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Dive into the research topics where Hiroyuki Hashizume is active.

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Featured researches published by Hiroyuki Hashizume.


PLOS Medicine | 2006

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

Makoto Matsumoto; Hiroyuki Hashizume; Tatsuo Tomishige; Masanori Kawasaki; Hidetsugu Tsubouchi; Hirofumi Sasaki; Yoshihiko Shimokawa; Makoto Komatsu

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.


Current Topics in Medicinal Chemistry | 2007

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

Makoto Matsumoto; Hiroyuki Hashizume; Hidetsugu Tsubouchi; Hirofumi Sasaki; Motohiro Itotani; Hideaki Kuroda; Tatsuo Tomishige; Masanori Kawasaki; Makoto Komatsu

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.


Antimicrobial Agents and Chemotherapy | 2017

Delamanid Kills Dormant Mycobacteria In Vitro and in a Guinea Pig Model of Tuberculosis

Xiuhao Chen; Hiroyuki Hashizume; Tatsuo Tomishige; Izuru Nakamura; Miki Matsuba; Mamoru Fujiwara; Ryuki Kitamoto; Erina Hanaki; Yoshio Ohba; Makoto Matsumoto

ABSTRACT Tuberculosis (TB) treatment is long and requires multiple drugs, likely due to various phenotypes of TB bacilli with variable drug susceptibilities. Drugs with broad activity are urgently needed. This study aimed to evaluate delamanids activity against growing or dormant bacilli in vitro as well as in vivo. Cultures of Mycobacterium bovis BCG Tokyo under aerobic and anaerobic conditions were used to study the activity of delamanid against growing and dormant bacilli, respectively. Delamanid exhibited significant bactericidal activity against replicating and dormant bacilli at or above concentrations of 0.016 and 0.4 mg/liter, respectively. To evaluate delamanids antituberculosis activity in vivo, we used a guinea pig model of chronic TB infection in which the lung lesions were similar to those in human TB disease. In the guinea pig TB model, a daily dose of 100 mg delamanid/kg of body weight for 4 or 8 weeks demonstrated strong bactericidal activity against Mycobacterium tuberculosis. Importantly, histological examination revealed that delamanid killed TB bacilli within hypoxic lesions of the lung. The combination regimens containing delamanid with rifampin and pyrazinamide or delamanid with levofloxacin, ethionamide, pyrazinamide, and amikacin were more effective than the standard regimen (rifampin, isoniazid, and pyrazinamide). Our data show that delamanid is effective in killing both growing and dormant bacilli in vitro and in the guinea pig TB model. Adding delamanid to current TB regimens may improve treatment outcomes, as demonstrated in recent clinical trials with pulmonary multidrug-resistant (MDR) TB patients. Delamanid may be an important drug for consideration in the construction of new regimens to shorten TB treatment duration.


Journal of Medicinal Chemistry | 2006

Synthesis and antituberculosis activity of a novel series of optically active 6 -nitro -2,3 -dihydroimidazo [2,1-b ]oxazoles

Hirofumi Sasaki; Yoshikazu Haraguchi; Motohiro Itotani; Hideaki Kuroda; Hiroyuki Hashizume; Tatsuo Tomishige; Masanori Kawasaki; Makoto Matsumoto; Makoto Komatsu; Hidetsugu Tsubouchi


Archive | 2003

2,3-DIHYDRO-6-NITROIMIDAZO[2,1-b]OXAZOLES

Hidetsugu Tsubouchi; Hirofumi Sasaki; Hideaki Kuroda; Motohiro Itotani; Takeshi Hasegawa; Yoshikazu Haraguchi; Takeshi Kuroda; Takayuki Matsuzaki; Kuninori Tai; Makoto Komatsu; Makoto Matsumoto; Hiroyuki Hashizume; Tatsuo Tomishige; Yuji Seike; Masanori Kawasaki; Takumi Sumida; Shin Miyamura


Bioorganic & Medicinal Chemistry | 2008

Halicyclamine A, a marine spongean alkaloid as a lead for anti-tuberculosis agent.

Masayoshi Arai; Mari Sobou; Catherine Vilchèze; Anthony D. Baughn; Hiroyuki Hashizume; Patamaporn Pruksakorn; Shunsuke Ishida; Makoto Matsumoto; William R. Jacobs; Motomasa Kobayashi


Archive | 2004

2,3-Dihydro-6-Nitroimidazo (2,1-b) Oxazole Compounds for the Treatment of Tuberculosis

Hidetsugu Tsubouchi; Hirofumi Sasaki; Motohiro Itotani; Yoshikazu Haraguchi; Shin Aza Kitakawamukai Ninokoshi Miyamura; Makoto Matsumoto; Hiroyuki Hashizume; Tatsuo Tomishige; Masanori Kawasaki; Kinue Ohguro; Takumi Sumida; Takeshi Hasegawa; Kazuho Tanaka; Isao Takemura


Archive | 2006

Antituberculous composition comprising oxazole compounds

Makoto Matsumoto; Hiroyuki Hashizume; Tatsuo Tomishige; Masanori Kawasaki; Yoshihiko Shimokawa


Archive | 2012

6,7-DIHYDROIMIDAZO[2,1-B][1,3]OXAZINE BACTERICIDES

Yoshikazu Kawano; Yoshikazu Haraguchi; Hirofumi Sasaki; Yukitaka Uematsu; Hidetsugu Tsubouchi; Hiromi Yata; Hiroshi Shimizu; Kazuho Kohashi; Motohiro Itotani; Kuninori Tai; Isao Takemura; Mikayo Hayashi; Hiroyuki Hashizume; Miki Matsuba; Izuru Nakamura; Xiuhao Chen; Makoto Matsumoto


Archive | 2006

Antituberculosis drug combination comprising oxazole compounds

Makoto Matsumoto; Hiroyuki Hashizume; Tatsuo Tomishige; Masanori Kawasaki; Yoshihiko Shimokawa

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