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Design, synthesis, and evaluation of novel O-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer's disease.

ABSTRACT: Herein, a series of novel O-alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities in vitro showed that compounds 5a, 5d, 5e, 5f, and 5h indicated significantly selective MAO-B inhibitory potency (IC₅₀ = 0.32, 0.56, 0.54, 0.73, and 0.86 μM, respectively) and moderate antioxidant activity. Moreover, compounds 5a, 5d, 5e, 5f, and 5h showed potent anti-inflammatory properties, remarkable effects on self-induced Aβ_1-42 aggregation, and potent neuroprotective effect on Aβ_1-42-induced PC12 cell injury. Furthermore, compounds 5a, 5d, 5e, 5f, and 5h presented good blood-brain barrier permeation in vitro and drug-like properties. More interesting, the PET/CT images with [¹¹C]5f demonstrated that [¹¹C]5f could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound 5f would be a promising multi-functional agent for the treatment of AD.

SUBMITTER: Zhu G

PROVIDER: S-EPMC9116242 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Design, synthesis, and evaluation of novel O-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer's disease.

Zhu Gaofeng G Bai Ping P Wang Keren K Mi Jing J Yang Jing J Hu Jiaqi J Ban Yujuan Y Xu Ran R Chen Rui R Wang Changning C Tang Lei L Sang Zhipei Z

Journal of enzyme inhibition and medicinal chemistry 20221201 1

Herein, a series of novel O-alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities in vitro showed that compounds 5a, 5d, 5e, 5f, and 5h indicated significantly selective MAO-B inhibitory potency (IC50 = 0.32, 0.56, 0.54, 0.73, and 0.86 μM, respectively) and moderate antioxidant activity. Moreover, compounds 5a, 5d, 5e, 5f</ ...[more]

PMID: 35549612

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Project description:A series of indole derivatives was designed and synthesised to improve on activity and circumvent pharmacokinetic limitations experienced with the structurally related compound, ladostigil. The compounds consisted of a propargylamine moiety (a known MAO inhibitor and neuroprotector) at the N1 position and a ChE inhibiting diethyl-carbamate/urea moiety at the 5 or 6 position of the indole ring. In order to prevent or slow down the in vivo hydrolysis and deactivation associated with the carbamate function of ladostigil, a urea moeity was incorporated into selected compounds to obtain more metabolically stable structures. The majority of the synthesised compounds showed improved MAO-A inhibitory activity compared to ladostigil. The compounds possessing the propargylamine moiety showed good MAO-B inhibitory activity with 6 and 8 portraying IC50 values between 14-20 fold better than ladostigil. The ChE assay results indicated that the compounds have non-selective inhibitory activities on eeAChE and eqBuChE regardless of the type or position of substitution (IC50: 2-5 μM). MAO-A and MAO-B docking results showed that the propargylamine moiety was positioned in close proximity to the FAD cofactor suggesting that the good inhibitory activity may be attributed to the propargylamine moiety and irreversible inhibition as confirmed in the reversibility studies. Docking results also indicated that the compounds have interactions with important amino acids in the AChE and BuChE catalytic sites. Compound 6 was the most potent multifunctional agent showing better inhibitory activity than ladostigil in vitro on all enzymes tested (hMAO-A IC50 = 4.31 μM, hMAO-B IC50 = 2.62 μM, eeAChE IC50 = 3.70 μM, eqBuChE IC50 = 2.82 μM). Chemical stability tests confirmed the diethyl-urea containing compound 6 to be more stable than its diethyl-carbamate containing counterpart compound 8. Compound 6 also exerted significant neuroprotection (52.62% at 1 μM) against MPP+ insult to SH-SY5Y neural cells and has good in silico predicted ADMET properties. The favourable neuronal enzyme inhibitory activity, likely improved pharmacokinetic properties in vivo and the potent neuroprotective ability of compound 6 make it a promising compound for further development.

Dataset Information

Design, synthesis, and evaluation of novel O-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer's disease.

Publications

Design, synthesis, and evaluation of novel <i>O</i>-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer's disease.

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