Université de Toulouse, UPS, UMR 152 (Laboratoire Pharmadev), Faculté de Pharmacie, 35 Chemin des maraîchers, F-31062 Toulouse cedex 9, France.
Malar J. 2012 Mar 9;11:67. doi: 10.1186/1475-2875-11-67.
Nitidine is thought to be the main active ingredient in several traditional anti-malarial remedies used in different parts of the world. The widespread use of these therapies stresses the importance of studying this molecule in the context of malaria control. However, little is known about its potential as an anti-plasmodial drug, as well as its mechanism of action.
In this study, the anti-malarial potential of nitidine was evaluated in vitro on CQ-sensitive and -resistant strains. The nitidine's selectivity index compared with cancerous and non-cancerous cell lines was then determined. In vivo assays were then performed, using the four-day Peter's test methodology. To gain information about nitidine's possible mode of action, its moment of action on the parasite cell cycle was studied, and its localization inside the parasite was determined using confocal microscopy. The in vitro abilities of nitidine to bind haem and to inhibit β-haematin formation were also demonstrated.
Nitidine showed similar in vitro activity in CQ-sensitive and resistant strains, and also a satisfying selectivity index (> 10) when compared with a non-cancerous cells line. Its in vivo activity was moderate; however, no sign of acute toxicity was observed during treatment. Nitidine's moment of action on the parasite cycle showed that it could not interfere with DNA replication; this was consistent with the observation that nitidine did not localize in the nucleus, but rather in the cytoplasm of the parasite. Nitidine was able to form a 1-1 complex with haem in vitro and also inhibited β-haematin formation with the same potency as chloroquine.
Nitidine can be considered a potential anti-malarial lead compound. Its ability to complex haem and inhibit β-haematin formation suggests a mechanism of action similar to that of chloroquine. The anti-malarial activity of nitidine could therefore be improved by structural modification of this molecule to increase its penetration of the digestive vacuole in the parasite, where haemoglobin metabolization takes place.
啶在世界不同地区的几种传统抗疟疗法中被认为是主要的活性成分。这些疗法的广泛应用强调了在疟疾控制背景下研究这种分子的重要性。然而，关于其作为抗疟药物的潜力及其作用机制知之甚少。
在这项研究中，体外评估了啶对敏感和耐药株的抗疟潜力。然后确定了啶与癌细胞和非癌细胞系的选择性指数。然后使用为期四天的彼得斯试验方法进行体内试验。为了获得关于啶可能作用模式的信息，研究了其对寄生虫细胞周期的作用时机，并使用共聚焦显微镜确定了其在寄生虫内部的定位。还证明了啶在体外结合血红素和抑制β-血红素形成的能力。
啶在敏感和耐药株中的体外活性相似，与非癌细胞系相比，选择性指数也令人满意（>10）。其体内活性适中；然而，在治疗过程中没有观察到急性毒性的迹象。啶对寄生虫周期的作用时机表明，它不能干扰 DNA 复制；这与啶不定位在细胞核中，而是定位于寄生虫细胞质中的观察结果一致。啶能够在体外与血红素形成 1:1 复合物，并且抑制β-血红素形成的效力与氯喹相同。
啶可以被认为是一种有潜力的抗疟先导化合物。它结合血红素和抑制β-血红素形成的能力表明其作用机制类似于氯喹。啶的抗疟活性可以通过对该分子进行结构修饰来提高，以增加其在寄生虫消化液泡中的穿透性，血红素代谢发生在那里。
