Nguyen Corinne, Kasinathan Ganasan, Leal-Cortijo Isabel, Musso-Buendia Alexander, Kaiser Marcel, Brun Reto, Ruiz-Pérez Luis M, Johansson Nils G, González-Pacanowska Dolores, Gilbert Ian H
Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3XF, UK.
J Med Chem. 2005 Sep 22;48(19):5942-54. doi: 10.1021/jm050111e.
This paper describes a structure-activity study to identify novel, small-molecule inhibitors of the enzyme deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) from parasitic protozoa. The successful synthesis of a variety of analogues of dUMP is described in which the substituents are introduced at the 3'- and 5'-positions, together with variation in the heteroatom at the 5'-position. The compounds were assayed against recombinant Plasmodium falciparum and Leishmania major enzymes and the human enzyme to give a measure of selectivity. The compounds were also tested in vitro against the intact parasites P. falciparum and L. donovani. A number of potent and selective inhibitors of the P. falciparum dUTPase that show drug-like properties and represent good leads for future development were identified. The best inhibitors included the compounds 5'-tritylamino-2',5'-dideoxyuridine (2j) (Ki = 0.2 microM) and 5'-O-triphenylsilyl-2',3'-didehydro-2',3'-dideoxyuridine (5h) (Ki = 1.3 microM), with selectivity greater than 200-fold compared to the human enzyme. Structural features important for antiplasmodial activity were determined. The correlation observed between the inhibition of the enzyme and the inhibition of the parasite growth in vitro demonstrates that the P. falciparum dUTPase constitutes a valid and attractive novel target for the development of much-needed new antimalarial drugs.
本文描述了一项构效关系研究，旨在从寄生原生动物中鉴定脱氧尿苷5'-三磷酸核苷酸水解酶（dUTPase）的新型小分子抑制剂。文中描述了多种dUMP类似物的成功合成，其中在3'-和5'-位引入了取代基，并改变了5'-位的杂原子。对这些化合物针对重组恶性疟原虫和硕大利什曼原虫的酶以及人源酶进行了测定，以衡量其选择性。这些化合物还在体外针对完整的恶性疟原虫和杜氏利什曼原虫进行了测试。鉴定出了一些对恶性疟原虫dUTPase具有强效和选择性抑制作用的化合物，它们具有类药性质，是未来开发的良好先导化合物。最佳抑制剂包括化合物5'-三苯氨基-2',5'-二脱氧尿苷（2j）（Ki = 0.2 microM）和5'-O-三苯基甲硅烷基-2',3'-二脱氢-2',3'-二脱氧尿苷（5h）（Ki = 1.3 microM），与人类酶相比，选择性大于200倍。确定了对抗疟活性重要的结构特征。酶抑制与体外寄生虫生长抑制之间的相关性表明，恶性疟原虫dUTPase是开发急需的新型抗疟药物的有效且有吸引力的新靶点。
