23 research outputs found
Rational design, synthesis, molecular modeling and evaluation of ïą-carboline and 5H-indeno[1,2-c]pyridazin-5-one derivatives as potential MAO and IDO inhibitors : Conception rationnelle, synthĂšse, modĂ©lisation molĂ©culaire et Ă©valuation de dĂ©rivĂ©s ïą-carbolines et 5H-indĂ©no[1,2-c]pyridazin-5-ones comme inhibiteurs potentiels de la MAO et dâIDO
Monoamine oxidase A (MAO-A) and âB (MAO-B) are attractive targets for a broad range of treatments against pathologies including depression, anxiety disorders, Parkinsonâs and Alzheimerâs 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 âB 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 âB inhibitors derived from ÎČ-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 ïą-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-ïą-carboline derivatives with amino groups and directly derived from 3-butyl-ïą-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-ïą-carboline. Howerver, first results tend to demonstrate that the introduction of a positive charge abolishes the inhibition of IDO.La monoamine oxydase A (MAO-A) et âB (MAO-B) sont des cibles intĂ©ressantes pour une large gamme de thĂ©rapies contre des pathologies telles que la dĂ©pression, lâanxiĂ©tĂ© et les maladies de Parkinson et dâAlzheimer. La plupart des inhibiteurs actuels mĂšnent Ă des effets secondaires par un manque dâaffinitĂ© et de sĂ©lectivitĂ© envers une des isoformes. RĂ©cemment, les structures cristallographiques de hMAO-A et âB en complexe avec des inhibiteurs ont ouvert le chemin vers la dĂ©couverte de nouveaux inhibiteurs plus sĂ©lectifs et plus puissants. En consĂ©quence, lâobjectif principal de ce travail, fut la conception de nouveaux inhibiteurs plus puissants, rĂ©versibles et sĂ©lectifs de MAO-A ou âB Ă partir des motifs ÎČ-carbolines et 5H-indĂ©no[1,2-c]pyridazin-5-ones respectivement, en suivant une stratĂ©gie classique comprenant une approche expĂ©rimentale (synthĂšse et Ă©valuation biologique) et thĂ©orique (modĂ©lisation molĂ©culaire). Les pouvoirs dâinhibition sur la MAO ont montrĂ© que la substitution du groupe mĂ©thoxy de lâharmine par des groupes plus lipophiles augmente lâinhibition de MAO-A. Des Ă©tudes sur les 5H-indĂ©no[1,2-c]pyridazin-5-ones substituĂ©es Ă la fois aux positions 3 et 8 par des groupes lipophiles ont montrĂ© que la substitution en position 3 influence significativement les propriĂ©tĂ©s dâinhibition de la MAO-B.
De plus, lâimplication Ă travers une mĂȘme voie mĂ©tabolique et la similaritĂ© dans les propriĂ©tĂ©s structurales de la MAO avec lâindolĂ©amine 2,3-dioxygĂ©nase (IDO) et la lysine spĂ©cifique dĂ©mĂ©thylase 1 (LSD1) respectivement, nous ont amenĂ© Ă lâinvestigation des ïą-carbolines et 5H-indĂ©no[1,2-c]pyridazin-5-ones comme inhibiteurs potentiels dâIDO et de LSD1. Cependant, les deux series nâinhibent pas ces deux systĂšmes enzymatiques et sont donc sĂ©lectives de MAO.
Finalement, en partant de la mĂȘme stratĂ©gie utilisĂ©e pour la MAO, nous nous sommes aussi intĂ©ressĂ©s Ă la synthĂšse de deux nouvelles ïą-carbolines substitutĂ©es en position 3 par des groupements aminĂ©s et directement dĂ©rivĂ©es du 3-butyl-ïą-carboline, un inhibiteur connu dâIDO. Ces deux composĂ©s prĂ©sentent en effet une charge positive Ă pH physiologique laquelle pourrait Ă©tablir une interaction coulombienne supplĂ©mentaire avec le 7-propionate de lâhĂšme comparĂ© au 3-butyl-ïą-carboline. Cependant, les premiers rĂ©sultats tendent Ă dĂ©montrer que lâintroduction dâune charge positive abolit lâinhibition dâIDO.(DOCSC02) -- FUNDP, 201
SYNTHESIS OF BOAT LOCKED GALACTOSIDES AS ENZYME INHIBITORS AND CONFORMATIONAL PROBES
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