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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >N, N ', N ''-trisubstituted guanidines: Synthesis, characterization and evaluation of their leishmanicidal activity
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N, N ', N ''-trisubstituted guanidines: Synthesis, characterization and evaluation of their leishmanicidal activity

机译：n，n'，n'' - 脱硫的胍：它们的Leishmanicidal活性的合成，表征和评估

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摘要

Leishmaniasis is a group of diseases caused by protozoan parasites from the genus Leishmania. There are estimated 1.3 million new cases annually with a mortality of 20,000-30,000 per year, when patients are left untreated. Current chemotherapeutic drugs available present high toxicity and low efficacy, the latter mainly due to the emergence of drug-resistant parasites, which makes discovery of novel, safe, and efficacious antileishmanial drugs mandatory. The present work reports the synthesis, characterization by ESI-MS, H-1 and C-13 NMR, and FTIR techniques as well as in vitro and in vivo evaluation of leishmanicidal activity of guanidines derivatives presenting lower toxicity. Among ten investigated compounds, all being guanidines containing a benzoyl, a benzyl, and a substituted phenyl moiety, LQOF-G2 (IC50-ama 5.6 mu M: SI = 131.8) and LQOF-G7 (IC50-ama 7.1 mu M; SI = 87.1) were the most active against L. amazonensis intracellular amastigote, showing low cytotoxicity to the host cells according to their selectivity index. The most promising compound, LQOF-G2, was further evaluated in an in vivo model and was able to decrease 60% of the parasite load in foot lesions at a dose of 0.25 mg/kg/day. Moreover, this guanidine derivative demonstrated reduced hepatotoxicity compared to other leishmanicidal compounds and did not show nephrotoxicity, as determined by the analyses of biomarkers of hepatic damage and renal function, which make this compound a potential new hit for therapy against leishmaniasis. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：Leishmaniaisis是由Leishmania属的原生动物寄生虫引起的一组疾病。当患者未经治疗时，每年估计每年130万新案例，每年死亡率为20,000-30,000。目前的化学治疗药物可提供高毒性和低疗效，后者主要是由于耐药寄生虫的出现，这使得发现新颖，安全和有效的抗溃疡种药物强制性。本作者报告了ESI-MS，H-1和C-13 NMR的合成，表征，以及FTIR技术以及体外和体内评估脱毒药衍生物的Leishmanical活性。在十种研究的化合物中，所有是含有苯甲酰基，苄基和取代的苯基部分的胍，LQOF-G2（IC50-AMA 5.6 mu M：Si = 131.8）和LQOF-G7（IC50-AMA7.1μm; si = 87.1）对L. Amazonensis细胞内的神经内引起最活跃，根据其选择性指数显示对宿主细胞的低细胞毒性。最有希望的化合物LQOF-G2在体内模型中进一步评估，并且能够在0.25mg / kg /天的剂量下减少60％的寄生虫载荷。此外，与其他Leishmanicidal化合物相比，这种胍衍生物证明了肝毒性降低，并且未显示肾毒性，通过分析肝损伤和肾功能的生物标志物来确定，这使得该化合物对LeishManiaisis进行潜在的新袭击。 （c）2019年Elsevier Masson SAS。版权所有。

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