Damiani Céline, Soler Floriane, Le Govic Yohann, Totet Anne, Bentzinger Guillaume, Bouchut Anne, Mustière Romain, Agnamey Patrice, Dassonville-Klimpt Alexandra, Sonnet Pascal
Agents Infectieux, Résistance et Chimiothérapie (AGIR), UR 4294, Université de Picardie Jules Verne, 1 rue des Louvels, 80037 Amiens, France.
Laboratoire de Parasitologie et Mycologie, Centre de Biologie Humaine, CHU Amiens-Picardie, 1 Rond-Point du Pr Cabrol, 80054 Amiens, France.
Microorganisms. 2024 Dec 7;12(12):2524. doi: 10.3390/microorganisms12122524.
Currently, artemisinin-based combination therapy is recommended as first-line treatment of uncomplicated malaria. Arylamino alcohols (AAAs) such as mefloquine (MQ) are the preferred partner drugs due to their longer half-life, reliable absorption and strong antimalarial activity. However, the mode of action of MQ remains poorly understood and its neurotoxicity limits its use. Furthermore, the emergence of drug-resistant parasites requires development of new antimalarial drugs. The aim of this study was to evaluate the -hematin inhibition capacity of three pairs of enantiopure AAAs ( and ) derived from MQ or enpiroline (ENP), a pyridine-based MQ analog with strong antimalarial activity. Inhibition of -hematin-the synthetic counterpart of hemozoin formation-was determined for each compound. Antimalarial activity against W2 and 3D7 strains as well as percentages of inhibition of -hematin formation were compared to those of reference molecules, i.e., chloroquine (CQ), MQ and ENP. Furthermore, a cytotoxicity study on the human-derived hepatocarcinoma cell line HepG2 was performed. With high antimalarial activity, stronger ability to inhibit -hematin formation and low cytotoxicity, AAAs and are the most promising. These findings provide a better understanding of their potential mechanisms of action and may pave the way toward developing new lead compounds.
目前，基于青蒿素的联合疗法被推荐为非复杂性疟疾的一线治疗方法。诸如甲氟喹（MQ）之类的芳基氨基醇（AAA）因其较长的半衰期、可靠的吸收性和强大的抗疟活性而成为首选的联合用药。然而，甲氟喹的作用方式仍知之甚少，且其神经毒性限制了其使用。此外，耐药寄生虫的出现需要开发新的抗疟药物。本研究的目的是评估源自甲氟喹或恩吡罗啉（ENP，一种具有强大抗疟活性的吡啶类甲氟喹类似物）的三对对映体纯的芳基氨基醇（ 和 ）的血红素抑制能力。测定了每种化合物对血红素（疟原虫色素形成的合成对应物）的抑制作用。将针对W2和3D7菌株的抗疟活性以及血红素形成的抑制百分比与参考分子（即氯喹（CQ）、甲氟喹和恩吡罗啉）进行了比较。此外，还对人源肝癌细胞系HepG2进行了细胞毒性研究。芳基氨基醇 和 具有高抗疟活性、更强的抑制血红素形成的能力以及低细胞毒性，是最有前景的。这些发现有助于更好地理解它们潜在的作用机制，并可能为开发新的先导化合物铺平道路。
