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Synthesis of 5‐[(1 H ‐indol‐3‐yl)methyl]‐1,3,4‐oxadiazole‐2(3 H )‐thiones and their protective activity against oxidative stress
Author(s) -
Iškauskienė Monika,
Kadlecová Alena,
Voller Jiří,
Janovská Lucie,
Malinauskienė Vida,
Žukauskaitė Asta,
Šačkus Algirdas
Publication year - 2021
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.202100001
Subject(s) - chemistry , oxadiazole , alkylation , glutathione , stereochemistry , in vivo , indole test , organic chemistry , enzyme , microbiology and biotechnology , biology , catalysis
A small library of 2‐[(1 H ‐indol‐3‐yl)methyl]‐5‐(alkylthio)‐1,3,4‐oxadiazoles was prepared, starting from indole‐3‐acetic acid methyl ester and its 5‐methyl‐substituted derivative. The synthetic route involved the formation of intermediate hydrazides, their condensation with carbon disulfide, and intramolecular cyclization to corresponding 5‐[(1 H ‐indol‐3‐yl)methyl]‐1,3,4‐oxadiazole‐2(3 H )‐thiones. The latter were then S‐alkylated, and in case of ester derivatives, they were further hydrolyzed into corresponding carboxylic acids. All 5‐[(1 H ‐indol‐3‐yl)methyl]‐1,3,4‐oxadiazole‐2(3 H )‐thiones and their S‐alkylated derivatives were then screened for their protective effects in vitro and in vivo. Methyl substitution on the indole ring and propyl, butyl, or benzyl substitution on sulfhydryl group‐possessing compounds were revealed to protect Friedreich's ataxia fibroblasts against the effects of glutathione depletion induced by the γ‐glutamylcysteine synthetase inhibitor, buthionine sulfoximine. Two of the active compounds also reproducibly increased the survival of Caenorhabditis elegans exposed to juglone‐induced oxidative stress.