Synthesis, biological evaluation and SAR of sulfonamide 4-methoxychalcone derivatives with potential antileishmanial activity
Synthesis, biological evaluation and SAR of sulfonamide 4-methoxychalcone derivatives with potential antileishmanial activity
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DOI：
10.1016/j.ejmech.2008.04.016
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发表时间：
2009-02-01
影响因子：
6.7
通讯作者：
Castro, Helena C.
中科院分区：
文献类型：
--
作者：
Andrighetti-Frohner, Carla R.;de Oliveira, Kely N.;Castro, Helena C.
尽管利什曼病是一种影响88个国家120亿人的传染病，具有重要的临床意义，但由于其疗效有限、成本昂贵和不良副作用，治疗仍然不令人满意。为了开发新的抗利什曼原虫先导化合物，我们采用合理的方法合成了一系列新的磺酰胺类4-甲氧基查尔酮衍生物（3a-3 i），并评价了磺酰胺和甲氧基部分作为查尔酮加成基团的前景。为此目的，我们测试了这一新的一套针对巴西利什曼原虫前鞭毛体和细胞内无鞭毛体，并确定其细胞毒性概况。有趣的是，所有化合物都呈现出浓度依赖性的抗利什曼原虫特征，并且苄基氨基衍生物（3 i）显示出比喷他脒更好的生物活性。这些化合物均不影响克氏锥虫外鞭毛体，这表明具有特定的抗利什曼原虫特征。对磺酰胺类4-甲氧基查尔酮衍生物的构效关系分析表明，分子体积、查尔酮分子的HOMO密度以及化合物的构象是其抗利什曼原虫活性的重要结构和立体电子特征。此外，这些化合物也符合Lipinski规则5，并呈现出与抗利什曼病药物相似的药物样。总之，这些结果指出，磺胺4-甲氧基查耳酮衍生物作为潜在的先导化合物设计新的候选治疗利什曼病。(c)2008年，Elsevier Masson SAS。All rights reserved.
Despite clinical importance of leishmaniasis, an infectious disease that affects 12 thousand million people in 88 countries, the treatment is still unsatisfactory due to its limited efficacy, cost expensive and undesirable side effects. Aiming to develop new antileishmanial lead compounds, we used a rational approach to synthesize a new set of sulfonamide 4-methoxychalcone derivatives (3a-3i) and evaluate the sulfonamide and methoxy moieties as promising adding-groups to chalcones. For that purpose we tested this new set against Leishmania braziliensis promastigotes and intracellular amastigotes and determined its cell toxicity profile. Interestingly all compounds presented a concentration-dependent antileishmanial profile and the benzylamino, derivative (3i) showed a biological activity better than pentamidine. None of these compounds affected Trypanosoma cruzi epimastigotes, which suggests a specific antileishmanial profile. The structure-activity analysis of these sulfonamide 4-methoxychalcone derivatives pointed the molecular volume, the HOMO density concentrated in the chalcone moiety and the conformational structure of the compounds as important structural and stereoelectronic features for the antileishmanial activity. In addition, these compounds also fulfilled Lipinski rule of 5 and presented druglikeness similar to antileishmanial drugs. Altogether these results point the sulfonamide 4-methoxychalcone derivatives as potential lead compounds for designing new candidates for leishmaniasis treatment. (c) 2008 Elsevier Masson SAS. All rights reserved.