Discovery of highly potent and selective antiparasitic new oxadiazole and hydroxy-oxindole small molecule hybrids

被引：18

作者：

Fernandes, Fabio S. ^{[1
]}

Santos, Hugo ^{[1
]}

Lima, Samia R. ^{[1
]}

Conti, Caroline ^{[1
]}

Rodrigues Jr, Manoel T. ^{[1
]}

Zeoly, Lucas A. ^{[1
]}

Ferreira, Leonardo L. G. ^{[2
]}

Krogh, Renata ^{[2
]}

Andricopulo, Adriano D. ^{[2
]}

Coelho, Fernando ^{[1
]}

机构：

[1] Univ Estadual Campinas, Inst Chem, Lab Synth Nat Prod & Drugs, POB 6154, BR-13083970 Campinas, SP, Brazil

[2] Univ Sao Paulo, Inst Phys Sao Carlos, Lab Med & Computat Chem, Ave Joao Dagnone 1100, BR-13563120 Sao Carlos, SP, Brazil

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 201卷

基金：

巴西圣保罗研究基金会;

关键词：

Trypanosomiasis; Leishmaniasis; Heterocycles; Morita-Baylis-Hillman; Olefin metathesis; Grubbs catalyst; Organocatalysis; BAYLIS-HILLMAN REACTION; IN-VITRO; DRUG DISCOVERY; ISATINS; DERIVATIVES; HETEROCYCLES; MECHANISM; PARASITES; ADDUCTS; DESIGN;

D O I：

10.1016/j.ejmech.2020.112418

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of highly active hybrids were discovered as novel antiparasitic agents. Two heterocyclic scaffolds (1,2,4-oxadiazole and 3-hydroxy-2-oxindole) were linked, and the resulting compounds showed in vitro activities against intracellular amastigotes of two protozoan parasites, Tiypanosoma cruzi and Leishmania infantum. Their cytotoxicity was assessed using HFF-1 fibroblasts and HepG2 hepatocytes. Compounds 5b, 5d, 8h and 8o showed selectivity against L. infantum (IC50 values of 3.89, 2.38, 2.50 and 2.85 mu M, respectively). Compounds 4c, 4q, 8a and 8k were the most potent against T. cruzi, exhibiting IC50 values of 6.20, 2.20, 2.30 and 2.20 mu M, respectively. Additionally, the most potent anti-T. cruzi compounds showed in vitro efficacies comparable or superior to that of benznidazole. These easy-to-synthesize molecules represent novel chemotypes for the design of potent and selective lead compounds for Chagas disease and leishmaniasis drug discovery. (C) 2020 Elsevier Masson SAS. All rights reserved.

引用

页数：14

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