Evaluation of Homobivalent Carbolines as Designed Multiple Ligands for the Treatment of Neurodegenerative Disorders

Abstract

Neurodegenerative diseases represent a challenge for biomedical research due to their high prevalence and lack of mechanism-based treatments. Because of the complex pathology of neurodegenerative disorders, multifunctional drugs have been increasingly recognized as potential treatments. We identified homobivalent γ-carbolinium salts as potent inihitors of both cholinesterases, N-methyl-D-aspartate receptors, and monoamine oxidases. Homobivalent γ-carbolines displayed similar structure-activity relationships on all tested targets and may present promising designed multiple ligands for the treatment of neurodegenerative disorders.

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

“…Surprisingly, curcumin and ferulic acid were found to inhibit hMAO-A selectively, whereas the F I G U R E 3 7 γ-Carbolines (55, 56a-e, 57a-h, and 58a-e). 177 which was lower than that of selegiline (K i = 0.13 ± 0.09 µM). Further, a gradual shift was observed from hMAO-B selectivity (61a, 61b) to nonselectivity (61c-f) as there was an increase in chain length at the amino terminus.…”

“…Otto et al identified homobivalent γ‐carbolines ( 55 , 56a ‐ e , 57a ‐ h , and 58a ‐ e ) as potent inhibitors of MAO‐B, thereby presenting promising ligands for the treatment of NDDs (Figure ). The bivalent γ‐carbolines displayed inhibitory activities against MAO‐B, with IC 50 values in the micromolar to submicromolar range.…”

“…γ‐Carbolines ( 55 , 56a ‐ e , 57a ‐ h , and 58a ‐ e ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration…”

“…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.…”

Preparation of Pyrido[2,3‐b]indole Derivatives Using Silicates of Group 1 and 2 Metals

“…A significant number of carbolines have been exploited for diverse pharmaceutical applications. Some γ‐carbolinium salts are found to be potent inhibitors of cholinesterases, N ‐methyl‐D‐aspartate receptors, and monoamine oxidases . Harmine, a β‐carboline, has been identified as an inhibitor of DYRK family of kinases .…”