Vida Malinauskienė

A general approach towards the synthesis of tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one, tetrahydro[1,4]diazepino[1,2-a]indol-1-one and tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]diazepin-1-one derivatives was introduced. A regioselective strategy was developed for synthesizing ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylates from easily accessible 3(5)-aryl- or methyl-1H-pyrazole-5(3)-carboxylates. Obtained intermediates were further treated with amines resulting in oxirane ring-opening and direct cyclisation—yielding target pyrazolo[1,5-a][1,4]diazepin-4-ones. A straightforward two-step synthetic approach was applied to expand the current study and successfully functionalize ethyl 1H-indole- and ethyl 1H-benzo[d]imidazole-2-carboxylates. The structures of fused heterocyclic compounds were confirmed by ¹H, ¹³C, and ¹⁵N-NMR spectroscopy and HRMS investigation.

Methyl 2-amino-4-[1-(tert-butoxycarbonyl)azetidin-3-yl]-1,3-selenazole-5-carboxylate as a newly functionalized heterocyclic amino acid was obtained via [3+2] cycloaddition. The structure of the novel 1,3-selenazole was unequivocally confirmed by detailed ¹H, ¹³C, ¹⁵N, and ⁷⁷Se NMR spectroscopic experiments, HRMS and elemental analysis.

A small library of 2‐[(1H‐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‐[(1H‐indol‐3‐yl)methyl]‐1,3,4‐oxadiazole‐2(3H)‐thiones. The latter were then S‐alkylated, and in case of ester derivatives, they were further hydrolyzed into corresponding carboxylic acids. All 5‐[(1H‐indol‐3‐yl)methyl]‐1,3,4‐oxadiazole‐2(3H)‐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.