Design, synthesis and evaluation of indole derivatives as multifunctional agents against Alzheimer's disease

Abstract

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 1 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 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 and portraying IC 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 (IC: 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 was the most potent multifunctional agent showing better inhibitory activity than ladostigil on all enzymes tested (hMAO-A IC = 4.31 μM, hMAO-B IC = 2.62 μM, eeAChE IC = 3.70 μM, eqBuChE IC = 2.82 μM). Chemical stability tests confirmed the diethyl-urea containing compound to be more stable than its diethyl-carbamate containing counterpart compound. Compound also exerted significant neuroprotection (52.62% at 1 μM) against MPP insult to SH-SY5Y neural cells and has good predicted ADMET properties. The favourable neuronal enzyme inhibitory activity, likely improved pharmacokinetic properties and the potent neuroprotective ability of compound make it a promising compound for further development.

Benzofuran and Indole: Promising Scaffolds for Drug Development in Alzheimer's Disease

“…Recently, Joubert and co‐workers designed and synthesized a series of indole derivatives 79 a – d (structurally based on the compound ladostigil) that are able to inhibit hMAO‐A, hMAO‐B, eeAChE, and eqBuChE and provide neuroprotection (Figure ) . Compound 79 b shows AChE and MAO‐B inhibitory activities that are 9 and 14 times higher than those of ladostigil, respectively.…”

“…Recently,J oubert and co-workersd esigned and synthesized as eries of indole derivatives 79 a-d (structurally based on the compound ladostigil) that are able to inhibith MAO-A, hMAO-B, eeAChE, and eqBuChEa nd provide neuroprotection ( Figure 61). [149] Compound 79 b showsA ChE and MAO-B inhibitory activities that are 9a nd 14 times higher than those of ladostigil, respectively.C ompound 79 b inhibitsM AO-A,M AO-B, AChE, and BuChE with IC 50 values of 4.31, 2.62, 3.70, and 2.82 mm,r espectively.C ompound 79 b shows neuroprotection (52.62 %a t1mm)a gainst 1-methyl-4-phenylpyridinium (MPP + ) insult to SH-SY5Y cells.…”

“…Structureso f6-sub-stituted3 ,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives 78 a and 78 b [148]. Structureso fladostigil and compounds 79 [149].…”

Design, synthesis and biological evaluation of edaravone derivatives bearing the N-benzyl pyridinium moiety as multifunctional anti-Alzheimer’s agents

“…The co-crystallised structure of Tc AChE with donepezil (PDB accession code: 1EVE) was acquired from the Protein Data Bank (PDB) 38 . The following protocol was employed, as previously described 42 , to simulate the orientation and binding interactions of the test compounds. Firstly, the test compounds were drawn using ChemSketch v2019.2.1 and saved as a mol files.…”

A Convenient Synthesis and Biological Research of Novel 5,6,7,8‐Tetrahydro‐1,6‐naphthyridin‐2(1H)‐one Derivatives Hydrochloride as Cytotoxic Agents

“…Nitrogen is the most favorite heteroelement in life science research, and heterocyclic compounds containing N attract great interest of the researchers . Naphthyridine is an important member of N‐containing compounds, and its derivatives have gained special attention of researchers on account of their variety of interesting biological activities in medicinal chemistry.…”