New Amides Containing Selenium as Potent Leishmanicidal Agents Targeting Trypanothione Reductase

Abstract

Two new series of twenty-eight selenocyanate and diselenide derivatives containing amide moiety 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 EC50 values lower than the reference drug miltefosine (EC50 = 2.84 μM). In addition, for six of them the selectivity index ranged from 9 to > 1442, greater than both references used. The most potent and selective compounds were 2h, 2k and 2m that displayed EC50 values of 0.52, 1.19 and 0.50 μM and a high selectivity index (SI) when tested against THP-1 monocytic cells (SI = >1442, > 672 and >1100, respectively). These derivatives showed an efficacy similar to that of the reference drugs but much better SI. They also showed very 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. Even though the new analogues exhibited comparable or better inhibitory activities than reference TryR inhibitors more studies are necessary to confirm this target. To sum up, our findings suggest that the three presented compounds could constitute lead leishmanicidal drug candidates.

New Amides and Phosphoramidates Containing Selenium: Studies on Their Cytotoxicity and Antioxidant Activities in Breast Cancer

“…Synthesis, purification and characterization of the compounds have been previously described [30]. Chemicals were purchased from E. Merck (Darmstadt, Germany), Panreac Química S.A: (Montcada I Reixac, Barcelona, Spain), Sigma-Aldrich Química S.A. (Alcobendas, Madrid, Spain) and Across Organics (Janssen Pharmaceuticals, Geel, Belgium).…”

“…The route adopted for the synthesis of the novel forty-one compounds presented in this work has been previously reported [30,31]. Structures are summarized in Figure 1.…”

“…The synthesis of both series of compounds followed similar synthetic routes. Briefly, 4-aminophenylselenocyanate (0A) and bis-(4-aminophenyl)diselenide (0B) were achieved as previously reported [30]. For series I, selenocyanate derivatives (1a-1n) were obtained by the reaction of the amine 0A with the corresponding acid chlorides.…”

“…For series I, selenocyanate derivatives (1a-1n) were obtained by the reaction of the amine 0A with the corresponding acid chlorides. Diselenides were synthesized by the reaction between 0B and the corresponding acid chloride (2d, 2k and 2m) or by the reduction of the corresponding selenocyanate analogs with sodium borohydride to yield 2a-2c, 2e-2j, 2i and 2n [30].…”

“…For series II, 0A and 0B were treated dropwise with the corresponding phosphoryl chlorides under different temperatures, atmospheric conditions and reaction times [31].…”