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Pyrrolidine-Acridine hybrid in Artemisinin-based combination: a pharmacodynamic study

机译：基于青蒿素的组合中的吡咯烷-A啶杂化物：药效学研究

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摘要

Aiming to develop new artemisinin-based combination therapy (ACT) for malaria, antimalarial effect of a new series of pyrrolidine-acridine hybrid in combination with artemisinin derivatives was investigated. Synthesis, antimalarial and cytotoxic evaluation of a series of hybrid of 2-(3-(substitutedbenzyl)pyrrolidin-1-yl)alkanamines and acridine were performed and mode of action of the lead compound was investigated. In vivo pharmacodynamic properties (parasite clearance time, parasite reduction ratio, dose and regimen determination) against multidrug resistant (MDR) rodent malaria parasite and toxicological parameters (median lethal dose, liver function test, kidney function test) were also investigated. 6-Chloro-N-(4-(3-(3,4-dimethoxybenzyl)pyrrolidin-1-yl)butyl)-2-methoxyacridin-9-amine (15c) has shown a dose dependent haem bio-mineralization inhibition and was found to be the most effective and safe compound against MDR malaria parasite in Swiss mice model. It displayed best antimalarial potential with artemether (AM) in vitro as well as in vivo. The combination also showed favourable pharmacodynamic properties and therapeutic response in mice with established MDR malaria infection and all mice were cured at the determined doses. The combination did not show toxicity at the doses administered to the Swiss mice. Taken together, our findings suggest that compound 15c is a potential partner with AM for the ACT and could be explored for further development.
机译：为了开发新的基于青蒿素的疟疾联合疗法（ACT），研究了一系列新的吡咯烷-ac啶杂化物与青蒿素衍生物联合的抗疟作用。进行了一系列的2-（3-（取代的苄基）吡咯烷基-1-基）烷胺与a啶的杂合物的合成，抗疟和细胞毒性评估，并研究了先导化合物的作用方式。还研究了针对多药耐药（MDR）啮齿动物疟疾寄生虫的体内药效学性质（寄生虫清除时间，寄生虫减少率，剂量和方案确定）和毒理学参数（中位数致死剂量，肝功能测试，肾脏功能测试）。 6-氯-N-（4-（3-（3,4-二甲氧基苄基）吡咯烷-1-基）丁基）-2-甲氧基ac啶-9-胺（15c）显示出剂量依赖性的血红素生物矿化抑制作用，并且在瑞士小鼠模型中被发现是对抗MDR疟疾寄生虫最有效，最安全的化合物。它在体外和体内都与蒿甲醚（AM）表现出最佳的抗疟疾潜力。该组合在已建立MDR疟疾感染的小鼠中也显示出良好的药效特性和治疗反应，所有小鼠均以确定的剂量治愈。该组合在施用于瑞士小鼠的剂量下未显示毒性。综上所述，我们的发现表明化合物15c是AM与ACT的潜在合作伙伴，可以进行进一步开发。

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