Center of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa.
Department of Pharmacology, University of Cape Town, Groote Schuur Hospital, Observatory 7925, Cape Town, South Africa.
Eur J Med Chem. 2014 Apr 9;76:470-81. doi: 10.1016/j.ejmech.2014.01.040. Epub 2014 Feb 18.
A series of artemisinin-triazine hybrids and hybrid-dimers were synthesized and their in vitro antimalarial activity against the chloroquine sensitive (CQS), the gametocytocidal (NF54) and the choroquine resistant (CQR) Dd2 strains of Plasmodium falciparum determined, while their toxicity against CHO cells were also established. These compounds were prepared by linking artemisinin and triazine pharmacophores through nucleophilic substitution, using conventional and microwave assisted methods. These hybrids and hybrid-dimers were all found to be active against all three Plasmodium strains, with the p-anisidino-substituted triazine hybrid-dimer 22 being the most active of all. It showed good antigametocytocidal activity against the NF54 strain, with a 50% inhibitory concentration value in the nanomolar range, while having a potency comparable to that of artesunate against the Dd2 strain. This hybrid-dimer further demonstrated selective toxicity towards the parasitic cells. This dimer hence showed the necessary potential as candidate for further investigation in the search for malaria transmission blocking drugs so desperately needed.
一系列青蒿素-三嗪杂合体和杂二聚体被合成，并对氯喹敏感（CQS）、配子体杀灭（NF54）和氯喹耐药（CQR）的恶性疟原虫 Dd2 株进行了体外抗疟活性测定，同时也测定了它们对 CHO 细胞的毒性。这些化合物是通过青蒿素和三嗪药效团之间的亲核取代反应制备的，采用了常规和微波辅助方法。这些杂合体和杂二聚体对所有三种疟原虫株均有活性，其中对甲氧基取代的三嗪杂二聚体 22 是最有效的。它对 NF54 株表现出良好的配子体杀灭活性，半数抑制浓度值在纳摩尔范围内，而对 Dd2 株的效力与青蒿琥酯相当。这种杂二聚体进一步显示了对寄生细胞的选择性毒性。因此，这种二聚体具有作为候选药物进一步研究的必要潜力，以寻找急需的疟疾传播阻断药物。
