Jones Simon M, Urch Jonathan E, Kaiser Marcel, Brun Reto, Harwood John L, Berry Colin, 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):5932-41. doi: 10.1021/jm049067d.
Analogues of the natural antibiotic thiolactomycin (TLM), an inhibitor of the condensing reactions of type II fatty acid synthase, were synthesized and evaluated for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum. Alkylation of the C4 hydroxyl group led to the most significant increase in growth inhibition (over a 100-fold increase in activity compared to TLM). To investigate the mode of action, the P. falciparum KASIII enzyme was produced for inhibitor assay. A number of TLM derivatives were identified that showed improved inhibition of this enzyme compared to TLM. Structure-activity relationships for enzyme inhibition were identified for some series of TLM analogues, and these also showed weak correlation with inhibition of parasite growth, but this did not hold for other series. On the basis of the lack of a clear correlation between inhibition of pfKASIII activity and parasite growth, we conclude that pfKASIII is not the primary target of TLM analogues. Some of the analogues also inhibited the growth of the parasitic protozoa Trypanosoma cruzi, T. brucei, and Leishmania donovani.
天然抗生素硫内酯霉素（TLM）是II型脂肪酸合酶缩合反应的抑制剂，其类似物已被合成，并对它们抑制疟原虫恶性疟原虫生长的能力进行了评估。C4羟基的烷基化导致生长抑制作用最显著增强（与TLM相比，活性增加超过100倍）。为了研究作用模式，制备了恶性疟原虫KASIII酶用于抑制剂测定。鉴定出了一些TLM衍生物，与TLM相比，它们对该酶的抑制作用有所改善。确定了一些系列的TLM类似物的酶抑制构效关系，这些关系也显示出与寄生虫生长抑制的弱相关性，但其他系列并非如此。基于pfKASIII活性抑制与寄生虫生长之间缺乏明确的相关性，我们得出结论，pfKASIII不是TLM类似物的主要靶点。一些类似物还抑制了寄生原生动物克氏锥虫、布氏锥虫和杜氏利什曼原虫的生长。
