| Autor: |
de Sousa NF; Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil., da Silva Souza HD; Post-Graduate Program in Chemistry, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil., de Menezes RPB; Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil., da Silva Alves F; Post-Graduate Program in Chemistry, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil., Acevedo CAH; Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil., de Lima Nunes TA; Infectious Diseases Laboratory, Federal University of Delta of Parnaíba, Av. São Sebastião, nº 2819-Nossa Sra. de Fátima, Parnaíba 64202-020, PI, Brazil., Sessions ZL; Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA., Scotti L; Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil., Muratov EN; Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA., Mendonça-Junior FJB; Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil., da Franca Rodrigues KA; Infectious Diseases Laboratory, Federal University of Delta of Parnaíba, Av. São Sebastião, nº 2819-Nossa Sra. de Fátima, Parnaíba 64202-020, PI, Brazil., de Athayde Filho PF; Post-Graduate Program in Chemistry, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil., Scotti MT; Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil. |
| Abstrakt: |
The World Health Organization classifies Leishmania as one of the 17 “neglected diseases” that burden tropical and sub-tropical climate regions with over half a million diagnosed cases each year. Despite this, currently available anti-leishmania drugs have high toxicity and the potential to be made obsolete by parasite drug resistance. We chose to analyze organoselenides for leishmanicidal potential given the reduced toxicity inherent to selenium and the displayed biological activity of organoselenides against Leishmania. Thus, the biological activities of 77 selenoesters and their N-aryl-propanamide derivatives were predicted using robust in silico models of Leishmania infantum, Leishmania amazonensis, Leishmania major, and Leishmania (Viannia) braziliensis. The models identified 28 compounds with >60% probability of demonstrating leishmanicidal activity against L. infantum, and likewise, 26 for L. amazonesis, 25 for L. braziliensis, and 23 for L. major. The in silico prediction of ADMET properties suggests high rates of oral absorption and good bioavailability for these compounds. In the in silico toxicity evaluation, only seven compounds showed signs of toxicity in up to one or two parameters. The methodology was corroborated with the ensuing experimental validation, which evaluated the inhibition of the Promastigote form of the Leishmania species under study. The activity of the molecules was determined by the IC50 value (µM); IC50 values < 20 µM indicated better inhibition profiles. Sixteen compounds were synthesized and tested for their activity. Eight molecules presented IC50 values < 20 µM for at least one of the Leishmania species under study, with compound NC34 presenting the strongest parasite inhibition profile. Furthermore, the methodology used was effective, as many of the compounds with the highest probability of activity were confirmed by the in vitro tests performed. |
