Structure-activity relationship of new growth inhibitors of Trypanosoma cruzi
Structure-activity relationship of new growth inhibitors of Trypanosoma cruzi
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DOI：
10.1021/jm970860z
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发表时间：
1998-04-23
影响因子：
7.3
通讯作者：
Gros, EG
中科院分区：
文献类型：
--
作者：
Cinque, GM;Szajnman, SH;Gros, EG
设计、合成了几种具有4-苯氧基苯氧基骨架和其他密切相关结构的药物，并评价了其作为抗克氏锥虫（Trypanosoma cruzi）（恰加斯病的病原体）的抗增殖剂。这类新的药物是通过修饰非极性的4-苯氧基苯氧基部分，通过亲电芳族取代反应用不同的基团取代选定的芳族质子，以及在极性末端引入硫原子来设想的。在所设计的化合物中，含硫衍生物被证明是有效的抗T。克鲁兹在这些药物中，4-苯氧基苯氧基乙基硫氰酸酯（化合物56）被证明是一个非常活跃的生长抑制剂的上鞭毛体形式的T。cruzi，显示出2.2 μ M的IC 50。在相同的测定条件下，该药物比目前临床上用于控制该疾病的药物之一硝呋莫司活性高得多。这种硫氰酸盐衍生物也是一种非常活跃的抑制剂，对细胞内形式的寄生虫在纳摩尔水平。制备的其他硫衍生物也表现出非常有效的抗T细胞增殖作用。克鲁兹硫原子在该化合物家族的极性极端的存在似乎对生物作用非常重要，因为该原子总是与高抑制值相关。4-苯氧基苯氧基乙基硫氰酸酯不仅作为先导药物，而且作为潜在的化疗药物具有很好的前景。
Several drugs bearing the 4-phenoxyphenoxy skeleton and other closely related structures were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the etiologic agent of Chagas' disease. The new class of drugs was envisioned by modifying the nonpolar 4-phenoxyphenoxy moiety replacing selected aromatic protons by different groups via electrophilic aromatic substitution reactions as well as introducing a sulfur atom at the polar extreme. Of the designed compounds, sulfur-containing derivatives were shown to be potent antireplicative agents against T. cruzi. Among these drugs, 4-phenoxyphenoxyethyl thiocyanate (compound 56) proved to be an extremely active growth inhibitor of the epimastigote forms of T. cruzi and displayed an IC50 of 2.2 mu M. Under the same assay conditions, this drug was much more active than Nifurtimox, one of the drugs currently in clinical use to control this disease. This thiocyanate derivative was also a very active inhibitor against the intracellular form of the parasite at the nanomolar level. Other sulfur derivatives prepared also exhibited very potent antiproliferative action against T. cruzi. The presence of a sulfur atom at the polar extreme for this family of compounds seems to be very important for biological action because this atom was always associated with high inhibition values. 4-Phenoxyphenoxyethyl thiocyanate presents very good prospective not only as a lead drug but also as a potential chemotherapeutic agent.