Fisher Gillian M, Bua Silvia, Del Prete Sonia, Arnold Megan S J, Capasso Clemente, Supuran Claudiu T, Andrews Katherine T, Poulsen Sally-Ann
Griffith Institute for Drug Discovery, Griffith University, Queensland, Australia.
Neurofarba Department, Sezione di Scienze Farmaceutiche Nutraceutiche, and Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Sesto Fiorentino, Florence, Italy.
Int J Parasitol Drugs Drug Resist. 2017 Apr;7(1):61-70. doi: 10.1016/j.ijpddr.2017.01.003. Epub 2017 Jan 13.
In the past decade there has been a significant reduction in deaths due to malaria, in part due to the success of the gold standard antimalarial treatment - artemisinin combination therapies (ACTs). However the potential threat of ACT failure and the lack of a broadly effective malaria vaccine are driving efforts to discover new chemical entities (NCEs) to target this disease. The primary sulfonamide (PS) moiety is a component of several clinical drugs, including those for treatment of kidney disease, glaucoma and epilepsy, however this chemotype has not yet been exploited for malaria. In this study 31 PS compounds sourced from the GlaxoSmithKline (GSK) Tres Cantos antimalarial set (TCAMS) were investigated for their ability to selectively inhibit the in vitro growth of Plasmodium falciparum asexual stage malaria parasites. Of these, 14 compounds were found to have submicromolar activity (IC 0.16-0.89 μM) and a modest selectivity index (SI) for the parasite versus human cells (SI > 12 to >43). As the PS moiety is known to inhibit carbonic anhydrase (CA) enzymes from many organisms, the PS compounds were assessed for recombinant P. falciparum CA (PfCA) mediated inhibition of CO hydration. The PfCA inhibition activity did not correlate with antiplasmodial potency. Furthermore, no significant difference in IC was observed for P. falciparum versus P. knowlesi (P > 0.05), a Plasmodium species that is not known to contain an annotated PfCA gene. Together these data suggest that the asexual intraerythrocytic stage antiplasmodial activity of the PS compounds examined in this study is likely unrelated to PfCA inhibition.
在过去十年中，疟疾死亡人数显著减少，部分原因是黄金标准抗疟治疗——青蒿素联合疗法（ACTs）取得了成功。然而，ACT治疗失败的潜在威胁以及缺乏广泛有效的疟疾疫苗，促使人们努力寻找针对这种疾病的新化学实体（NCEs）。伯胺磺胺（PS）部分是几种临床药物的组成部分，包括用于治疗肾脏疾病、青光眼和癫痫的药物，然而这种化学类型尚未用于疟疾治疗。在本研究中，对从葛兰素史克（GSK）的坎托斯三村抗疟药物集（TCAMS）中获取的31种PS化合物进行了研究，以考察它们选择性抑制恶性疟原虫无性期疟原虫体外生长的能力。其中，发现14种化合物具有亚微摩尔活性（IC 0.16 - 0.89 μM），并且对寄生虫与人细胞具有适度的选择性指数（SI）（SI > 12至> 43）。由于已知PS部分可抑制许多生物体中的碳酸酐酶（CA），因此对PS化合物进行了重组恶性疟原虫CA（PfCA）介导的CO水合抑制评估。PfCA抑制活性与抗疟效力不相关。此外，未观察到恶性疟原虫与诺氏疟原虫之间的IC有显著差异（P > 0.05），诺氏疟原虫是一种未知含有注释PfCA基因的疟原虫物种。这些数据共同表明，本研究中检测的PS化合物的无性红细胞内期抗疟活性可能与PfCA抑制无关。
