PDF(Pubmed)
Abstract：
Toxoplasmosis is a globally prevalent zoonotic disease with significant clinical implications, including neurotoxoplasmosis, a leading cause of cerebral lesions in AIDS patients. The current pharmacological treatments for toxoplasmosis face clinical limitations, necessitating the urgent development of new therapeutics. Natural sources have yielded diverse bioactive compounds, serving as the foundation for clinically used derivatives. The exploration of marine bacteria-derived natural products has led to marinoquinolines, which feature a pyrroloquinoline core and demonstrate in vitro and in vivo anti-Plasmodium activity. This study investigates the in vitro anti-Toxoplasma gondii potential of six marinoquinoline derivatives. Additionally, it conducts absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions, and evaluates the in vivo efficacy of one selected compound. The compounds displayed half-maximal effective concentration (EC50) values between 1.31 and 3.78 µM and half-maximal cytotoxic concentration (CC50) values ranging from 4.16 to 30.51 µM, resulting in selectivity indices (SI) from 3.18 to 20.85. MQ-1 exhibiting the highest in vitro SI, significantly reduced tachyzoite numbers in the peritoneum of RH-infected Swiss mice when it was orally administered at 12.5 mg/kg/day for eight consecutive days. Also, MQ-1 significantly reduced the cerebral parasite burden in chronically ME49 infected C57BL/6 mice when it was orally administered at 25 mg/kg/day for 10 consecutive days. These findings underscore the promising anti-T. gondii activity of marinoquinolines and their potential as novel therapeutic agents against this disease.
摘要：
弓形虫病是一种全球流行的人畜共患疾病，具有重要的临床意义。包括神经弓形虫病,艾滋病患者脑部病变的主要原因。目前的药物治疗弓形虫病面临临床局限性,迫切需要开发新的疗法。天然来源产生了多种生物活性化合物，作为临床使用的衍生物的基础。海洋细菌衍生的天然产物的探索导致了marinoquinolines,其特征是吡咯并喹啉核心，并在体外和体内表现出抗疟原虫活性。这项研究调查了六种海藻喹啉衍生物的体外抗弓形虫潜力。此外,它进行吸收，分布，新陈代谢，排泄,和毒性(ADMET)预测，并评价一种选定化合物的体内功效。这些化合物显示出1.31至3.78µM的半最大有效浓度（EC50）值和4.16至30.51µM的半最大细胞毒性浓度（CC50）值。导致选择性指数(SI)从3.18到20.85。MQ-1表现出最高的体外SI，以12.5mg/kg/天的剂量连续八天口服时，RH感染的瑞士小鼠腹膜中的速殖子数量显着减少。此外，MQ-1以25mg/kg/天的剂量连续10天口服给药时，可显着降低慢性ME49感染的C57BL/6小鼠的脑寄生虫负担。这些发现强调了有希望的反T。marinoquinolines的刚地活性及其作为该疾病的新型治疗剂的潜力。
