Design, synthesis, and biological evaluation of aryloxyethyl thiocyanate derivatives against Trypanosoma cruzi
Design, synthesis, and biological evaluation of aryloxyethyl thiocyanate derivatives against Trypanosoma cruzi
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DOI：
10.1021/jm0201518
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发表时间：
2002-08-29
影响因子：
7.3
通讯作者：
Rodriguez, JB
中科院分区：
文献类型：
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作者：
Elhalem, E;Bailey, BN;Rodriguez, JB
作为我们旨在寻找新的和安全的化学治疗和化学预防剂以对抗美洲锥虫病（恰加斯病）的项目的继续，设计、合成了几种结构上与4-苯氧基苯氧基乙基硫氰酸酯（4）相关的药物，并评价了其作为抗寄生虫（血鞭毛虫原生动物克氏锥虫）增殖剂的效果。这种硫氰酸盐衍生物以前被证明是一种有效的抗T。克鲁兹扩散。几种具有硫氰酸根基团的药物被证明是有效的T.克鲁兹增长。在所设计的化合物中，重要的是指出11、23、38、53、90、99和117对寄生虫的外鞭毛体形式显示的极其有效的活性。所有这些化合物的IC 50值均在低微摩尔范围内，这些值与我们的先导药物4和酮康唑（一种众所周知的抗寄生虫药）的IC 50值相当。含氮衍生物90显示的活性非常有希望，IC 50值为3.3 μ M。其他几种硫氰酸盐衍生物也被证明是非常有效的T增殖抑制剂。克氏外鞭毛体，如化合物28、33、43、48、56、61、66、71、76和124。化合物43是一种很有前途的药物，因为它对无鞭毛体（临床上更相关的寄生虫形式）也非常有效。该化合物比4更有效，而11显示出与我们的先导药物几乎相同的抗细胞内T。克鲁兹非常令人惊讶的是，实验juvenoid 124虽然对外鞭毛体相当缺乏活性，但对成肌细胞中生长的细胞内无鞭毛体非常有效。其余设计的化合物显示出广泛程度的抑制作用，从中度活性药物到几乎没有抗寄生虫活性的药物。化合物43是一个有趣的例子，一个有效的抗痛风剂，提出了良好的前景，不仅作为一个先导药物，但也被用于进一步的体内研究。
As a continuation of our project aimed at the search for new and safe chemotherapeutic and chemoprophylactic agents against American trypanosomiasis (Chagas' disease), several drugs structurally related to 4-phenoxyphenoxyethyl thiocyanate (4) were designed, synthesized, and evaluated as antiproliferative agents against the parasite responsible for this disease, the hemoflagellated protozoan Trypanosoma cruzi. This thiocyanate derivative was previously shown to be an effective and potent agent against T. cruzi proliferation. Several drugs possessing thiocyanate groups proved to be effective growth inhibitors of T. cruzi growth. Among the designed compounds, it is important to point out the extremely potent activity shown by 11, 23, 38, 53, 90, 99, and 117 against the epimastigote forms of the parasite. All of them exhibited IC50 values in the low micromolar range, and these values were comparable with those presented by our lead drug 4 and ketokonazole, a well-known antiparasitic agent. The activity displayed by the nitrogen-containing derivative 90 was very promising with IC50 values of 3.3 muM. Several other thiocyanate derivatives also proved to be very potent inhibitors of the multiplication of T. cruzi epimastigotes, such as compounds 28, 33, 43, 48, 56, 61, 66, 71, 76, and 124. Compound 43 resulted in being a promising drug because it was also very effective against amastigotes, the clinically more relevant form of the parasite. This compound was Mold more potent than 4, while 11 showed nearly the same activity as our lead drug against intracellular T. cruzi. It was very surprising that the experimental juvenoid 124, although fairly devoid of activity against epimastigotes, was very effective against intracellular amastigotes growing in myoblasts. The rest of the designed compounds showed a broad degree of inhibitory action, from moderately active drugs to drugs almost devoid of antiparasitic activity. Compound 43 is an interesting example of an effective antichagasic agent that presents excellent prospectives not only as a lead drug but also to be used for further in vivo studies.