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Article

Synthesis and Antituberculosis Activity of a Novel Series of Optically Active 6-Nitro-2,3-dihydroimidazo[2,1-b]oxazoles

Supporting Info

Hirofumi Sasaki,^† Yoshikazu Haraguchi,^† Motohiro Itotani,^† Hideaki Kuroda,^† Hiroyuki Hashizume,^‡ Tatsuo Tomishige,^‡ Masanori Kawasaki,^‡ Makoto Matsumoto,^‡ Makoto Komatsu,^† and Hidetsugu Tsubouchi*^†

Medicinal Chemistry Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan, and Microbiological Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan

J. Med. Chem., 2006, 49 (26), pp 7854–7860

DOI: 10.1021/jm060957y

Publication Date (Web): December 6, 2006

†

Medicinal Chemistry Research Institute.

‡

Microbiological Research Institute.

To whom correspondence should be addressed. Phone: +81-88-665-2126. Fax: +81-88-665-6031. E-mail: h_tsubouchi@research.otsuka.co.jp.

Abstract

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 μg/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.