Synthesis, Anti‐Alzheimer Evaluation and In Silico Study of 4‐Methoxyphenyl)Sulfonyl Indole Hybrid Thiosemicarbazones
Uzma Ghaffar, Zahra Batool, Mussarat Tasleem, Nastaran Sadeghian, Parham Taslimi, Suraj N. Mali, Kholood A. Dahlous, Rahul D. Jawarkar, Shailesh S. Gurav, Xianliang Zhao, Iqra Munir, Zahid Shafiq
Abstract
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]−1 H ‐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 IC 50 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 IC 50 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.