Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA.
Chicago State University, College of Pharmacy, Department of Pharmaceutical Sciences, 9501 S. King Drive, Chicago, IL 60628, USA.
Int J Parasitol Drugs Drug Resist. 2020 Dec;14:80-90. doi: 10.1016/j.ijpddr.2020.08.006. Epub 2020 Aug 25.
Toxoplasma gondii and Cryptosporidium parvum are protozoan parasites that are highly prevalent and opportunistically infect humans worldwide, but for which completely effective and safe medications are lacking. Herein, we synthesized a series of novel small molecules bearing the diacyl urea scaffold and related structures, and screened them for in vitro cytotoxicity and antiparasitic activity against T. gondii and C. parvum. We identified one compound (GMG-1-09), and four compounds (JS-1-09, JS-2-20, JS-2-35 and JS-2-49) with efficacy against C. parvum and T. gondii, respectively, at low micromolar concentrations and showed appreciable selectivity in human host cells. Among the four compounds with efficacy against T. gondii, JS-1-09 representing the diacyl urea scaffold was the most effective, with an anti-Toxoplasma IC concentration (1.21 μM) that was nearly 53-fold lower than its cytotoxicity IC concentration, indicating that this compound has a good selectivity index. The other three compounds (JS-2-20, JS-2-35 and JS-2-49) were structurally more divergent from JS-1-09 as they represent the acyl urea and acyl carbamate scaffold. This appeared to correlate with their anti-Toxoplasma activity, suggesting that these compounds' potency can likely be enhanced by selective structural modifications. One compound, GMG-1-09 representing acyl carbamate scaffold, depicted in vitro efficacy against C. parvum with an IC concentration (32.24 μM) that was 14-fold lower than its cytotoxicity IC concentration in a human intestinal cell line. Together, our studies unveil a series of novel synthetic acyl/diacyl urea and acyl carbamate scaffold-based small molecule compounds with micromolar activity against T. gondii and C. parvum that can be explored further for the development of the much-needed novel anti-protozoal drugs.
刚地弓形虫和微小隐孢子虫是两种原生动物寄生虫，在全球范围内广泛存在且具有机会致病性，但目前缺乏完全有效和安全的药物。在此，我们合成了一系列含有二酰基脲骨架和相关结构的新型小分子，并对其进行了体外细胞毒性和抗刚地弓形虫和微小隐孢子虫活性筛选。我们鉴定了一种化合物（GMG-1-09）和四种化合物（JS-1-09、JS-2-20、JS-2-35 和 JS-2-49），它们在低微摩尔浓度下对微小隐孢子虫和刚地弓形虫均具有疗效，并且在人源宿主细胞中具有显著的选择性。在对刚地弓形虫有效的四种化合物中，JS-1-09 代表的二酰基脲骨架是最有效的，其抗刚地弓形虫的半数抑制浓度（IC 浓度）（1.21μM）比其细胞毒性 IC 浓度低近 53 倍，表明该化合物具有良好的选择性指数。其他三种化合物（JS-2-20、JS-2-35 和 JS-2-49）在结构上与 JS-1-09 差异较大，代表酰基脲和酰基氨基甲酸酯骨架。这似乎与它们的抗刚地弓形虫活性相关，表明通过选择性结构修饰可以提高这些化合物的效力。一种化合物 GMG-1-09 代表酰基氨基甲酸酯骨架，在体外对微小隐孢子虫的疗效表现为半数抑制浓度（IC 浓度）（32.24μM）比其在人肠细胞系中的细胞毒性 IC 浓度低 14 倍。总之，我们的研究揭示了一系列新型的合成酰基/二酰基脲和酰基氨基甲酸酯骨架的小分子化合物，它们对刚地弓形虫和微小隐孢子虫具有微摩尔活性，可以进一步探索用于开发急需的新型抗原生动物药物。
