Computational & experimental evaluation of the structure/activity relationship of ß-carbolines as DYRK1A inhibitors.

DYRK1A has been associated with Down's syndrome and neurodegenerative diseases, therefore it is an important target for novel pharmacological interventions. We combined a ligand-based pharmacophore design with a structure-based protein/ligand docking using the software MOE in order to evaluate the underlying structure/activity relationship. Based on this knowledge we synthesized several novel ß-carboline derivatives to validate the theoretical model. Furthermore we identified a modified lead structure as a potent DYRK1A inhibitor (IC50=130 nM) with significant selectivity against MAO-A, DYRK2, DYRK3, DYRK4 & CLK2.

Comparative study of the trypanocidal activity of the methyl 1-nitrophenyl-1,2,3,4-9H-tetrahydro-beta-carboline-3-carboxylate derivatives and benznidazole using theoretical calculations and cyclic voltammetry.

The cis and trans isomers of methyl 1-(m-nitro)phenyl and 1-(p-nitro)phenyl-1,2,3,4-tetrahydro-9H-beta-carboline-3-carboxylates (compounds 3a,b, 4a and b) were synthesized and evaluated in vitro against epimastigote forms of Trypanosoma cruzi. Among all of the evaluated tetrahydro-beta-carboline derivatives, the compound trans-methyl 1-(m-nitro)phenyl-1,2,3,4-9H-tetrahydro-beta-carboline-3-carboxylate (3b) was found to exhibit significant trypanocidal activity (IC(50)=22.2 microM). Theoretical studies of molecular conformations and electronic properties for the synthesized compounds and benznidazole, as well as, the cyclic voltammetric (CV) behaviors' determination were performed. A comparative study of the trypanocidal activity of the nitrophenyl-tetrahydro-beta-carbolines derivatives and benznidazole, using the results of theoretical calculations and of the cyclic voltammetry experiments, is presented.