Invention of Inexpensive Antimalarials

我们对这两年合成的以4，4‘(41，4.TetramethylenedicarbonyldiamineThis(1-hexyl-吡啶溴化铵为先导化合物的化合物的构效关系进行了评价。结果发现：1)吡啶环亚硝基上的取代基对抗疟活性有很大贡献；2)当吡啶环亚硝基上的烷基碳数为8时，该取代基的抗疟活性最强；3)当该取代基体积较大时，如苯基或环己基一样，抗疟活性推断4)连接两个吡啶环的连接基的碳数从3到10的变化对抗疟活性的影响不大。我们还评估了这两年在体外表现出优异抗疟疾活性的化合物在体内的抗疟疾活性。以小鼠4天抑制试验为评价方法。结果表明，在剂量为15 mg/kg时，该化合物的ED50为7.3 mg/kg。这一数值表明，我们的化合物是有效的，尽管我们的化合物的活性仅比现有药物氯喹(ED50值；1.3 mg/kg)的(1/5~1/6)低1/5~1/6。然而，在我们大院的情况下，感染疟疾的小鼠没有达到完全恢复，存活率为186%。而氯喹则让疟疾感染完全痊愈。随着该化合物给药时间的延长，明显的微生物系数有明显的改善。也就是说，通过延长给药时间，疟疾寄生虫的抑制作用被明确地认识到(不到2%)。根据这些结果，我们认为我们的化合物不能完全抑制疟疾感染，但我们的化合物与现有的抗疟疾药物联合使用将达到完全恢复疟疾感染死亡的目的。

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.