Investigation of novel benzimidazole-based indole/thiazole hybrids derivatives as effective anti-diabetics and anti-alzheimer's agents: Structure-activity relationship insight, in vitro and in silico approaches

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are common in developed countries and their incidence is increasing. The research is mostly concentrated on the exploration of novel therapies to remedy or avert these ailments. AD and T2DM have several molecular pathways in common that contributes to their degenerative development.A novel series of ten hybrid analogues (1-10) based on benzimidazole bearing indole analogues were synthesized and these scaffolds were characterized by spectroscopic techniques like HR-EIMS, 13CNMR and 1HNMR. Furthermore,the synthesized moieties were screened for α-amylase and α-glucosidase inhibitory activities. All these synthesized analogues showed good to moderate α-amylase and α-glucosidase inhibition potency ranging (4.90 ± 0.10 to 15.30 ± 0.60 µM) and (5.30 ± 0.10 to 16.10 ± 0.60 µM) while acarbose was used as a reference standard (IC50 = 10 .30 ±0.20µM), (IC50 = 9.80 ± 0.20 µM). Another series of ten hybrid analogues (11-20) based on benzimidazole bearing thiazole moieties were synthesized and were evaluated for AChE and BuChE inhibition activities. All these newly afforded analogues showed good to moderate AChE and BuChE inhibitory potential ranging of (IC50 = 0.20 ± 0.01 µM), (IC50 = 0.15 ± 0.01 µM) to (IC50 = 3.90 ± 0.20 µM), (IC50 = 3.80 ± 0.10 µM) while Donepezil was taken as a reference standard with (IC50 = 0.016 ± 0.01 µM), (IC50 = 0.30 ± 0.010 µM).The scaffolds were also characterized using spectroscopic techniques such as HR-EIMS, 13CNMR and 1HNMR for a better understanding of their structure. SAR was done for all synthesized analogues for substituents.In addition, docking research was conducted to determine the binding mode of interaction between the active site of analogues and targeted enzymes. This work aims to estimate the potential of the synthesized scaffolds as competitors to existing drugs. Incorporating molecular docking analysis with in vitro activities improves the accuracy of predictions and validates the possibility of these compounds as options for treating type-2 diabetes and Alzheimer's disease.