Rational design, synthesis, molecular modeling and evaluation of β-carboline and 5H-indeno[1,2-c]pyridazin-5-one derivatives as potential MAO and IDO inhibitors

Abstract

Monoamine oxidase A (MAO-A) and –B (MAO-B) are attractive targets for a broad range of treatments against pathologies including depression, anxiety disorders, Parkinson’s and Alzheimer’s diseases. Most current MAO inhibitors lead to side effects by a lack of affinity and selectivity towards one of the isoforms. Recently, the crystal structures of hMAO-A and –B in complex with inhibitors opened the way towards the discovery of new, more selective and potent inhibitors. Thus, the main objective of this work, was the design of new, more potent, reversible and selective MAO-A or –B inhibitors derived from β-carboline and 5H-indeno[1,2-c]pyridazin-5-one scaffolds respectively, following a classical strategy including experimental (synthesis and biological evaluation) and theoretical (molecular modeling) approaches. The MAO inhibitory potencies showed that the replacement of the methoxy group of harmine by more lipophilic groups increases the inhibition for MAO-A. Studies on 5H-indeno[1,2-c]pyridazin-5-one scaffold bearing lipophilic groups in the 3 and 8-positions showed that the substitution in the 3-position dramatically influences the MAO-B-inhibiting properties. Furthermore, the involvement through a same metabolic pathway and the similarity in the structural properties of MAO with indoleamine 2,3-dioxygenase (IDO) and lysine specific demethylase 1 (LSD1) respectively, led us to the investigation of the -carboline and 5H-indeno[1,2-c]pyridazin-5-one derivatives as potential IDO and LSD1 inhibitors. However, the two series show no inhibition of those two enzymes and are thus selective of MAO. Finally, starting from the same strategy used for MAO, we are also interested in the synthesis of two new 3-substituted--carboline derivatives with amino groups and directly derived from 3-butyl--carboline, a known IDO inhibitor. Indeed, these two compounds display a positive charge at physiological pH which might establish an additional coulomb interaction with 7-propionate of the heme compared to 3-butyl--carboline. Howerver, first results tend to demonstrate that the introduction of a positive charge abolishes the inhibition of IDO.

Date of Award	4 Oct 2011
Original language	English
Awarding Institution	University of Namur Unit of theoretical and structural physico-chemistry
Supervisor	Johan Wouters (Supervisor), Raphaël Frederick (Jury), Carine Michiels (Jury), Stephane Vincent (President) & Robert Kiss (Jury)