ANTIFUNGAL AGENTS .9. 3-ARYL-4-[ALPHA-(1H-IMIDAZOL-1-YL)ARYLMETHYL]PYRROLES - A NEW CLASS OF POTENT ANTICANDIDA AGENTS
ANTIFUNGAL AGENTS .9. 3-ARYL-4-[ALPHA-(1H-IMIDAZOL-1-YL)ARYLMETHYL]PYRROLES - A NEW CLASS OF POTENT ANTICANDIDA AGENTS
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DOI：
10.1021/jm00021a011
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发表时间：
1995-10-13
影响因子：
7.3
通讯作者：
STRIPPOLI, V
中科院分区：
文献类型：
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作者：
ARTICO, M;DISANTO, R;STRIPPOLI, V
描述了一类新的有效抗真菌剂，即3-芳基-4-[α-（1H-咪唑-1-基）芳基甲基]-吡咯。这些化合物与联苯苄唑和硝吡咯有关，这两种化合物属于抗真菌药物类别。以1，3-二芳基-2-丙烯-1-酮为原料，与对甲苯磺酰甲基异腈反应，得到3-芳酰基-4-芳基吡咯。所得化合物经氢化铝锂还原得到相应的醇类化合物，再与1，1 '-羰基二咪唑反应得到所需的咪唑衍生物。通过上述方法制备了在3-芳基吡咯结构中引入（芳基甲基）咪唑部分的44个新吡咯，并在体外测试了其对白色念珠菌和念珠菌属的抑制作用。在供试化合物中，发现10个化合物对C.白色念珠菌。活性最强的衍生物（27）的MIC（90）是联苯苄唑的两倍，活性是咪康唑和酮康唑的4倍。另外9个化合物的抗真菌活性与联苯苄唑的活性相当，分别为100%和100%。活性是咪康唑和酮康唑的2倍。在体内测试的衍生物21和27针对C.白色念珠菌A（170）对家兔皮肤念珠菌病有很好的疗效。化合物27、7和其他相关吡咯（19、35、36、38、39和49）的药理学研究正在进行中，以选择其中之一作为临床实验的潜在候选者。
A new class of potent antifungal agents, namely, 3-aryl-4-[alpha-(1H-imidazol-1-yl)arylmethyl]-pyrroles, is described. These compounds are related to bifonazole and pyrrolnitrin, two compounds belonging to the class of antimycotic drugs. The synthesis of the title pyrroles has been performed starting from 1,3-diaryl-2-propen-1-ones, which were reacted with tosylmethyl isocyanide to give 3-aroyl-4-arylpyrroles. Reduction of the resulting compounds by lithium alumium hydride furnished the related alcohols, which were treated with 1,1'-carbonyldiimidazole to afford the required imidazole derivatives. Forty-four new pyrroles which incorporate an (arylmethyl)imidazole moiety in the 3-arylpyrrole structure were prepared by the above procedure and tested in vitro against Candida albicans and Candida spp. Among test compounds, 10 were found to be highly active against C. albicans. The most active derivative (27) was twice as potent (MIC(90)) as bifonazole, and its activity was 4 times greater than those of miconazole and ketoconazole. The other nine compounds showed antifungal activity of the same order of that of bifonazole and were ca. 2 times as active as miconazole and ketoconazole. Derivatives 21 and 27 tested in vivo against C. albicans A(170) were shown to be highly effective in rabbit skin candidosis. Pharmacological studies on compounds 27;7 and other related pyrroles (19, 35, 36, 38, 39, and 49) are in progress to select one of them as a potential candidate for clinical experiments.