Hidetsugu Tsubouchi

OPC-67683, a Nitro-Dihydro-Imidazooxazole Derivative with Promising Action against Tuberculosis In Vitro and In Mice

Background Tuberculosis (TB) is still a leading cause of death worldwide. Almost a third of the worlds population is infected with TB bacilli, and each year approximately 8 million people develop active TB and 2 million die as a result. Todays 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 infections 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 Findings Here 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. Conclusions We 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.

Screening for Novel Antituberculosis Agents that are Effective Against Multidrug Resistant Tuberculosis

The challenges in preventing and controlling tuberculosis are further complicated by the deadly rise of multi-drug-resistant tuberculosis (MDR-TB). Recognizing the seriousness of the situation, we initiated a program to screen new agents that would satisfy these unmet needs and have a favorable safety profile. Mycobacteria are well known for their lipid-rich properties. In Mycobacterium tuberculosis, mycolic acid in particular has been established the wall component related to the pathogenesis in the host. There are approximately 250 identified genes related to biosynthesis of the lipid turnover that contain InhA, the main target of isoniazid. Thus, the logical approach for developing a chemotherapy agent against tubercle bacilli included screening compounds that could inhibit the biosyntheses of mycolic acid and that had a novel chemical structure to ensure improved efficacy against MDR-TB. Some of the screening systems established for those purposes and some of the candidates are outlined.

Synthesis and structure-activity relationships of novel antiseptics

Abstract For the purpose of developing new antiseptics, we searched for compounds having high biocidal activity covering both gram-positive and gram-negative bacteria. Accordingly, we designed 1,5-disubstituted biguanides and synthesized them using two alternative efficient reaction schemes. The bactericidal activity of these biguanides was assayed by the micro titration plate method. Among the biguanides synthesized, 3,4-dichlorobenzyl derivatives were found to exhibit particularly high bactericidal activity. Ultimately, compound 11 was chosen as a candidate novel antiseptic, which is currently under continued evaluation.

A convenient one pot asymmetric synthesis of cis-β-lactams: Key precursors for optically active 2-oxaisocephems

Abstract Asymmetric annelation of the disilylated imine 3 generated in situ from D-threonine 2 with arid chlorides 4 and triethylamine followed by esterificadon provided cis-β-lactams 5 and 6 in excellent yields with high diastereoselectivity under mild conditions. And conversion of compounds 5 into 15 , derivatives of 2-oxaisocephems having a thio-subsdtuted methyl group at the 3-position and a 2-aminothiazol-4-yl moiety at the 7-position, is described. Biological activities of the new compounds are presented. In particular, 15b showed potent antibacterial activity against Methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis which cause a serious clinical problem in antibacterial chemotherapy.

Synthesis and biological activity of new optically active 2-oxaisocephems : 3-(N-alkylpyridinium-4'-thio)methyl derivatives

Abstract A convenient synthesis of new optically active 2-oxaisocephems with (N-alkylpyridinium-4′-thio)methyl groups at the 3-position and their biological activities are described. In particular, 10b and 10d having [2-(2-aminothiazol-4-yl)-2-(Z)-cyclopentyloxyimino]acetamido group at the 7-position were found to possess high in vivo potency and showed excellent in vivo efficacy.

Long-term safety profile of tolvaptan in autosomal dominant polycystic kidney disease patients: TEMPO Extension Japan Trial [Corrigendum]

[This corrects the article on p. 93 in vol. 9, PMID: 29123425.].