RESUMO
Leishmaniasis is a growing health problem worldwide. As there are certain drawbacks with the drugs currently used to treat human leishmaniasis and resistance to these drugs is emerging, there is a need to develop novel antileishmanial compounds, among which isoquinoline alkaloids are promising candidates. In this study, 18 novel oxoisoaporphine derivatives were synthesized and their possible antileishmanial activity was evaluated. The in vitro activity of these derivatives against Leishmania amazonensis axenic amastigotes was first evaluated, and the selected compounds were then tested in an inhibition assay with promastigotes of L. infantum, L. braziliensis, L. amazonensis and L. guyanensis, and with intracellular amastigotes of L. infantum and L. amazonensis. Finally, the most active compounds, OXO 1 (2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one) and OXO 13 (2,3,8,9,10,11-hexahydro-7H-dibenzo[de,h]quinolin-7-one), were tested in BALB/c mice infected with L. infantum. Treatment of mice at a dose of 10 mg/kg with OXO 1 yielded significant reductions (p<0.05) in parasite burden in liver and spleen (99% and 78%, respectively) whereas with OXO 13 were not significant. Although previous reports suggest that this family of molecules displays inhibitory activity against monoamine oxidase A and acetylcholinesterase, these enzymes were not confirmed as targets for antileishmanial activity on the basis of the present results. However, after development of a new bioinformatics model to analyze the Leishmania proteome, we were able to identify other putative targets for these molecules. The most promising candidates were four proteins: two putative pteridine reductase 2 (1MXF and 1MXH), one N-myristoyltransferase (2WUU) and one type I topoisomerase (2B9S).
Assuntos
Alcaloides/farmacologia , Aporfinas/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Aciltransferases/metabolismo , Animais , DNA Topoisomerases Tipo I/metabolismo , Isoquinolinas/farmacologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
With the significant increase of life expectancy of populations in societies today, the importance of the discovery of drugs associated with neurodegenerative diseases has emerged. Therefore, neurodegenerative diseases are an important topic in Medicinal Chemistry. Although drug discovery is considered a complex and slow process, new approaches and methods have been developed with the intention of finding new chemical entities in more efficient ways. This work provides a review of virtual methodologies applied in drug discovery and especially a new model for the prediction of MAO-A inhibitors using a multi-target QSAR methodology. This model involves a mixed approach containing simple descriptors based on atom-centered fragments and functional groups (DRAGON) and topological substructural molecular design descriptors (MODESLAB). This unified multi-species QSAR model was validated through a virtual screening of a new series of oxoisoaporphine derivatives, taking into account the information in the calculated fragmental contributions. Therefore, this method represents a useful tool for the in silico screening of MAO-A inhibitors.