Benzimidazole analogues active against adult Schistosoma mansoni: SAR analyses, In vivo efficacy in mice, and preliminary mechanistic studies as potential inhibitors of hemozoin formation

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL
Godwin A. Dziwornu , Henrietta Dede Attram , Cécile Haeberli , Keabetswe Masike , Mathew Njoroge , Jennifer Keiser
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引用次数: 0

Abstract

For over three decades, praziquantel (PZQ) has been the mainstay chemotherapy for prevention and treatment of schistosomiasis. The excessive use of PZQ, coupled with the lack of advanced drug candidates in the current anti-schistosomiasis drug development pipeline, emphasizes the genuine need for new drugs. In the current work, we investigated the antischistosomal potential of a new series of compounds derived from the privileged benzimidazole scaffold, which exhibited low micromolar IC50 potency in the range of 1.0–2.7 μM against Schistosoma mansoni adult worms, in vitro. However, representative compounds showed low in vivo activity. One compound (15) reduced worm burden by 51.9 %, although the reduction was not statistically significant. Furthermore, by invoking inhibition of hemozoin formation, an immutable drug target in Schistosoma adult worms, as a likely contributing mode of action, we observed that the most potent analogues were equally potent inhibitors of β-hematin (synthetic hemozoin) formation in a cell-free assay.

Abstract Image

Abstract Image

对成年曼氏血吸虫有活性的苯并咪唑类似物:SAR分析,小鼠体内疗效,以及作为血色素形成潜在抑制剂的初步机制研究
三十多年来,吡喹酮(PZQ)一直是预防和治疗血吸虫病的主要化疗药物。PZQ的过度使用,加上目前抗血吸虫病药物开发管道中缺乏先进的候选药物,强调了对新药的真正需求。在本研究中,我们研究了从苯并咪唑支架中衍生的一系列化合物的体外抗血吸虫潜能,这些化合物对曼氏血吸虫成虫的IC50在1.0 ~ 2.7 μM范围内具有较低的微摩尔IC50效力。但代表性化合物的体内活性较低。其中一种化合物(15)减少了51.9%的虫负荷,但效果不显著。此外,通过抑制血色素(血吸虫成虫中一种不可变的药物靶点)的形成,作为一种可能的作用模式,我们观察到在无细胞实验中,最有效的类似物是同样有效的β-血红素(合成血色素)形成抑制剂。
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来源期刊
CiteScore
11.70
自引率
9.00%
发文量
863
审稿时长
29 days
期刊介绍: The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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