Abstract：
Emerging resistance to current antimalarials is reducing their effectiveness and therefore there is a need to develop new antimalarial therapies. Toward this goal, high throughput screens against the P. falciparum asexual parasite identified the pyrazolopyridine 4-carboxamide scaffold. Structure-activity relationship analysis of this chemotype defined that the N1-tert-butyl group and aliphatic foliage in the 3- and 6-positions were necessary for activity, while the inclusion of a 7\'-aza-benzomorpholine on the 4-carboxamide motif resulted in potent anti-parasitic activity and increased aqueous solubility. A previous report that resistance to the pyrazolopyridine class is associated with the ABCI3 transporter was confirmed, with pyrazolopyridine 4-carboxamides showing an increase in potency against parasites when the ABCI3 transporter was knocked down. The low metabolic stability intrinsic to the pyrazolopyridine scaffold and the slow rate by which the compounds kill asexual parasites resulted in poor performance in a P. berghei asexual blood stage mouse model. Lowering the risk of resistance and mitigating the metabolic stability and cytochrome P450 inhibition will be challenges in the future development of the pyrazolopyrimidine antimalarial class.
摘要：
对当前抗疟药物的新出现的抗性正在降低其有效性,因此需要开发新的抗疟疗法。为了这个目标,针对恶性疟原虫无性寄生虫的高通量筛选鉴定了吡唑并吡啶4-甲酰胺支架。此化学型的结构-活性关系分析定义了N1-叔丁基和3-和6-位的脂肪族叶子是活性所必需的，而在4-甲酰胺基序上包含7'-氮杂-苯并吗啉会导致有效的抗寄生虫活性和增加的水溶性。先前的报告证实了对吡唑并吡啶类的抗性与ABCI3转运蛋白有关，当ABCI3转运蛋白被击倒时，吡唑并吡啶4-甲酰胺对寄生虫的效力增加。吡唑并吡啶支架固有的低代谢稳定性和化合物杀死无性寄生虫的缓慢速率导致伯氏疟原虫无性血液阶段小鼠模型的性能差。降低耐药性风险和减轻代谢稳定性和细胞色素P450抑制将是吡唑并嘧啶抗疟类未来发展的挑战。
