BackgroundTuberculosis (TB) is still a leading cause of death worldwide. Almost a third of the world's population is infected with TB bacilli, and each year approximately 8 million people develop active TB and 2 million die as a result. Today's TB treatment, which dates back to the 1970s, is long and burdensome, requiring at least 6 mo of multidrug chemotherapy. The situation is further compounded by the emergence of multidrug-resistant TB (MDR-TB) and by the infection's lethal synergy with HIV/AIDS. Global health and philanthropic organizations are now pleading for new drug interventions that can address these unmet needs in TB treatment.Methods and FindingsHere we report OPC-67683, a nitro-dihydro-imidazooxazole derivative that was screened to help combat the unmet needs in TB treatment. The compound is a mycolic acid biosynthesis inhibitor found to be free of mutagenicity and to possess highly potent activity against TB, including MDR-TB, as shown by its exceptionally low minimum inhibitory concentration (MIC) range of 0.006–0.024 μg/ml in vitro and highly effective therapeutic activity at low doses in vivo. Additionally, the results of the post-antibiotic effect of OPC-67683 on intracellular Mycobacterium tuberculosis showed the agent to be highly and dose-dependently active also against intracellular M. tuberculosis H37Rv after a 4-h pulsed exposure, and this activity at a concentration of 0.1 μg/ml was similar to that of the first-line drug rifampicin (RFP) at a concentration of 3 μg/ml. The combination of OPC-67683 with RFP and pyrazinamide (PZA) exhibited a remarkably quicker eradication (by at least 2 mo) of viable TB bacilli in the lung in comparison with the standard regimen consisting of RFP, isoniazid (INH), ethambutol (EB), and PZA. Furthermore, OPC-67683 was not affected by nor did it affect the activity of liver microsome enzymes, suggesting the possibility for OPC-67683 to be used in combination with drugs, including anti-retrovirals, that induce or are metabolized by cytochrome P450 enzymes.ConclusionsWe concluded that based on these properties OPC-67683 has the potential to be used as a TB drug to help combat the unmet needs in TB treatment.

In an effort to develop potent new antituberculosis agents that would be effective against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis, we prepared a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles substituted at the 2-position with various phenoxymethyl groups and a methyl group and investigated the in vitro and in vivo activity of these compounds. Several of these derivatives showed potent in vitro and in vivo activity, and compound 19 (OPC-67683) in particular displayed excellent in vitro activity against both drug-susceptible and drug-resistant strains of M. tuberculosis H37Rv (MIC = 0.006 microg/mL) and dose-dependent and significant in vivo efficacy at lower oral doses than rifampicin in mouse models infected with M. tuberculosis Kurono. The synthesis and structure-activity relationships of these new compounds are presented.

SummaryBlood glucose levels of streptozocin (STZ)-induced diabetic rats dropped from hyperglycemic levels to hypoglycemic levels within 24-48 h after treatment with vanadyl sulfate (VS) by intraperitoneal injection. Results of the glucose tolerance test indicated that the diabetes was completely improved by VS administration, but the plasma insulin levels were still low. Determination of both vanadyl and total vanadium in VS-treated STZ-rats suggested that the vanadyl is possibly in a pharmacologically active form. Several vanadyl complexes such as vanadyl-cysteine methyl ester (VCys), -oxalate (VOX), -malonate (VMA), -salicylaldehyde (VSA) , and -(+)-tartarate (VTA) were tested by oral administration. The order of normoglycemic effect in STZ-rats was VMA > VCys > VTA > VSA > VOX. The action of VCys was dosedependent in the range of 1-10 mg V/kg body weight, and this complex was shown to be a potent agent in restoring the normoglycemic level in STZ-induced diabetic rats.

A high-performance anode system based on a combination of mediator-polymer-modified graphite felt and bacteria capable of reducing extracellular materials shows significant potential for practical use in microbial fuel cells (MFCs).