The design of novel 4,6-dimethoxyindole based hydrazide- hydrazones: Molecular modeling, synthesis and anticholinesterase activity

Biologically important hydrazide-hydrazone (e(C 1/4O)NHN 1/4 CH) functionality was located at two different positions on 4,6-dimethoxyindole moiety and novel compounds 11a-c and 12a-c were generated by the condensation reactions of indole hydrazones 7 and 8, derived from the corresponding indole carbaldehydes 4 and 6, and carboxylic acids 9a-c in the presence of amide coupling reagent (EDC). The anticholinesterase potency was investigated towards the acetyl- and butrylcholinesterase enzymes (AChE and BChE) and complementary determination of biological potency was obtained by the evaluation of binding scores. The compound 11b resulted the best binding behaviors due to the hydrophobic interactions with the responsible amino acids on the different active sites of enzymes pocket. The structural analysis revealed that the most favorable binding pose was mainly dependent on the presence of aromatic moiety administered by the benzoic acid as well as the hydrazide-hydrazone linker but not related with the location on indole ring. Most importantly, the biological study was found to be compatible with the molecular modeling study and the highest inhibition was determined in the presence of compound 11b with the values of 83.31 and 73.55 for AChE and BChE, respectively. (c) 2020 Elsevier B.V. All rights reserved.