NOVEL UREA, THIOUREA AND SELENOUREA DERIVATIVES OF DISELENIDES: SYNTHESIS AND LEISHMANICIDAL ACTIVITY [Chemistry; Biosynthesis]

A novel series of thirty-one N-substituted urea, thiourea and selenourea derivatives containing diphenyldiselenide entity were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity with EC₅₀ values lower than the reference drug miltefosine (EC₅₀ = 2.84 μM). In addition, the derivatives 9, 11, 42 and 47 with EC₅₀ between 1.1 and 1.95 μM also displayed an excellent selectivity (SI ranged from 12.4 to 22.7) and were also tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes with EC₅₀ values similar to those observed for the standard drug edelfosine. SAR analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leishmanicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase (TryR). Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their comparable activity with the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.

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