Chowdhury S F, Villamor V B, Guerrero R H, Leal I, Brun R, Croft S L, Goodman J M, Maes L, Ruiz-Perez L M, Pacanowska D G, Gilbert I H
Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, UK.
J Med Chem. 1999 Oct 21;42(21):4300-12. doi: 10.1021/jm981130+.
This paper concerns the design, synthesis, and evaluation of inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Initially study was made of the structures of the leishmanial and human enzyme active sites to see if there were significant differences which could be exploited for selective drug design. Then a series of compounds were synthesized based on 5-benzyl-2, 4-diaminopyrimidines. These compounds were assayed against the protozoan and human enzymes and showed selectivity for the protozoan enzymes. The structural data was then used to rationalize the enzyme assay data. Compounds were also tested against the clinically relevant forms of the intact parasite. Activity was seen against the trypanosomes for a number of compounds. The compounds were in general less active against Leishmania. This latter result may be due to uptake problems. Two of the compounds also showed some in vivo activity in a model of African trypanosomiasis.
本文涉及利什曼原虫和锥虫二氢叶酸还原酶抑制剂的设计、合成及评估。最初对利什曼原虫和人类酶活性位点的结构进行了研究,以确定是否存在可用于选择性药物设计的显著差异。然后基于5-苄基-2,4-二氨基嘧啶合成了一系列化合物。这些化合物针对原生动物酶和人类酶进行了测定,并对原生动物酶表现出选择性。随后利用结构数据对酶测定数据进行了合理分析。化合物还针对完整寄生虫的临床相关形式进行了测试。许多化合物对锥虫显示出活性。这些化合物对利什曼原虫的活性一般较低。后一结果可能是由于摄取问题。其中两种化合物在非洲锥虫病模型中也显示出一定的体内活性。