Ogata M, Matsumoto H, Takahashi K, Shimizu S, Kida S, Murabayashi A, Shiro M, Tawara K
J Med Chem. 1987 Jun;30(6):1054-68. doi: 10.1021/jm00389a016.
To find orally active antifungal agents, novel imidazolyl- and 1,2,4-triazolylpropanolones I and related compounds II-IV were synthesized. Compounds I were derived from ketones V (method A), alpha-diketone IX (method B), alpha-hydroxy ketones X (method C), alpha-chloro ketone XII (method D), and enones VI (method E). Diols II, synthesized from I with NaBH4, were cyclized to five-membered cyclic compounds III by using N,N'-carbonyldiimidazole, thionyl chloride, N,N'-(thiocarbonyl)diimidazole, bromochloromethane, 2,2-dimethoxypropane, and cyclohexanone dimethyl ketal. Diols IV were synthesized from I by Grignard reaction (method F), hydroxymethylation of X (method G), and reaction of ketones XXI with 1-[(trimethylsily)methyl]-1,2,4-triazole (method H). Compounds I-IV were examined for their antifungal activities in vitro by evaluation of broth dilution MIC values against three species of fungi and the inhibitory effect on pseudomycelium of Candida albicans, and they were examined for oral efficacy in vivo against subacute systemic candidiasis in mice and superficial dermatophytosis in guinea pigs. Compounds 2, 12, 38, 39, and 92 exhibited strong oral antifungal activity. An asymmetric synthesis and the structure-activity relationships of the compounds examined are discussed.
为了寻找口服活性抗真菌剂，合成了新型咪唑基和1,2,4 - 三唑基丙醇酮I及相关化合物II - IV。化合物I由酮V（方法A）、α - 二酮IX（方法B）、α - 羟基酮X（方法C）、α - 氯酮XII（方法D）和烯酮VI（方法E）衍生而来。由I与硼氢化钠合成的二醇II，通过使用N,N'-羰基二咪唑、亚硫酰氯、N,N'-（硫羰基）二咪唑、溴氯甲烷、2,2 - 二甲氧基丙烷和环己酮二甲基缩酮环化得到五元环状化合物III。二醇IV通过格氏反应（方法F）、X的羟甲基化反应（方法G）以及酮XXI与1 - [(三甲基硅基)甲基]-1,2,4 - 三唑的反应（方法H）由I合成。通过评估对三种真菌的肉汤稀释MIC值以及对白色念珠菌假菌丝体的抑制作用，对化合物I - IV进行了体外抗真菌活性检测，并对其在小鼠亚急性系统性念珠菌病和豚鼠浅表皮肤癣菌病中的体内口服疗效进行了检测。化合物2、12、38、39和92表现出较强的口服抗真菌活性。讨论了所检测化合物的不对称合成及其构效关系。
