1,3-苯并恶唑-4-腈作为具有高效体内疗效的新型抗真菌剂的构效关系

Structure-activity relationships of 1,3-benzoxazole-4-carbonitriles as novel antifungal agents with potent in vivo efficacy.

作者信息

Kuroyanagi Jun-ichi, Kanai Kazuo, Horiuchi Takao, Takeshita Hiroshi, Kobayashi Shozo, Achiwa Issei, Yoshida Kumi, Nakamura Koichi, Kawakami Katsuhiro

机构信息

Lead Discovery & Optimization Research Laboratories II, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

出版信息

Chem Pharm Bull (Tokyo). 2011;59(3):341-52. doi: 10.1248/cpb.59.341.

DOI:10.1248/cpb.59.341

PMID:21372416

Abstract

A series of 1,3-benzoxazole-4-carbonitriles was synthesized and evaluated for its antifungal activity, solubility, and metabolic stability. Among those compounds, 4-cyano-N,N,5-trimethyl-7-[(3S)-3-methyl-3-(methylamino)pyrrolidin-1-yl]-6-phenyl-1,3-benzoxazole-2-carboxamide (16b) exhibited potent in vitro activity against Candida species, higher water solubility, and improved metabolic stability compared to lead compound 1. Compound 16b showed potent in vivo efficacy against mice Candida infection models and good bioavailability in rats.

摘要

合成了一系列1,3-苯并恶唑-4-腈，并对其抗真菌活性、溶解度和代谢稳定性进行了评估。在这些化合物中，4-氰基-N,N,5-三甲基-7-[(3S)-3-甲基-3-(甲氨基)吡咯烷-1-基]-6-苯基-1,3-苯并恶唑-2-甲酰胺（16b）与先导化合物1相比，对念珠菌属表现出强大的体外活性、更高的水溶性和改善的代谢稳定性。化合物16b在小鼠念珠菌感染模型中显示出强大的体内疗效，在大鼠中具有良好的生物利用度。