Invention of Inexpensive Antimalarials

廉价抗疟药的发明

• 批准号: 17590088
• 负责人: SASAKI Kenji
• 金额: $ 2.3万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590088/
• 关键词: quaternary ammonium salt dimer; anti-malarials; thioether; selective toxicity; N-alkyl chain; inexpensive; in vitro; in vivo; リンカー; 熱帯熱マラリア原虫; チオエーテル結合; アミド結合; リンカー長

We evaluated the structure-activity relationship of the compounds which were prepared in these two years and whose lead compound is 4,4'(41,4.TetramethylenedicarbonyldiamineThis(1-hexyl- pyridinium bromide). As a result, it was found that 1) substituent on pyridine ring nitroigen contributes to antimalarial activity greatly; 2) this substituent show the highest activity in the case that the number of tha alkyl chain carbone on pyridine ring nitroigen is 8; 3) when this substituent is bulky just like a benzyl or cyclohexyl group, the antimalarial activity deduced 4) the change of the carbon numbers of the linker which joines two pyridine rings from 3 to 10 did not give so large influence for the antimalarial activity. We also evaluated the compound which showed superior antimalarial activity in vitro in these two years for antimalarial activity in vivo. The 4 days suppressive test on mouse was used for the evaluation methods. As a result, ED50 value of our compound was 7.3 mg/kg in dosage of 15 mg/kg. This value showed that our compound is effective although the activity of our compound was only partial response inferior to (1/5~1/6) in chloroquine (ED50 value ; 1.3 mg/kg) which was existing medicine. However, in the case of our compound, malaria infected mise did not reach to complete recovery and survival ratio was 186%. While chloroquine have let malaria infection mise recover completely. When the duration of administration of this compound was extended, amelioration of clear macrobiotic coefficient was recognized. That is, by the extention of the duration of administration, inhibitory effect of malarial parasite was clearly recognized (less than 2%). From these results, it is thought that our compound cannot completely restrain malaria infection alone, however, combination use of our compound with existing antimalarials will reach to complete recovery of malaria infection dieses.

本文对近两年合成的以4，4 '-（41，4-四亚甲基二羰基二胺）-（1-己基溴化吡啶）为先导化合物的化合物进行了构效关系评价。结果表明：（1）吡啶环氮杂环上的取代基对抗疟活性有较大贡献，（2）吡啶环氮杂环上的碳链数为8时，取代基的抗疟活性最高; 3）当该取代基就像苄基或环己基一样大体积时，4）连接两个吡啶环的连接基的碳数从3变为10对抗疟活性没有太大影响。我们还评价了这两年在体外显示出上级抗疟活性的化合物的体内抗疟活性。评价方法采用小鼠4天抑制试验。结果表明，本化合物在15 mg/kg剂量下的ED_（50）值为7.3mg/kg。该值表明本发明化合物是有效的，尽管本发明化合物的活性仅部分低于现有药物氯喹（ED 50值; 1.3mg/kg）的（1/5~1/6）。然而，在我们的化合物的情况下，疟疾感染的患者没有达到完全康复，存活率为186%。而氯喹则让疟疾感染者完全康复。当该化合物的给药持续时间延长时，可确认明显的长寿系数改善。也就是说，通过延长给药持续时间，可以清楚地识别出疟原虫的抑制作用（小于2%）。根据这些结果，认为我们的化合物不能单独完全抑制疟疾感染，然而，我们的化合物与现有抗疟药的组合使用将达到完全恢复疟疾感染疾病。