Selene-Ethylenelacticamides and <i>N</i>-Aryl-Propanamides as Broad-Spectrum Leishmanicidal Agents
Natália Ferreira de Sousa,
Helivaldo Diógenes da Silva Souza,
Renata Priscila Barros de Menezes,
Francinara da Silva Alves,
Chonny Alexander Herrera Acevedo,
Thaís Amanda de Lima Nunes,
Zoe L. Sessions,
Luciana Scotti,
Eugene N. Muratov,
Francisco Jaime Bezerra Mendonça-Junior,
Klinger Antônio da Franca Rodrigues,
Petrônio Filgueiras de Athayde Filho,
Marcus Tullius Scotti
Affiliations
Natália Ferreira de Sousa
Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
Helivaldo Diógenes da Silva Souza
Post-Graduate Program in Chemistry, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
Renata Priscila Barros de Menezes
Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
Francinara da Silva Alves
Post-Graduate Program in Chemistry, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
Chonny Alexander Herrera Acevedo
Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
Thaís Amanda de Lima Nunes
Infectious Diseases Laboratory, Federal University of Delta of Parnaíba, Av. São Sebastião, nº 2819-Nossa Sra. de Fátima, Parnaíba 64202-020, PI, Brazil
Zoe L. Sessions
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
Luciana Scotti
Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
Eugene N. Muratov
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
Francisco Jaime Bezerra Mendonça-Junior
Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
Klinger Antônio da Franca Rodrigues
Infectious Diseases Laboratory, Federal University of Delta of Parnaíba, Av. São Sebastião, nº 2819-Nossa Sra. de Fátima, Parnaíba 64202-020, PI, Brazil
Petrônio Filgueiras de Athayde Filho
Post-Graduate Program in Chemistry, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
Marcus Tullius Scotti
Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
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 50 values 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.