Synthesis and biological activities of benzofuran antifungal agents targeting fungal N-myristoyltransferase |
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Authors: | Masubuchi Miyako Ebiike Hirosato Kawasaki Ken-ichi Sogabe Satoshi Morikami Kenji Shiratori Yasuhiko Tsujii Shinji Fujii Toshihiko Sakata Kiyoaki Hayase Michiko Shindoh Hidetoshi Aoki Yuko Ohtsuka Tatsuo Shimma Nobuo |
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Affiliation: | Chugai Pharmaceutical Kamakura Research Center (formerly Nippon Roche Research Center), 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. |
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Abstract: | The C-4 side chain modification of lead compound 1 has resulted in the identification of a potent and selective Candida albicans N-myristoyltransferase (CaNmt) inhibitor RO-09-4609, which exhibits antifungal activity against C. albicans in vitro. Further modification of its C-2 substituent has led to the discovery of RO-09-4879, which exhibits antifungal activity in vivo. The drug design is based on X-ray crystal analysis of a CaNmt complex with benzofuran derivative 4a. The optimization incorporates various biological investigations including a quasi in vivo assay and pharmacokinetic study. The computer aided drug design, synthesis, structure-activity relationships, and biological properties of RO-09-4879 are described in detail. |
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