Novel 2-(Adamantan-1-ylamino)Thiazol-4(5H)-One Derivatives and Their Inhibitory Activity towards 11β-HSD1—Synthesis, Molecular Docking and In Vitro Studies

Abstract

A common mechanism in which glucocorticoids participate is suggested in the pathogenesis of such metabolic diseases as obesity, metabolic syndrome, or Cushing’s syndrome. The enzyme involved in the control of the availability of cortisol, the active form of the glucocorticoid for the glucocorticoid receptor, is 11β-HSD1. Inhibition of 11β-HSD1 activity may bring beneficial results for the alleviation of the course of metabolic diseases such as metabolic syndrome, Cushing’s syndrome or type 2 diabetes. In this work, we obtained 10 novel 2-(adamantan-1-ylamino)thiazol-4(5H)-one derivatives containing different substituents at C-5 of thiazole ring and tested their activity towards inhibition of two 11β-HSD isoforms. For most of them, over 50% inhibition of 11β-HSD1 and less than 45% inhibition of 11β-HSD2 activity at the concentration of 10 µM was observed. The binding energies found during docking simulations for 11β-HSD1 correctly reproduced the experimental IC50 values for analyzed compounds. The most active compound 2-(adamantan-1-ylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one (3i) inhibits the activity of isoform 1 by 82.82%. This value is comparable to the known inhibitor-carbenoxolone. The IC50 value is twice the value determined by us for carbenoxolone, however inhibition of the enzyme isoform 2 to a lesser extent makes it an excellent material for further tests.

11β-HSD as a New Target in Pharmacotherapy of Metabolic Diseases

“…The studies were conducted using liver microsomes. The obtained results support the participation of GCs in the pathogenesis of such metabolic diseases as obesity, metabolic syndrome, or Cushing’s syndrome [ 101 ].…”

11β-Hydroxysteroid Dehydrogenase Type 1 as a Potential Treatment Target in Cardiovascular Diseases

“…The biological activity of a compound depends on its chemical structure, hence structural fragments characteristic for inhibitors that have reached the stage of clinical trials are observed in the new tested compounds. In vitro studies were carried out for various structures, of which the group of compounds containing a thiazole ring [ 117 , 133 , 134 , 135 ] or its partially hydrogenated form, thiazol-4-one [ 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 ], seems to be the most numerous and promising ( Figure 5 ). Compounds containing fused systems with a thiazole ring [ 144 , 145 ] and other various heterocyclic systems with nitrogen atoms [ 146 , 147 , 148 , 149 , 150 , 151 , 152 ] were also analyzed as potential selective inhibitors of 11β-HSD1 ( Figure 6 ).…”

“…For example cyclic sulfonamides are highly selective inhibitors [ 154 , 155 , 156 , 157 ]. In many tested compounds with high activity and selectivity, the adamantyl substituent [ 139 , 146 , 149 , 150 , 151 , 153 , 154 , 156 ] and other polycyclic condensed systems [ 142 , 158 , 159 ] as well as halo-substituted phenyl rings [ 133 , 136 , 143 , 154 , 160 ] are constituents of the structure ( Figure 6 ).…”

“… Selected selective 11β-HSD1 inhibitors with thiazole and thiazol-4-one moiety in in vitro studies. Data refer to tests for human (h) or murine (m) 11β-HSD1 [ 133 , 137 , 138 , 139 , 140 , 141 , 142 , 143 ]. …”

Weak Noncovalent Interactions in Three Closely Related Adamantane-Linked 1,2,4-Triazole N-Mannich Bases: Insights from Energy Frameworks, Hirshfeld Surface Analysis, In Silico 11β-HSD1 Molecular Docking and ADMET Prediction

“…In addition, the desadamantyl 1,2,4-triazole derivatives IV [21], V [22] and VI [23], are currently under clinical investigations as 11β-HSD1 inhibitors for the treatment of type 2 diabetes and obesity (Figure 1). According to experimental and molecular docking studies for the identification of chemical features of 11β-HSD1 inhibitors, a combination of an adamantane cage-and 1,2,4-triazole or other azole moieties could result in potent 11β-HSD1 inhibitors [15,16,[24][25][26][27][28][29]. In continuation with ongoing interest in the structural properties [30][31][32][33][34][35] and biological applications of adamantane-based derivatives [35][36][37][38][39], we report herein on the molecular structure insights, Hirshfeld surface analysis and pairwise interaction energies of three adamantane-linked 1,2,4-triazole N-Mannich bases, namely ethyl 4-[(3adamantan-1-yl)-4-ethyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl]piperazine-1carboxylate (1), 5-(adamantan-1-yl)-4-ethyl-2-[(4-(pyridin-2-yl)piperazin-1-yl)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (2) and 5-(adamantan-1-yl)-4-allyl-2-[(4-(pyridin-2yl)piperazin-1-yl)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (3), which were proven to possess marked hypoglycemic activity [39].…”