Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

Abstract

A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and their in vitro leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED 50 ) values ranging from 0.45 to 1.27 M and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3=-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

“…Our data revealed that some of these compounds possess potent activity with higher selectivity than the reference drugs miltefosine and edelfosine. Additionally, leishmanicidal activity in infected macrophages (THP-1 cells) was comparable to that of edelfosine (9)(10)(11)(12)(13)(14)(15)(16). Among the different selenium entities tested, 4,4=-diaminodiphenyldiselenide showed one of the most promising leishmanicidal activities.…”

“…Thus, this spacer causes a drop in the leishmancidal activity in selenoureas, while in ureas and thioreas it is responsible for a significant increase. With regard to the introduction of alkyl side chains, this modification confers a marked leishmanicidal increase in the three series of compounds (9,10,11,20,21,22,46, 47, and 48), with seven of them being more active than miltefosine. This phenomenon indicates that the activity correlates with an increase in the lipophilicity of the compounds.…”

Library of Seleno-Compounds as Novel Agents against Leishmania Species

“…The group I compounds were obtained by the nucleophilic substitution of the halogen atom of the corresponding alkyl or benzyl halides by a selenocyanate group using potassium selenocyanate (KSeCN) under reflux conditions according to previously reported methods (29,30). Thus, the corresponding organic halide was refluxed for 2 to 4 h in acetone with potassium selenocyanate.…”

“…The solid obtained was purified either by recrystallization or by washing with different solvents. Group II derivatives were synthesized by reduction of the corresponding selenocyanate from group I using sodium borohydride following the previously described procedure (29,30). In order to do so, sodium borohydride was added with caution to a stirring solution of the corresponding selenocyanate from group I in absolute ethanol.…”

Theoretical Investigation of Cyano‐Chalcogen Dimers and Their Importance in Molecular Recognition

“…[60] Similarly, selenium plays an important role in normal biological function [61] through its incorporation into processes that protect against oxidative stress, and its bioactivity mechanism has been studied using DFT calculations. [62] Selenocyanatecontaining derivatives have been found to possess anticancer and chemopreventive, [63][64][65] antifungal, [66] and antileishmanial [67,68] activity. Therefore, their synthesis, characterization, and uses in chemistry and molecular recognition have recently gained a lot of interest.…”