Síntese e avaliação farmacológica de novas 3-(imidazo[1,2-α]piridinas)-cumarinas planejadas para o tratamento da Doença de Alzheimer

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease that has complex pathogenesis, inducing memory loss and cognitive disorders, which usually present in old age. The coumarins and imidazopyridines (IM) are classes of compounds with wide pharmacological activity and several promising studies related to the treatment of AD acting on several targets such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), aggregation of β-amyloid plaques (Aβ), and among others. Thus, the general objective of this work is the synthesis of new 3- (imidazo [1,2-α] pyridin-2-yl) -coumarins, based on classic bioisosterism of 4-(dimethylamino) phenyl groups by imidazopyridines (IM) as possible cholinesterase inhibitors for the treatment of AD. The first series is originated from the synthesis of 3-(imidazo [1,2-α] pyridines)-coumarins (66a-d) involving 5 reaction steps: synthesis of 3-acetyl-coumarins (67a-c) (yields 70 % to 90%) (step 1), α-bromination of 3-acetyl-coumarins (yields 51 to 73%) (step 2), formation of the IM nucleus (step 3) (64 to 69% yield), alkylation of the IMs with conversions of 74% to 88% (step 4) and, finally, the amination step with the formation of the final compounds (66a-b). The second series came from the synthesis of 3-(imidazo [1,2-α] pyridines-9'-ethylcarboxylate)-coumarins, involving Knoevenagel condensation steps to form compounds with coumarin nucleus (89) (86% yield), O-alkylation (93a-d) (yields from 30 to 74%), core formation of MIs (102a-d) (yields from 42 to 74%) and amination (103a-d) (yields from 31% to 79%). Initial screening at a fixed concentration of 30 μM, for two final compounds 66b and 103b, showed an enzymatic inhibition of approximately 91.7% (AChE) / 92.4% (BuChE) and 98.1% (AChE) / 88, 6% (BuChE), respectively. In addition to the activity, in sílico studies of molecular modeling and ADME parameters were carried out. Based on these preliminary results, new compounds are being synthesized, the IC50 and the enzymatic kinetics against cholinesterases will be determined.