Synthesis, Anti-Alzheimer Evaluation and In Silico Study of 4-Methoxyphenyl)Sulfonyl Indole Hybrid Thiosemicarbazones

Abstract

Alzheimer's disease (AD) is a multifaceted neurological disorder linked to behavioral, psychological, and language abnormalities as well as memory loss. A series of 1-[(4-methoxyphenyl)sulfonyl]−1H-indole-3-carbaldehyde-based thiosemicarbazones 5(a–v) had been synthesized and screened for their potential against AD. The compounds were tested for their inhibitory effects against cholinesterases (AChE and BChE) and monoamine oxidase A (MAO-A). Compounds 5l, 5v, and 5r showed remarkable activity on AChE, BChE, and MAO-A enzymes, having IC₅₀ values ranging between 1.57 and 4.56 nM (K_i = 1.43 ± 0.44 to 3.43 ± 0.21 nM), between 25.68 and 35.06 nM (K_i = 22.53 ± 7.70 to 34.82 ± 2.32 nM), and between 22.98 and 27.23 nM, respectively. Compound 5l with trifluoromethyl substitution at the 3 and 5 positions was the most effective derivative of AChE and BChE, having K_i values of 1.43 ± 0.44 nM and 22.53 ± 7.70 nM, respectively. Compound 5v with chloro substitution at the 2 and 6 positions of the phenyl ring was the most potent inhibitor of MAO-A, with IC₅₀ values of 22.98 nM. Structure–activity analysis exhibited that the electron-withdrawing substituents and di-substitution on the phenyl ring play a significant role in the inhibition potential of synthesized compounds. The most effective inhibitors’ binding interactions with the active sites of AChE, BChE, and MAO-A were described via molecular docking studies. In silico ADME, pharmacokinetics, and drug-likeness studies were conducted and compared with the standard drugs galantamine and clorgyline.