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

疟疾是全球人类最致命的疾病之一，每年有超过250万人死于疟疾。由于恶性疟原虫氯喹抗性株的出现和持续传播，包括对常规抗疟疾药物的多重耐药株，开发全新的抗疟疾药物成为重点。最近，我们发现作为新型抗菌剂的季铵盐二聚体中的一种具有抗疟疾活性。本研究合成了多种季铵盐二聚体的衍生物，并对其抗疟疾活性进行了评价。并对这些季铵盐二聚体的抗疟疾活性进行了构效关系研究。结果表明，抗疟药效最强的是S，S的四亚甲基双(1-己基-4-硫代吡啶碘)，其连接基的亚甲基碳数为3，选择性毒性为667。…此外，在S、S的四亚甲基双(1-己基-4-硫代吡啶碘)系列化合物中，当连接基部分的亚甲基部分的碳数较小时，IC_(50)有降低的趋势。在烷链夹在两个酰胺基团中的N，N‘-tetramethylenebis(4-carbamoyl-1-hexylpyridinium溴)系列中，当连接基部分的亚甲基部分的碳数为6，N-烷基部分的正则数为8时，选择性毒性最高，为580.N-烷基链的碳数与疟原虫的IC50&gt；有很好的相关性，即N-烷基链的碳数越小，IC50&gt；越低。关于接头部分的亚甲基部分的碳数，目前还没有一个最佳值。本研究中的化合物的分子结构与传统的抗疟疾药物完全不同。因此，我们的新型抗疟疾药物有望成为对抗恶性疟原虫药物敏感株和耐药株的新候选药物。较少

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