RESUMO
Loxosceles spiders' venoms consist of a mixture of proteins, including the sphingomyelinases D (SMases D), which are the main toxic components responsible for local and systemic effects in human envenomation. Herein, based on the structural information of SMase D from Loxosceles laeta spider venom and virtual docking-based screening approach, three benzene sulphonate compounds (named 1, 5 and 6) were identified as potential Loxosceles SMase D inhibitors. All compounds inhibited the hydrolysis of the sphingomyelin substrate by both recombinant and native SMases D. Compounds 5 and 6 acted as SMases D uncompetitive inhibitors with Ki values of 0.49 µM and 0.59 µM, respectively. Compound 1 is a mixed type inhibitor, and presented a Ki value of 0.54 µM. In addition, the three compounds inhibited the binding of SMases D to human erythrocytes and the removal of glycophorin C from the cell surface, which are important events in the complement-dependent haemolysis induced by Loxosceles venom. Moreover, compounds 5 and 6 reduced the binding of SMases to human keratinocytes membrane and the venom induced cell death. Importantly, compounds 5 and 6 also controlled the development of the necrotic lesion in an in vivo model of loxoscelism. Together, our findings indicate that the novel SMase D inhibitors presented here are able to suppress both local and systemic reactions induced by Loxosceles venoms. Since the number of Loxosceles envenomation accidents is currently growing worldwide, our results indicate that both inhibitors are promising scaffolds for the rational design of new drugs targeting SMases D from these spiders.
Assuntos
Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Dermatopatias/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Picada de Aranha/tratamento farmacológico , Animais , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Humanos , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Coelhos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , AranhasRESUMO
We report herein a new, practical, and economic synthesis of the phosphodiesterase inhibitor Rolipram on a multigram scale as well as the synthesis of new 4-aryl pyrrolidones and beta-aryl-gamma-amino butyric acids (GABA derivatives) employing an efficient Heck-Matsuda arylation of 3-pyrroline with aryldiazonium tetrafluoroborates. Racemic Rolipram was resolved into its enantiomers using chiral simulated moving bed chromatography having the low-cost microcrystalline cellulose triacetate as a chiral stationary phase.
Assuntos
Boratos/química , Compostos de Flúor/química , Inibidores de Fosfodiesterase/síntese química , Prolina/análogos & derivados , Pirrolidinonas/síntese química , Rolipram/síntese química , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/síntese química , Boratos/metabolismo , Cromatografia por Troca Iônica/métodos , Compostos de Diazônio/química , Compostos de Diazônio/metabolismo , Compostos de Flúor/metabolismo , Prolina/química , Pirrolidinonas/química , EstereoisomerismoRESUMO
A series of isoxazolopyridazinones and analogues has been prepared and evaluated as Leishmania mexicana phosphodiesterase (PDE) inhibitors. Some of the synthesized compounds showed a moderate PDE inhibitory activity at 100 microM and preliminary structure-activity relationships were discussed.