Synthesis of 4- and 5-arylthiazolinethiones as inhibitors of indoleamine 2,3-dioxygenase

Monaem Balti; Aurélie Plas; Céline Meinguet; Marie Haufroid; Quentin Thémans; Mohamed Lotfi Efrit; Johan Wouters; Steve Lanners

doi:10.1016/j.bmcl.2016.06.052

Synthesis of 4- and 5-arylthiazolinethiones as inhibitors of indoleamine 2,3-dioxygenase

Bioorg Med Chem Lett. 2017 Aug 1;27(15):3607-3610. doi: 10.1016/j.bmcl.2016.06.052. Epub 2016 Jun 18.

Authors

Monaem Balti¹, Aurélie Plas², Céline Meinguet², Marie Haufroid², Quentin Thémans², Mohamed Lotfi Efrit³, Johan Wouters², Steve Lanners⁴

Affiliations

¹ NAMEDIC-NARILIS, University of Namur, 61 Rue de Bruxelles, 5000 Namur, Belgium; Laboratory of Organic Synthesis and Heterocyclic Chemistry, Department of Chemistry, College of Sciences at Tunis, El Manar University, Campus, 1060 Tunis, Tunisia.
² NAMEDIC-NARILIS, University of Namur, 61 Rue de Bruxelles, 5000 Namur, Belgium.
³ Laboratory of Organic Synthesis and Heterocyclic Chemistry, Department of Chemistry, College of Sciences at Tunis, El Manar University, Campus, 1060 Tunis, Tunisia.
⁴ NAMEDIC-NARILIS, University of Namur, 61 Rue de Bruxelles, 5000 Namur, Belgium. Electronic address: steve.lanners@unamur.be.

PMID: 28651980
DOI: 10.1016/j.bmcl.2016.06.052

Abstract

Docking studies of 4-phenylthiazolinethione on human IDO1 suggest complexation of the heme iron by the exocyclic sulfur atom further reinforced by hydrophobic interactions of the phenyl ring within pocket A of the enzyme. On this basis, chemical modifications were proposed to increase inhibition activity. Synthetic routes had to be adapted and optimized to yield the desired substituted 4- and 5-arylthiazolinethiones. Their biological evaluation shows that 5-aryl regioisomers are systematically less potent than the corresponding 4-aryl analogs. Substitution on the phenyl ring does not significantly increase inhibition potency, except for 4-Br and 4-Cl derivatives.

Keywords: 4-Phenyl thiazolinethione; Anti-cancer; Aryl-thiazoline thione; IDO inhibition; Indoleamine 2,3-dioxygenase (IDO).

MeSH terms

Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Molecular Docking Simulation
Stereoisomerism
Structure-Activity Relationship
Thiazolidines / chemical synthesis
Thiazolidines / chemistry*
Thiazolidines / pharmacology*
Thiones / chemical synthesis
Thiones / chemistry*
Thiones / pharmacology*

Substances

Enzyme Inhibitors
IDO1 protein, human
Indoleamine-Pyrrole 2,3,-Dioxygenase
Thiazolidines
Thiones