Produção Nacional
Revisado por pares
Structure-guided discovery of thiazolidine-2,4-dione derivatives as a novel class of Leishmania major pteridine reductase 1 inhibitors
2016; Elsevier BV; Volume: 123; Linguagem: Inglês
10.1016/j.ejmech.2016.07.060
ISSN1768-3254
AutoresFranco Henrique Andrade Leite, Priscila Brandão Gomes da Silva Santiago, Thamires Quadros Froes, João da Silva Filho, Suellen Gonçalves da Silva, Rafael Matos Ximenes, Antônio Rodolfo de Faria, Dalci José Brondani, Julianna Ferreira Cavalcanti de Albuquerque, Marcelo Santos Castilho,
Tópico(s)Synthesis and biological activity
ResumoLeishmania major, as other protozoan parasites, plague human kind since pre-historic times but it remains a worldwide ailment for which the therapeutic arsenal remains scarce. Although L. major is pteridine- and purine-auxotroph, well-established folate biosynthesis inhibitors, such as methotrexate, have poor effect over the parasite survival. The lack of efficiency is related to an alternative biochemical pathway in which pteridine reductase 1 (PTR1) plays a major role. For this reason, this enzyme has been considered a promising target for anti-leishmanial drug development and several inhibitors that share the substrate scaffold have been reported. In order to design a novel class of PTR1 inhibitors, we employed the thiazolidinone ring as a bioisosteric replacement for pteridine/purine ring. Among seven novel thiazolidine-2,4-dione derivatives reported herein, 2d was identified as the most promising lead by thermal shift assays (ΔTm = 11 °C, p = 0,01). Kinetic assays reveal that 2d has IC50 = 44.67 ± 1.74 μM and shows a noncompetitive behavior. This information guided docking studies and molecular dynamics simulations (50 000 ps) that supports 2d putative binding profile (H-bonding to Ser-111 and Leu-66) and shall be useful to design more potent inhibitors.
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