Mazzone Flaminia, Klischan Moritz K T, Greb Julian, Smits Sander H J, Pietruszka Jörg, Pfeffer Klaus
Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, University Hospital Düsseldorf, Düsseldorf, Germany.
Institute of Bioorganic Chemistry, Heinrich Heine University Düsseldorf at Forschungszentrum Jülich, Jülich, Germany.
Front Chem. 2024 Jul 22;12:1406307. doi: 10.3389/fchem.2024.1406307. eCollection 2024.
Toxoplasmosis is a zoonotic disease caused by , an apicomplexan parasite that infects approximately a third of the world's human population. This disease can cause serious complications during pregnancy and can be fatal in immunocompromised hosts. The current treatment options for toxoplasmosis face several limitations. Thus, to address the urgent medical need for the discovery of novel anti-toxoplasma potential drug candidates, our research focused on exploring a series of monomeric and dimeric chalcones, polyphenolic molecules belonging to the class of flavonoids. Chalcones - and axially chiral A-A'-connected bichalcones - were evaluated against the proliferation of the parasite in a cell-based assay. A comparison of the efficacy demonstrated that, in several cases, bichalcones exhibited increased bioactivity compared to their corresponding monomeric counterparts. Among these compounds, a bichalcone with a phenyl substituent and a methyl moiety showed the most potent and selective inhibitory activity in the nanomolar range. Both enantiomers of this bichalcone were synthesized using an axially chiral biphenol building block. The biaryl bond was forged using Suzuki cross-coupling in water under micellar catalysis conditions. Separation of the atropisomers of this biphenol building block was conducted by chiral HPLC on a preparative scale. The biological evaluation of the enantiomers revealed that the ( )-enantiomer ( )- is the eutomer. These studies suggest that bichalcones may be important drug candidates for further evaluations for the discovery of anti-toxoplasma drugs.
弓形虫病是一种人畜共患疾病，由一种顶复门寄生虫引起，这种寄生虫感染了世界上约三分之一的人口。这种疾病在怀孕期间可导致严重并发症，在免疫功能低下的宿主中可能致命。目前弓形虫病的治疗方案存在一些局限性。因此，为了满足发现新型抗弓形虫潜在药物候选物的迫切医疗需求，我们的研究集中在探索一系列单体和二聚查耳酮，它们是属于黄酮类的多酚分子。在基于细胞的试验中评估了查耳酮以及轴向手性A - A'连接的双查耳酮对寄生虫增殖的影响。疗效比较表明，在几种情况下，双查耳酮与其相应的单体类似物相比表现出增强的生物活性。在这些化合物中，一种带有苯基取代基和甲基部分的双查耳酮在纳摩尔范围内表现出最有效和选择性的抑制活性。使用轴向手性联苯酚结构单元合成了这种双查耳酮的两种对映体。在胶束催化条件下于水中通过铃木交叉偶联形成联芳基键。通过制备规模的手性高效液相色谱法分离该联苯酚结构单元的阻转异构体。对映体的生物学评估表明，（ ）-对映体（ ）-是优映体。这些研究表明，双查耳酮可能是用于进一步评估以发现抗弓形虫药物的重要候选药物。
