Bernal Freddy A, Gerhards Marcel, Kaiser Marcel, Wünsch Bernhard, Schmidt Thomas J
Institut für Pharmazeutische Biologie und Phytochemie (IPBP), Westfälische Wilhelms-Universität Münster, Corrensstraße 48, D-48149, Münster, Germany.
Swiss Tropical and Public Health Institute (Swiss TPH), Socinstr. 57, Basel, CH-4051, Switzerland; University of Basel, Petersplatz 1, Basel, CH-4003, Switzerland.
Eur J Med Chem. 2020 Nov 1;205:112493. doi: 10.1016/j.ejmech.2020.112493. Epub 2020 Jul 23.
Leishmaniasis, a neglected tropical disease caused by parasites of the genus Leishmania, causes a serious burden of disease around the world, represents a threat to the life of millions of people, and therefore is a major public health problem. More effective and non-toxic new treatments are required, especially for visceral leishmaniasis, the most severe form of the disease. On the backdrop that dihydrobenzofurans have previously shown antileishmanial activity, we present here the synthesis of a set of seventy trans-2-phenyl-2,3-dihydrobenzofurans and evaluation of their in vitro activity against Leishmania donovani as well as a discussion of structure-activity relationships. Compounds 8m-o and 8r displayed the highest potency (IC < 2 μmol/L) and interesting selectivity of the antileishmanial activity over cytotoxicity against mammalian cells (SI > 4.6). Nonetheless, structural optimization as further requirement was inferred from the high clearance of the most potent compound (8m) observed during determination in vitro of its metabolic stability. On the other hand, chiral separation of 8m and subsequent biological evaluation of its enantiomers demonstrated no effect of chirality on activity and cytotoxicity. Holistic analysis of in silico ADME-like properties and ligand efficiency metrics by a simple scoring function estimating druglikeness highlighted compounds 16c, 18 and 23 as promising candidates for further development. Overall, the potential of trans-2-phenyl-2,3-dihydrobenzofurans as leishmanicidal agents was confirmed.
利什曼病是一种由利什曼原虫属寄生虫引起的被忽视的热带病，在全球造成了严重的疾病负担，对数以百万计的人的生命构成威胁，因此是一个重大的公共卫生问题。需要更有效且无毒的新疗法，尤其是针对最严重形式的疾病——内脏利什曼病。鉴于二氢苯并呋喃此前已显示出抗利什曼原虫活性，我们在此展示了一组70种反式-2-苯基-2,3-二氢苯并呋喃的合成及其对杜氏利什曼原虫的体外活性评估，以及对构效关系的讨论。化合物8m - o和8r表现出最高的效力（IC<2 μmol/L），并且在抗利什曼原虫活性方面对哺乳动物细胞的细胞毒性具有有趣的选择性（SI>4.6）。尽管如此，从在体外测定其代谢稳定性时观察到的最有效化合物（8m）的高清除率推断，进一步的结构优化是必要的。另一方面，8m的手性拆分及其对映体的后续生物学评估表明，手性对活性和细胞毒性没有影响。通过一个估计药物相似性的简单评分函数对计算机模拟的类ADME性质和配体效率指标进行整体分析，突出了化合物16c、18和23作为有前景的进一步开发候选物。总体而言，反式-2-苯基-2,3-二氢苯并呋喃作为杀利什曼原虫剂的潜力得到了证实。
