Multitarget‐Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H₃R Antagonism for Neurodegenerative Diseases

Abstract

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

“…Furyl‐propargylamine ( 243 ), indolyl‐propargylamine ( 244a ‐ f , 245 ) and indole‐2‐carboxylate ( 244g ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration…”

“…Recently, Baustista‐Aguilera et al reported novel indole derivatives as potential MAO‐BIs (Figure ). All compounds ( 244a ‐ g ) showed IC 50 values in micromolar to nanomolar range with compound 244d (contilisant) as potent among others.…”

“…On account of tangled multifactorial pathology of NDDs, multifunctional drugs have been extensively apprehended as promising therapeutics. With the emerging trend on the design of hybrid analogs by multitarget directed ligand (MTDL) strategy, targeting multiple enzymes/receptors/protein in the CNS, MAOs being one primary target has been explored largely with ChEs 160,161,164,167,171,172,175,177,182,193,213,215,219,222,225,231,242,243,250,253 (as dual MAO-B/ChEs inhibitors), Aβ (as dual MAO-B/Aβ-aggregation inhibitors), 166,183,232,233 and HIS H3 receptors 248,249 (as dual MAO/ChE inhibitors with H3R antagonism and sigma 1R agonism) for intervention of AD in addition to adenosine A2A receptors 252 F I G U R E 9 5 Popular scaffolds with potential monoamine oxidase-B inhibitory profile (as dual adenosine A2A receptor antagonists/MAO-BIs) for PD. This MTDL approach has resulted in the identification of several lead molecular entities with multifunctional properties which can simultaneously target several pathological involvements thereby offering a ray of hope for discovery and development of new and effective molecules for the treatment of NDDs.…”

“…synthesized libraries of phenylxanthine derivatives(249 and 250) and screened them for their potential toward MAO-B inhibition(Figure 91). The compounds were found to show activity in micromolar to F I G U R E 9 0 Pyridazine-coumarin hybrids(246)(247)(248) 251. hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration; SI, selectivity index submicromolar range with K i values ranging from 0.25 to 10 µM.…”

New tacrine–acridine hybrids as promising multifunctional drugs for potential treatment of Alzheimer's disease

“…When it comes to MTDLs in AD, they are usually able to interact with both symptomatic and disease‐modifying targets. Most of them are dual binding site cholinesterase inhibitors with additional mechanisms: Aβ anti‐aggregating activity, neuroprotective and antioxidant activity, calcium channel blocking, cannabinoid CB1 receptor antagonism, BACE‐1 inhibition, histamine H3 receptor antagonism, NMDA receptor channel blocking, serotonin 5‐HT3 receptor antagonism, serotonin transporter inhibition . The other big group of MTDL contain MAO‐B inhibitors with iron‐chelating agents, metal chelators with BACE‐1 inhibitors, metal chelators with antioxidants, and modulators of γ‐secretase with PPARγ activities …”