Novel indolotacrine hybrids as acetylcholinesterase inhibitors: design, synthesis, biological evaluation, and molecular docking studies

被引：2

作者：

Babaee, Saeed ^{[1
]}

Zolfigol, Mohammad Ali ^{[1
]}

Chehardoli, Gholamabbas ^{[2
]}

Faramarzi, Mohammad Ali ^{[3
]}

Mojtabavi, Somayeh ^{[3
]}

Akbarzadeh, Tahmineh ^{[4
,5
]}

Hariri, Roshanak ^{[4
]}

Rastegari, Arezoo ^{[5
]}

Homayouni Moghadam, Farshad ^{[6
]}

Mahdavi, Mohammad ^{[7
]}

Najafi, Zahra ^{[8
]}

机构：

[1] Bu Ali Sina Univ, Fac Chem, Dept Organ Chem, Hamadan, Iran

[2] Hamadan Univ Med Sci, Med Plants & Nat Prod Res Ctr, Sch Pharm, Dept Med Chem, Hamadan, Iran

[3] Univ Tehran Med Sci, Fac Pharm, Dept Pharmaceut Biotechnol, Tehran, Iran

[4] Univ Tehran Med Sci, Fac Pharm, Dept Med Chem, Tehran, Iran

[5] Univ Tehran Med Sci, Persian Med & Pharm Res Ctr, Tehran, Iran

[6] Royan Inst Biotechnol, Cell Sci Res Ctr, Dept Anim Biotechnol, ACECR, Esfahan, Iran

[7] Univ Tehran Med Sci, Endocrinol & Metab Clin Sci Inst, Endocrinol & Metab Res Ctr, Tehran, Iran

[8] Hamadan Univ Med Sci, Sch Pharm, Dept Med Chem, Hamadan, Iran

来源：

JOURNAL OF THE IRANIAN CHEMICAL SOCIETY | 2023年 / 20卷 / 05期

关键词：

Indole; Tacrine; Synthesis; Molecular docking; Acetylcholinesterase inhibitors; Alzheimer's disease; ALZHEIMERS-DISEASE; IN-VITRO; DERIVATIVES;

D O I：

10.1007/s13738-022-02726-1

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

A new class of indolotacrine hybrids including cyclopenta- and cyclohexa-indolotacrine derivatives was designed, synthesized, and assessed as acetylcholinesterase inhibitors (AChEIs). Some of the designed derivatives indicated a good inhibitory effect against acetylcholinesterase (AChE). Among them, cyclopenta-indolotacrine hybrids showed a slightly better anti-AChE activity than cyclohexa-indolotacrine hybrids. Compound 5-amino-4-(4-chlorophenyl)-2-(1H-indol-3-yl)-4,6,7,8-tetrahydrocyclopenta[b]pyrano[3,2-e]pyridine-3-carbonitrile (8g) including 4-chlorophenyl and cyclopentane ring showed the best AChE inhibitory activity with IC50 value of 0.4 mu M. The kinetic study indicated that compound 8g acted as a competitive inhibitor. Based on molecular docking results, it occupied both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE. Using a neuroprotective assay against H2O2-induced cell death in PC12 neurons, only compound 8b with 4-methoxyphenyl moiety and cyclopentane ring illustrated significant protection (P < 0.0001) at a concentration of 100 mu M compared to quercetin at a concentration of 10 mu M (P < 0.0001). In silico ADME studies estimated good drug-likeness for the designed compounds. As a result, these indolotacrine hybrids can be a very encouraging AChE inhibitor to treat Alzheimer's disease.

引用

页码：1049 / 1060

页数：12

共 30 条

[1] Design, Synthesis, and Molecular Docking of Some Novel Tacrine Based Cyclopentapyranopyridine- and Tetrahydropyranoquinoline-Kojic Acid Derivatives as Anti-Acetylcholinesterase Agents [J].