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 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.


RESULTS
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 microg/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 microg/ml was similar to that of the first-line drug rifampicin (RFP) at a concentration of 3 microg/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.
Matsumoto
Makoto
M
Microbiological Research Institute, Otsuka Pharmaceutical, Tokushima, Japan. m_matsumoto@research.otsuka.co.jp
Hashizume
Hiroyuki
H
Tomishige
Tatsuo
T
Kawasaki
Masanori
M
Tsubouchi
Hidetsugu
H
Sasaki
Hirofumi
H
Shimokawa
Yoshihiko
Y
Komatsu
Makoto
M
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001769:Blood / Q000382:microbiology; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology; D008322:Mammals; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000382:microbiology; D009161:Mycobacterium / Q000187:drug effects / Q000378:metabolism; D009163:Mycobacterium bovis / Q000187:drug effects / Q000378:metabolism; D009171:Mycolic Acids / Q000037:antagonists & inhibitors; D009593:Nitroimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D014376:Tuberculosis / Q000097:blood / Q000188:drug therapy / Q000517:prevention & control*
D000995:Antitubercular Agents; D009171:Mycolic Acids; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles