Solid phase syntheses of S,N-substituted 2-mercaptobenzoimidazoles 

 

2-Mercaptobenzoimidazoles are an interesting class of heterocycles in medicinal chemistry as their core structure is part of different established therapeutics. The most prominent ones of these drugs are omeprazole, which acts as a protonpump inhibitor to prevent the production of an excess of gastric acid and fabomotizole (the former known as afobazole), an anxiolytic drug which interacts with ligand-dependent human ion channels (GABA receptors). Other 2-mercaptobenzoimidazoles, known for their antiviral activity, have been identified as potent ligands for estrogen and the CRTh2 receptors, and have been shown to act as allosteric modulators of the protein kinase PDK1. Recently, novel N-substituted 2-mercaptobenzo-imidazole derivatives have been shown to be potent candidates in the search for novel drugs against castration resistant prostate cancer. These new 2-mercaptobenzoimidazoles interact with the binding function 3 (BF3) pocket of the androgen receptor which results in a conformational change of a neighboured binding pocket and prevents its interaction with a steroid activator protein.

The synthesis of 2-mercaptobenzoimidazoles and derivatives thereof can be achieved via literature known procedures such as the reaction of 1,2-diaminobenzenes with carbon disulfide and subsequent alkylation with electrophiles or via direct alkylation of the sodium thiolate of 2-mercaptobenzoimidazole with chloroalkyl anilides. Besides manifold strategies in solution only few other procedures are reported that allow the syntheses of different 2-mercaptobenzoimidazoles on solid supports. An example for such a resin-based procedure is the synthesis of the 2-mercaptobenzoimidazole core on 4-methyl-benzhydrylamineresin (MBHA-resin) and reaction to biheterocyclic dihydroimidazole analogs, 2-alkylthio-imidazocoumarines, and 1-alkyl-2-alkylthio-5-carba-moyl-benzoimidazoles. Another application using poly-ethylene-glycol-resins as soluble polymers has been reported for the synthesis of different bisbenzoimidazoles via ring closure through intramolecular nucleophilic attack of an immobilized amino group on an amide carbonyl functionality.18 In this study, we aimed for the development of a novel solid supported protocol for the synthesis of N-substituted 2-mercaptobenzoimidazoles allowing a novel access to diverse derivatives of this attractive compound class.

The herein described procedure presents as far as we know the first strategy for the synthesis of S,N-alkylated 2-mercptobenzoimidazoles on solid phases enabling a combinatorial approach to N-alkylated 2-mercaptobenzoimidazole libraries. The modularity of this method has been demonstrated by a synthetic procedure consisting of two different linkers, on which the 2-mercaptobenzoimidazole was generated and modified on bead by Mitsunobu etherification. The resulting immobilized S,N-alkylated heterocycles have been cleaved in a multifunctional strategy either via transesterification or aminolysis. The herein developed methodology enables the extension of the protocol to increase the diversity of the synthesized N-substituted 2-mercaptobenzoimidazoles via exchange of the building blocks I–IV, e.g. through etherification with thiophenols or the attachment of other alkyl linker units in future applications.

 

Reference:

Susanto, Steven, Nicole Jung, and Stefan Bräse. “Solid phase syntheses of S, N-substituted 2-mercaptobenzoimidazoles.” RSC Advances 6.46 (2016): 39573-39576.

 

Related Products:

CAS Number Product Name Molecular Weight Molecular Formula Description
73590-58-6 Omeprazole 345.42 C17H19N3O3S Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia.
173352-21-1 Afobazole 307.41 C15H21N3O2S Fabomotizole (brand name Afobazole) is an anxiolytic drug launched in Russia in the early 2000s. It produces anxiolytic and neuroprotective effects without any sedative or muscle relaxant actions.