Synthesis and inhibition study of monoamine oxidase, indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase by 3,8-substituted 5H-indeno[1,2-c]pyridazin-5-one derivatives

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Abstract

Previous studies on 5H-indeno[1,2-c]pyridazin-5-one derivatives as inhibitors of MAO-B revealed that it was possible to increase the MAO-B inhibitory potency of 5H-indeno[1,2-c]pyridazin-5-ones by substituting the central heterocycle in the 3-position or C-8 with lipophilic groups which occupy the substrate cavity or the entrance of the binding site, respectively. Here, four new 5H-indeno[1,2-c]pyridazin-5-one derivatives containing lipophilic groups at both positions were synthesized and their inhibitory potency against human monoamine oxidase A and B were evaluated. Selectivity of these compounds against IDO and TDO, two enzymes sharing substrate similarity with MAO and involved in the serotonergic and kynurenine pathways was also studied. All compounds showed higher activity and selectivity against MAO-B, the most effective one being 3-methyl-8-meta-chlorobenzyloxy-5H-indeno[1,2-c]pyridazin-5- one (9a) which was shown to be a competitive inhibitor with a Ki value of 0.11 μM. Replacing the methyl group in the 3-position with a meta-CF3-phenyl group (7a, 7b and 7c) abolished the inhibitory potency against MAO-B. Indeed, the substitution of the 5H-indeno[1,2-c] pyridazin-5-one core in the 3-position dramatically influences the MAO-inhibiting properties of these compounds. Molecular docking studies of 9a within MAO-B suggest that the 5H-indeno[1,2-c]pyridazin-5-one scaffold is well stabilized into the substrate cavity with the meta-chlorobenzyloxy side chain extending towards a rather hydrophobic pocket at the entrance cavity.

Original languageEnglish
Pages (from-to)6104-6111
Number of pages8
JournalEuropean Journal of Medicinal Chemistry
Volume46
Issue number12
DOIs
Publication statusPublished - 1 Dec 2011

Fingerprint

Tryptophan Oxygenase
Indoleamine-Pyrrole 2,3,-Dioxygenase
Monoamine Oxidase
Derivatives
Substrates
Kynurenine
Scaffolds
Substitution reactions
Binding Sites

Keywords

  • 5H-indeno[1,2-c]pyridazin-5-one
  • Docking
  • Indoleamine 2,3-dioxygenase (IDO)
  • Monoamine oxidase (MAO)
  • Tryptophan 2,3-dioxygenase (TDO)
  • X-ray

Cite this

@article{e25ecb9172dd49f59dc85d77e581c965,
title = "Synthesis and inhibition study of monoamine oxidase, indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase by 3,8-substituted 5H-indeno[1,2-c]pyridazin-5-one derivatives",
abstract = "Previous studies on 5H-indeno[1,2-c]pyridazin-5-one derivatives as inhibitors of MAO-B revealed that it was possible to increase the MAO-B inhibitory potency of 5H-indeno[1,2-c]pyridazin-5-ones by substituting the central heterocycle in the 3-position or C-8 with lipophilic groups which occupy the substrate cavity or the entrance of the binding site, respectively. Here, four new 5H-indeno[1,2-c]pyridazin-5-one derivatives containing lipophilic groups at both positions were synthesized and their inhibitory potency against human monoamine oxidase A and B were evaluated. Selectivity of these compounds against IDO and TDO, two enzymes sharing substrate similarity with MAO and involved in the serotonergic and kynurenine pathways was also studied. All compounds showed higher activity and selectivity against MAO-B, the most effective one being 3-methyl-8-meta-chlorobenzyloxy-5H-indeno[1,2-c]pyridazin-5- one (9a) which was shown to be a competitive inhibitor with a Ki value of 0.11 μM. Replacing the methyl group in the 3-position with a meta-CF3-phenyl group (7a, 7b and 7c) abolished the inhibitory potency against MAO-B. Indeed, the substitution of the 5H-indeno[1,2-c] pyridazin-5-one core in the 3-position dramatically influences the MAO-inhibiting properties of these compounds. Molecular docking studies of 9a within MAO-B suggest that the 5H-indeno[1,2-c]pyridazin-5-one scaffold is well stabilized into the substrate cavity with the meta-chlorobenzyloxy side chain extending towards a rather hydrophobic pocket at the entrance cavity.",
keywords = "5H-indeno[1,2-c]pyridazin-5-one, Docking, Indoleamine 2,3-dioxygenase (IDO), Monoamine oxidase (MAO), Tryptophan 2,3-dioxygenase (TDO), X-ray",
author = "J. Reniers and C. Meinguet and L. Moineaux and B. Masereel and Vincent, {S. P.} and R. Frederick and J. Wouters",
year = "2011",
month = "12",
day = "1",
doi = "10.1016/j.ejmech.2011.09.042",
language = "English",
volume = "46",
pages = "6104--6111",
journal = "European journal of medicinal chemistry / Chimica therapeutica",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",
number = "12",

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TY - JOUR

T1 - Synthesis and inhibition study of monoamine oxidase, indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase by 3,8-substituted 5H-indeno[1,2-c]pyridazin-5-one derivatives

AU - Reniers, J.

AU - Meinguet, C.

AU - Moineaux, L.

AU - Masereel, B.

AU - Vincent, S. P.

AU - Frederick, R.

AU - Wouters, J.

PY - 2011/12/1

Y1 - 2011/12/1

N2 - Previous studies on 5H-indeno[1,2-c]pyridazin-5-one derivatives as inhibitors of MAO-B revealed that it was possible to increase the MAO-B inhibitory potency of 5H-indeno[1,2-c]pyridazin-5-ones by substituting the central heterocycle in the 3-position or C-8 with lipophilic groups which occupy the substrate cavity or the entrance of the binding site, respectively. Here, four new 5H-indeno[1,2-c]pyridazin-5-one derivatives containing lipophilic groups at both positions were synthesized and their inhibitory potency against human monoamine oxidase A and B were evaluated. Selectivity of these compounds against IDO and TDO, two enzymes sharing substrate similarity with MAO and involved in the serotonergic and kynurenine pathways was also studied. All compounds showed higher activity and selectivity against MAO-B, the most effective one being 3-methyl-8-meta-chlorobenzyloxy-5H-indeno[1,2-c]pyridazin-5- one (9a) which was shown to be a competitive inhibitor with a Ki value of 0.11 μM. Replacing the methyl group in the 3-position with a meta-CF3-phenyl group (7a, 7b and 7c) abolished the inhibitory potency against MAO-B. Indeed, the substitution of the 5H-indeno[1,2-c] pyridazin-5-one core in the 3-position dramatically influences the MAO-inhibiting properties of these compounds. Molecular docking studies of 9a within MAO-B suggest that the 5H-indeno[1,2-c]pyridazin-5-one scaffold is well stabilized into the substrate cavity with the meta-chlorobenzyloxy side chain extending towards a rather hydrophobic pocket at the entrance cavity.

AB - Previous studies on 5H-indeno[1,2-c]pyridazin-5-one derivatives as inhibitors of MAO-B revealed that it was possible to increase the MAO-B inhibitory potency of 5H-indeno[1,2-c]pyridazin-5-ones by substituting the central heterocycle in the 3-position or C-8 with lipophilic groups which occupy the substrate cavity or the entrance of the binding site, respectively. Here, four new 5H-indeno[1,2-c]pyridazin-5-one derivatives containing lipophilic groups at both positions were synthesized and their inhibitory potency against human monoamine oxidase A and B were evaluated. Selectivity of these compounds against IDO and TDO, two enzymes sharing substrate similarity with MAO and involved in the serotonergic and kynurenine pathways was also studied. All compounds showed higher activity and selectivity against MAO-B, the most effective one being 3-methyl-8-meta-chlorobenzyloxy-5H-indeno[1,2-c]pyridazin-5- one (9a) which was shown to be a competitive inhibitor with a Ki value of 0.11 μM. Replacing the methyl group in the 3-position with a meta-CF3-phenyl group (7a, 7b and 7c) abolished the inhibitory potency against MAO-B. Indeed, the substitution of the 5H-indeno[1,2-c] pyridazin-5-one core in the 3-position dramatically influences the MAO-inhibiting properties of these compounds. Molecular docking studies of 9a within MAO-B suggest that the 5H-indeno[1,2-c]pyridazin-5-one scaffold is well stabilized into the substrate cavity with the meta-chlorobenzyloxy side chain extending towards a rather hydrophobic pocket at the entrance cavity.

KW - 5H-indeno[1,2-c]pyridazin-5-one

KW - Docking

KW - Indoleamine 2,3-dioxygenase (IDO)

KW - Monoamine oxidase (MAO)

KW - Tryptophan 2,3-dioxygenase (TDO)

KW - X-ray

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U2 - 10.1016/j.ejmech.2011.09.042

DO - 10.1016/j.ejmech.2011.09.042

M3 - Article

C2 - 22018876

AN - SCOPUS:80955166260

VL - 46

SP - 6104

EP - 6111

JO - European journal of medicinal chemistry / Chimica therapeutica

JF - European journal of medicinal chemistry / Chimica therapeutica

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