To achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-action activity against . This work identified ,-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplasmodial chemotype (e.g., 96 h IC 550 nM; 96 h IC 160 nM) with a different action to delayed-death slow-action drugs. A series of analogues were synthesized from thiotetrazoles and carbomoyl derivatives using Huisgen 1,3,4-oxadiazole synthesis followed by oxidation of the resultant thioethers to target sulfones. Structure activity relationship analysis of analogues identified compounds with potent and selective activity against drug-sensitive and multi-drug resistant parasites (e.g., and 96 h IC <40 nM; SI > 2500). Subsequent studies in mice with compound , which had the best microsomal stability of the compounds assessed (T >255 min), demonstrated rapid clearance and poor oral efficacy in a murine malaria model. These data indicate that while ,-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines are a novel class of slow-acting antiplasmodial agents, the further development of this chemotype for malaria chemoprophylaxis will require pharmacokinetic profile improvements.

中文翻译：

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发现对恶性疟原虫疟原虫具有慢作用活性的 1,3,4-恶二唑


为了实现根除疟疾，需要与一线治疗药物作用不同的新预防药物。为了确定潜在的化学预防起点，我们筛选了 CSIRO 澳大利亚化合物库的子集，以寻找具有慢作用活性的化合物。这项工作确定了 ,-二烷基-5-烷基磺酰基-1,3,4-恶二唑-2-胺作为一种新的抗疟原虫化学型（例如，96 h IC 550 nM；96 h IC 160 nM），具有不同的延迟死亡作用缓慢作用的药物。使用Huisgen 1,3,4-恶二唑合成法，由硫代四唑和甲酰基衍生物合成了一系列类似物，然后将所得硫醚氧化为目标砜。类似物的结构活性关系分析确定了对药物敏感和多重耐药寄生虫具有有效和选择性活性的化合物（例如，96 h IC <40 nM；SI > 2500）。随后在使用化合物的小鼠中进行的研究表明，在小鼠疟疾模型中，化合物的微粒体稳定性最好（T>255分钟），其清除速度快，口服疗效较差。这些数据表明，虽然 ,-二烷基-5-烷基磺酰基-1,3,4-恶二唑-2-胺是一类新型的慢效抗疟原虫药物，但这种用于疟疾化学预防的化学型的进一步开发将需要药代动力学特征的改进。