N,N′-Disubstituted thiourea and urea derivatives: design, synthesis, docking studies and biological evaluation against nitric oxide synthase
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AutorChayah, Meriem; Camacho Quesada, Encarnación; Carrión Peregrina, María Dora; Gallo Mezo, Miguel Ángel; Romero, Miguel; Duarte, Juan
Royal Society of Chemistry
ThioureaUreaNitric oxide synthase
Chayah, M.; et al. N,N′-Disubstituted thiourea and urea derivatives: design, synthesis, docking studies and biological evaluation against nitric oxide synthase. MedChemComm, 7: 667-678 (2016). [http://hdl.handle.net/10481/47297]
PatrocinadorWe are very grateful to Dr. Pedro A. Sánchez-Murcia for his help. This work was partially supported by the Instituto de Salud Carlos III through grant FI11/00432 and by Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (RIC RD12/0042/0011).
The synthesis and biological evaluation of new types of N,N′-disubstituted thiourea and urea derivatives as inhibitors of both neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) are described. These compounds have been designed by reduction of the carbonyl group in the thiourea and urea kynurenamine derivatives 3 previously synthesized by our research group. The synthetic route performed to this new family also allows us to obtain the molecules 3 with less synthetic steps and higher global yield. Regarding the biological results, in general, the new derivatives 4a–q inhibit the neuronal NOS isoform better than the inducible one. Furthermore, thioureas exhibit higher inhibition than ureas for both isoenzymes. Among all the tested compounds, 4g shows significant nNOS (80.6%) and iNOS (76.6%) inhibition values without inhibiting eNOS. This molecule could be an interesting starting point for the design of new inhibitors with application in neurological disorders where both isoenzymes are implicated such as Parkinson's disease.