Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
J Med Chem. 2012 Dec 27;55(24):10948-57. doi: 10.1021/jm301328h. Epub 2012 Dec 14.
Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-α-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5'-urea-α- and β-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme-inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5'-urea-α-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC(50) = 28 nM; CC(50) = 29 μM).
疟原虫胸苷酸激酶（PfTMPK）是嘧啶核苷酸生物合成中的关键酶。3-三氟甲基-4-氯苯基-脲-α-胸苷已被报道为结核分枝杆菌 TMPK（MtTMPK）的抑制剂。基于这一点，我们设计、合成并评估了许多胸苷类似物作为抗疟药物。5'-脲-α-和β-胸苷衍生物均为 PfTMPK 的中等抑制剂，并且对寄生虫生长具有中等抑制作用。几种酶-抑制剂复合物的结构为改进抑制剂设计提供了依据。然而，我们发现某些 5'-脲-α-胸苷类似物具有抗疟活性，而 PfTMPK 的抑制不是主要作用模式。对该系列化合物进行优化得到了一种具有很强抗疟活性的化合物（EC50=28 nM；CC50=29 μM）。
