Re-styling an old scaffold: ebsulfur analogs with improved activity and selectivity against the infective stage of trypanosomes

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL
Cristina Quiroga, Marcelo Incerti, Diego Benítez, Martin Luzardo, Eduardo Manta, Alejandro Leyva, Margot Paulino, Marcelo A. Comini, Andrea Medeiros
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引用次数: 0

Abstract

Several species of trypanosomatids cause fatal and disabling diseases in humans and livestock animals. The current chemotherapy is limited and new drug candidates with improved efficacy and safety are needed. The benziso-thiazolone (e.g. Ebsulfur, EbS) and -selenazolone (e.g. Ebselen, EbSe) have been extensively investigated for their promising action towards transmissible and non-transmissible diseases.Here, we synthetized 23 benzisothiazolones and tested their anti-trypanosomatid activity against the clinically relevant stages of three major trypanosomatid species (Trypanosoma brucei brucei, Trypanosoma cruzi and Leishmania infantum). Several compounds presented nM or low μM activity and, at least a two-digit selectivity against Trypanosoma sp. but most proved inactive towards L. infantum. Structure-activity relationship analysis reveals that the chemotype of the top hits consisted of phenyl and benzyl rings occupying the N2 position of the benzisothiazolone scaffold and harboring polar substituents in the para position. Most compounds from these two clusters induced a rapid redox imbalance in the intracellular pool of low molecular weight thiols. None of the hits, but EbSe and EbS, affected Trypanothione synthetase activity (the enzyme producing the major low molecular weight thiol of trypanosomatids). However, at large enzyme:compound ratios, some inhibited irreversibly (and covalently) Trypanothione reductase (the enzyme maintaining trypanothione in a reduced state). Some hits exerted a minor effect on the rate of glucose consumption. Preliminary assessment of therapeutic efficacy in a murine infection model of acute African trypanosomiasis, the top candidate could not reduce parasite burden (monitored by in vivo imaging) but extended animal survival.

Abstract Image

改造旧支架:eb硫类似物对锥虫感染阶段具有更高的活性和选择性
有几种锥虫会对人类和家畜造成致命和致残性疾病。目前的化疗手段有限,需要疗效更好、安全性更高的新候选药物。苯并异噻唑啉酮(如 Ebsulfur,EbS)和硒唑啉酮(如 Ebselen,EbSe)因其对传染性和非传染性疾病具有良好的作用而受到广泛研究。在此,我们合成了 23 种苯并异噻唑啉酮类化合物,并测试了它们对三种主要锥虫(布鲁西锥虫、克鲁西锥虫和婴儿利什曼病)临床相关阶段的抗锥虫活性。一些化合物具有 nM 或低μM 活性,对布氏锥虫至少有两位数的选择性,但大多数化合物对婴儿利什曼原虫无活性。结构-活性关系分析表明,热门化合物的化学型由占据苯并异噻唑酮支架 N2 位的苯基和苄基环组成,并在对位上含有极性取代基。这两个化合物群中的大多数化合物都会引起细胞内低分子量硫醇池的快速氧化还原失衡。除 EbSe 和 EbS 外,其他化合物都不会影响锥硫蛋白合成酶(锥虫体内产生主要低分子量硫醇的酶)的活性。然而,当酶与化合物的比例较大时,有些化合物会不可逆地(共价地)抑制锥硫蛋白还原酶(维持锥硫蛋白还原状态的酶)。有些药物对葡萄糖消耗速度有轻微影响。在对急性非洲锥虫病小鼠感染模型的疗效进行初步评估后发现,最佳候选药物不能减轻寄生虫负担(通过体内成像监测),但能延长动物存活时间。
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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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