| Texto completo | |
| Autor(es): |
Mollo, Maria C.
;
Cambiaso, Mariana L.
;
Ferreira, Leonardo L. G.
;
Kilimciler, Natalia B.
;
Bisceglia, Juan A.
;
Andricopulo, Adriano D.
;
Orelli, Liliana R.
Número total de Autores: 7
|
| Tipo de documento: | Artigo Científico |
| Fonte: | BIOORGANIC CHEMISTRY; v. 154, p. 8-pg., 2024-12-24. |
| Resumo | |
This work describes the synthesis and biological evaluation of hitherto unknown N-arylspermidine derivatives 3. Compounds 3 were efficiently prepared from cyclic amidines through a novel synthetic approach comprising alkylation with omega-halonitriles followed by reduction. The cyclic N-arylamidine directs the alkylation to the unsubstituted nitrogen and also provides the N-benzyl group present in the triamine after simultaneous reduction of the resulting quaternary salt 2 and the cyano group. The N-aryl spermidines were tested in Leishmania infantum promastigotes and also in the more challenging form intracellular amastigotes. The compounds toxicity was also assessed in two cell lines, THP-1 and HepG2. In silico physicochemical and ADME predictions were also carried out. Eight out of ten compounds displayed EC50 around 5 mu M against L. infantum intracellular amastigotes. Among them, derivatives 3c, 3d, and 3h showed potency in the low micromolar range with SI > 5 and suitable predicted physicochemical ADME properties. The antileishmanial activity of the compounds would rely on the Narylspermidine moiety, as assessed by evaluation of related substructures which were inactive. This first series of compounds, among which two derivatives (3b,h) displayed EC50 values comparable to Miltefosine, represent a good starting point for further studies and multiparametric optimization to obtain more potent and selective candidates for the treatment of this neglected tropical disease. (AU) | |
| Processo FAPESP: | 13/25658-9 - Planejamento e Desenvolvimento de Candidatos a Fármacos para a Doença de Chagas |
| Beneficiário: | Leonardo Luiz Gomes Ferreira |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |
| Processo FAPESP: | 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos |
| Beneficiário: | Glaucius Oliva |
| Modalidade de apoio: | Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs |
| Processo FAPESP: | 15/50655-9 - Consórcio FAPESP/MMV/DNDI/UNICAMP/USP para descobrir novos medicamentos para o tratamento de doenças parasitárias tropicais |
| Beneficiário: | Luiz Carlos Dias |
| Modalidade de apoio: | Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE |
| Processo FAPESP: | 18/14268-9 - Descoberta de fármacos baseada na estrutura do receptor e do ligante para a Leishmaniose e a Doença de Chagas a partir de produtos naturais bioativos |
| Beneficiário: | Adriano Defini Andricopulo |
| Modalidade de apoio: | Auxílio à Pesquisa - Temático |