A novel derivatives of thiazol-4(5H)-one and their activity in the inhibition of 11β-hydroxysteroid dehydrogenase type 1
Graphical abstract
Introduction
In order to search for effective and selective inhibitors of 11β-HSD1, attention was paid to thiazole derivatives [1], [2], 2-amino-1,3-thiazol-4(5H)one [3], [4], (1,3-benzothiazol-2-yl)benzenesulfonamides [5]. 2-Aminothiazole and 2-amino-4,5-dihydrothiazole derivatives are compounds which exhibit a promising biological activity. Sulfathiazole, a drug from the group of sulfonamides showing bacteriostatic activity is the most known derivative of 2-aminothiazole [6]. Abafungin has a strong antifungal activity [7]. 4-Substituted derivatives of 2-aminothiazole: Biovitrum BVT-2733 and Biovitrum BVT-14225 are substances showing an activity towards the inhibition of 11β-hydroxysteroid dehydrogenase type 1 [2], [4], [8], [9]. The selective inhibitor of this enzyme is also the 2-aminothiazol-4(5H)-one derivative: Amgen 2922 (Fig. 1) [3], [4], [10].
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1, cortisone reductase) is a microsomal enzyme. It is an NADPH - dependent oxidoreductase with high expression in the liver, adipose tissue and brain. It catalyzes the conversion of inactive cortisone into physiologically active cortisol and to a lesser extent reverse reaction [3]. 11β-HSD1 with isoform 2 - 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), mainly located in the kidneys and colon, it forms a system for regulating cortisol levels in the organism (Fig. 2).
Increased expression of 11β-HSD1 is associated with the pathogenesis of disorders of lipid metabolism and insulin resistance [11]. Inhibition of 11β-hydroxysteroid dehydrogenase type 1 causes a reduction of cortisol level and thereby reducing the body fat. It is also suggested that compounds specifically inhibit 11β-HSD1 in patients with type 2 diabetes can lower blood glucose levels and thereby reduce insulin resistance and central obesity [12]. Research has shown that 11β-HSD1 inhibitors leads to reduction of glycogenolysis, which results in a reduced level of total cholesterol [13]. Currently, attempts are being made to use 11β-HSD1 inhibitors for therapeutic purposes that can ultimately be used to treat type 2 diabetes [14].
The role that 11β-hydroxysteroid dehydrogenase type 1 plays in diabetes and metabolic syndrome, as well as the uninterrupted need for the new methods of treatment for the above-mentioned diseases, induce to look for selective inhibitors of this enzyme. It can be crucial in the treatment of metabolic disorders.
In the present study, a series of novel 2-(allylamino)thiazol-4(5H)-one derivatives was profiled for inhibitory activity against 11β-HSD1. The possibility of their application in this direction was evaluated earlier by the PASS on line program whereas activity of 2-(allylamino)thiazol-4(5H)-one derivatives were tested in vitro.
Section snippets
General information
1H NMR and 13C NMR spectra were recorded on the Bruker Avance 300 Hz, 400 Hz and 700 Hz apparatus (TMS as an internal standard). MS spectra were recorded on the Finnigan MAT 95.
The progress of reactions and also the purity of the obtained compounds were monitored by TLC on TLC-Silica gel 60 F254 (Merck) plates with ethyl acetate as an eluent.
Reagents and solvents
All chemicals and solvents were purchased commercially and used without further purification. N-allylthiourea 98%, Ethyl 2-bromoisobutyrate 98%, Ethyl
Chemistry
Previous studies on the use of compounds containing thiazole [1], [2] and 4,5-dihydrothiazole ring [3], [4], [9], [10] as 11β-HSD1 inhibitors prompted us to synthesize a series of new derivatives of 2-amino-4,5-dihydrothiazol-4(5H)-one and investigate their inhibitory properties for the enzyme. In our earlier work, we developed a method for synthesizing 2-(allylamino)thiazol-4(5H)-one derivatives using N-allylthiourea and α-haloesters [15]. Currently, using other commercially available
Conclusion
In conclusion we obtained 10 2-(allylamino)thiazol-4(5H)-one derivatives with yield up to 68%. Some of them inhibits 11β-HSD1 activity (up to 71% at a concentration of 10 μM).
Molecular docking studies showed that the bound ligands exhibit contacts with both the NADP+ molecule and the sidechains of amino-acid residues located on the protein loops (primarily Tyr177, Tyr183, Thr124, Ile121). For the most active compound (3i) no hydrogen bonding with Thr124 is observed whereas more intensive
Funding
This work has been supported by Nicolaus Copernicus University, Collegium Medicum as part of statutory research project in 2018 year, No. 473.
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Thiazolo[3,2-a]pyrimidin-5-one derivatives as a novel class of 11β-hydroxysteroid dehydrogenase inhibitors
2018, Bioorganic ChemistryCitation Excerpt :The predicted positions of the ligands docked into 11β-HSD1 were characterized by a simultaneous lowering of the scoring function value, Docking Score [kJ/mol]; this corresponds to the high values of the ligand binding energy. In order to search for effective and selective inhibitors of 11β-HSD1, attention was paid to thiazole derivatives i.a. BVT-14225, BVT-2733, BVT-3498 [3,18], 2-amino-1,3-thiazol-4(5H)one [5,19,20], (1,3-benzothiazol-2-yl)benzenesulfonamides [21] and adamantyl amides [1]. The possibility of using thiazolo[3,2-a]pyrimidine-5-one derivatives as inhibitors of 11β-HSD1 have not been earlier studied and reported in the literature.
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