Open AccessNew Amides Containing Selenium as Potent Leishmanicidal Agents Targeting Trypanothione Reductase
Author(s) -
Mikel Etxebeste-Mitxeltorena,
Daniel Plano,
Socorro Espuelas,
Esther Moreno,
Carlos Aydillo,
Antonio Jiménez-Ruı́z,
Juan Carlos García-Soriano,
Carmen Sanmartín
Publication year - 2020
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00524-20
Subject(s) - miltefosine , chemistry , leishmania infantum , selectivity , amastigote , amide , stereochemistry , selenium , leishmania , thioredoxin reductase , leishmaniasis , pharmacology , biochemistry , biology , organic chemistry , enzyme , immunology , glutathione , parasite hosting , world wide web , computer science , catalysis , visceral leishmaniasis
Two new series of 28 selenocyanate and diselenide derivatives containing amide moieties were designed, synthesized, and evaluated for their leishmanicidal activity against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Eleven compounds exhibited excellent leishmanicidal activity with EC 50 values lower than the reference drug miltefosine (EC 50 = 2.84 μM). In addition, for six of them the selectivity index ranged from 9 to >1,442, greater than both references used. The most potent and selective compounds were compounds 2h, 2k, and 2m that displayed EC 50 values of 0.52, 1.19, and 0.50 μM, respectively, and a high selectivity index (SI) when tested against THP-1 monocytic cells (SI = >1,442, >672, and >1,100, respectively). These derivatives showed an efficacy similar to that of the reference drugs but much better SI values. They also showed interesting activity values against infected macrophages. Trypanothione reductase (TryR) activity and intracellular thiol level measurement assays were performed for the three best compounds in an attempt to elucidate their mechanism of action. Despite that the new analogs exhibited comparable or better inhibitory activities than the reference TryR inhibitors, more studies are necessary to confirm this result. In summary, our findings suggest that the three compounds described here could constitute leading leishmanicidal drug candidates.