Synthesis and structure-activity relationships of antimalarial 4-oxo-3-carboxyl quinolones.

Malaria is endemic in tropical and subtropical regions of Africa, Asia, and the Americas. The increasing prevalence of multi-drug-resistant Plasmodium falciparum drives the ongoing need for the development of new antimalarial drugs. In this light, novel scaffolds to which the parasite has not been exposed are of particular interest. Recently, workers at the Swiss Tropical Institute discovered two novel 4-oxo-3-carboxyl quinolones active against the intra-erythrocytic stages of P. falciparum while carrying out rationally directed low-throughput screening of potential antimalarial agents as part of an effort directed by the World Health Organization. Here we report the design, synthesis, and preliminary pharmacologic characterization of a series of analogues of 4-oxo-3-carboxyl quinolones. These studies indicate that the series has good potential for preclinical development.

疟疾在非洲、亚洲和美洲的热带及亚热带地区流行。恶性疟原虫对多种药物耐药性的日益增加，推动了对开发新型抗疟药物的持续需求。有鉴于此，疟原虫未曾接触过的新型结构特别令人关注。最近，瑞士热带病研究所的研究人员在按照世界卫生组织指导的一项工作，对潜在抗疟药物进行合理定向的低通量筛选时，发现了两种对恶性疟原虫红细胞内期有活性的新型4 - 氧代 - 3 - 羧基喹诺酮。在此我们报道了一系列4 - 氧代 - 3 - 羧基喹诺酮类似物的设计、合成以及初步药理学特性。这些研究表明该系列在临床前开发方面具有良好潜力。