Synthesis, molecular docking, and bioactivity study of bis-indole-sulfonamide analogues as acetylcholinesterase and butyrylcholinesterase inhibitors

Abstract

We have synthesized fourteen bis-indole-sulphonohydrazide hybrid analogues (1–14) from simple indole and benzoate as a starting material. All analogues were characterized through different spectroscopic techniques (¹H, ¹³C NMR, HREI-MS) and tested against acetylcholinesterase and butyrylcholinesterase enzymes. All analogues were found active and showed IC₅₀ values ranging from 0.60 ± 0.20 to 12.50 ± 0.30 µM (AChE) and 2.20 ± 0.10 to 19.60 ± 0.30 µM (BuChE) as compared to standard drug donepezil (IC₅₀ = 2.16 ± 0.12 and 4.5 ± 0.11 µM, respectively). Among the series, analogues 8 and 9 showed outstanding acetylcholinesterase and butyrylcholinesterase inhibitory potentials. Structure activity relationship was established which mainly depend upon the nature, position, number and electron donating/withdrawing effects of the substituent/s on phenyl ring. The binding modes of interactions between the active site of potent analogues and amino acid were determined through molecular docking studies. The compounds were synthesized by simple modes of synthesis like carboxylate, hydrazide and finally sulfonamide formation.