Synthesis, molecular docking, and bioactivity study of isoquinoline-sulfonamide hybrid analogues: A promising acetylcholinesterase and butyrylcholinesterase inhibitor candidate

Abstract

Isoquinoline-sulfonamide hybrid analogues (1–11) were synthesised and tested for their dual cholinesterase inhibitory potentials. All analogues showed a varied degree of inhibitory potential, with IC50 values ranging between 0.30 ± 0.05 to 26.30 ± 0.20 µM (AChE) and 0.80 ± 0.01 to 37.60 ± 0.70 µM (BuChE) as compared to standard drug donepezil (IC50 = 2.16 ± 0.12 and 4.5 ± 0.11 µM respectively). In case of AChE, analogue 2 (IC50 = 0.30 ± 0.05 μM) was most potent, while in case of BuChE, analogues 2, 11, and 5 with IC50 values of 0.80 ± 0.01, 1.20 ± 0.05 and 2.50 ± 0.10 μM respectively, were found most potent. Structure-activity relationship was investigated, which is primarily depending upon nature, number, position, and electron donating/withdrawing effect on phenyl ring. A molecular docking study was carried out to determine the binding interactions of the most potent analogues with the active site of enzymes. The compounds were synthesized by simple modes of synthesis like esterification, hydrazide and finally sulfonamide formation.