58.6, 57.8, 53.3, 53.0, 44.7 1-(4-(4-(3-(Benzyloxy)-2-nitrophenoxy)butyl)piperazin-1-yl)-2-(1H-imidazol-1-yl)ethanone (10). Trifluoroacetic acid (2 mL) was added dropwise to a solution of 9b (0.505 g, 1.04 mmol) in dichloromethane (8 mL), and the resultant mixture was stirred at room temperature for 3 h. The solution was concentrated to leave 9c (0.52 g, quantitative) as the crystalline trifluoroacetate salt.…”

“…4,5 Drugs that are active against resistant forms of TB are less potent, more toxic and need to be taken for an extended period of time (≥18 months). The recent emergence of virtually untreatable extensively drugresistant TB (XDR-TB) poses a new threat to TB control worldwide.…”

Rifabutin and rifampin resistance levels and associated rpoB mutations in clinical isolates of Mycobacterium tuberculosis complex

“…Although the effectiveness of RFB in treating patients with drug-susceptible TB has been demonstrated, documentation of successful treatment of MDR-TB patients with RFB, even in patients whose isolates are susceptible in vitro to RFB, is limited (2 – 5). This may partly be due to general concerns about potential cross-resistance among the rifamycins and the fact that clinical efficacy of RFB for treatment of RIF-resistant strains in MDR-TB patients has not yet been well-established (2, 6 – 10). …”

New treatment options for multidrug-resistant tuberculosis

“…They are active against both replicating extracellular and latent intracellular MTB [Cole and Riccardi, 2011]. With the exception of ciprofloxacin, they have an EBA similar to H [Garcia et al 2010;Gillespie, 2002;Sirgel et al 1997]. These drugs are generally well tolerated and have the convenience of once daily dosing.…”

“…It is also the favored rifamycin in patients with HIV taking protease inhibitors since it has the most modest effect on CYP450 enzyme induction, approximately 40% of that seen with R [Mitnick et al 2009;Nuermberger et al 2010]. There are other investigational rifamycins which may also be effective against R-resistant strains [Garcia et al 2010]. Based on evidence in a murine model, daily or thrice weekly dosing of rifapentine, another rifamycin, in a regimen where H is replaced by moxifloxacin, may allow TB treatment to be shortened from 6 to 3 months [Rosenthal et al 2007].…”