Synthesis and evaluation of the anti-malarial activity of the quaternary ammonium salt dimer as the new anti-malarial candidate

疟疾是全世界人类最致命的疾病之一，每年有250多万人死于疟疾。由于恶性疟原虫氯喹耐药菌株的出现和持续传播，包括对常规抗疟疾药物的多重耐药菌株，开发全新的抗疟疾药物成为重点。近年来，我们发现一种作为新型抗菌剂开发的季铵盐二聚体具有抗疟疾活性。本研究制备了多种季铵盐二聚体衍生物，并对其抗疟疾活性进行了评价。研究了这些季铵盐二聚体抗疟疾活性的构效关系。结果表明，最强的抗疟药为S，S′-四亚甲基双（1-己基-4-硫代碘化吡啶），其连接体亚甲基碳数为3，选择毒性为667。在S，S’-四亚甲基双（1-己基-4-硫代碘化吡啶）系列化合物中，随着连接体亚甲基部分碳数越小，IC_<50>的值越低。在烷基链夹在两个酰胺基团中的N，N'-四亚甲基双（4-氨基甲酰-1-己基溴化吡啶）系列中，当连接基团亚甲基部分的碳数为6，N -烷基链部分的碳数为8时，其选择性毒性最高，为580。n -烷基链碳数与疟原虫IC_<50>在该序列中表现出较好的相关性，即n -烷基链碳数越小，IC_<50>越低。关于连接体中亚甲基部分的碳数，目前还不清楚一个最优值。本研究中化合物的分子结构与传统抗疟疾药物完全不同。因此，我们的新抗疟药有望成为对恶性疟原虫药敏和耐药菌株有效的新候选药物。少

Malaria is one of the most deadly diseases for humans worldwide and more than 2.5 million people die from it each year. Due to the emergence and ongoing spread of the chloroquine-resistent strains of Plasmodium falciparum, including multi-drug resistant strains to conventional anti-malarial drugs, development of the entirely new anti-malarial drug is focused. Recently we have found that one of the quaternary ammonium salt dimers that had developed as the new antibacterial agent has the anti-malarial activity. In this research many derivatives of the quaternary ammonium salt dimer were prepared and evaluated for their anti-malarial activity. The structure-activity relationship of these quaternary ammonium salt dimers for their anti-malarial activity was also performed. It was found that the strongest anti-malarial agent was S,S'-tetramethylenebis(1-hexyl-4-thiopyridinium iodide) in which a carbon number of the methylenes of the linker moiety was three and its selective toxicity was 667. … More In this series of the compounds of S,S'-tetramethylenebis(1-hexyl-4-thiopyridinium iodide}, it has the tendency that IC_<50> was lower when the carbon number of the methylene part of the linker moiety is smaller. In the series of N,N'-tetramethylenebis(4-carbamoyl-1-hexylpyridinium bromide) in which alkyl chain is sandwiched in two amide groups, the highest selective toxicity was 580 when the carbon number of the methylene part of the linker moiety is six and the canon number of the N-alkyl chain moiety is eight. A carbon number of the N-alkyl chain and IC_<50> for malarial parasite showed a good correlation in this series, that is, IC_<50> became lower when the carbon number of the N-alkyl chain is smaller. About the carbon number of the methylene part in the linker moiety, an optimal value is not clear at present.The molecular structures of the compounds in this research are completely different from the conventional anti-malarial drugs. Therefore our new anti-malarial agents are expected as the new candidate which is active against drug-sensitive and drug resistant strains of P. falciparum. Less