Synthesis, biological evaluation and in silico molecular modelling studies of chloro substituted bis-indole containing benzohydrazide analogues as potential anti-diabetic and anti-Alzheimer's agents

Fifteen bis-indolylmethane analogues were synthesized, characterized through NMR (1H, 13C) and highresolution electron-impact mass spectrometry (HREI-MS), and tested against alpha-glucosidase, alpha-amylase, acetylcholinesterase, and butyrylcholinesterase inhibitory potentials. All analogues exhibited different inhibitory potentials, with IC50 values ranging between 7.5 f 0.92 to 58.4 f 0.07 mu M (alpha-glucosidase), and 0.80 f 0.05 to 15.30 f 0.10 mu M (alpha-amylase) as compared to the standard drug acarbose (IC50 = 38.45 f 0.80 and 8.90 f 0.10 mu M). Out of fifteen analogues, nine showed an excellent inhibitory potency that was manyfold better than standard drugs. A slight increase or decrease in inhibition was observed due to substituents attached at imine site. In the case of alpha-amylase inhibition, two analogues such as 2 and 11, showed excellent inhibitory potential with IC50 values of 0.80 f 0.05 and 0.90 f 0.10 mu M while all other analogues showed good potency. All analogues were also tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory potentials, and they showed good potentials ranging from 1.40 f 0.20 to 16.20 f 0.50 mu M (AChE) and 3.20 f 0.10 to 19.60 f 0.20 mu M (BuChE) as compared to the standard drug Donepezil (IC50 = 2.16 f 0.12 mu M and 4.5 f 0.11 mu M). In the case of AChE, analogue 3 is the most potent, and in the case of BuChE, analogue 9 is the most potent among the series. The structure-activity relationship was carried out, mainly associated with the nature, number, and position and the electron-donating and electron-withdrawing effects of the substituent(s) on the phenyl ring. The binding modes as well as binding free energy for alpha-glucosidase and alpha-amylase inhibitors were determined through docking studies.