Novel Thiourea and Oxime Ether Isosteviol-Based Anticoagulants: MD Simulation and ADMET Prediction.

Activated blood coagulation factor X (FXa) plays a critical initiation step of the blood-coagulation pathway and is considered a desirable target for anticoagulant drug development. It is reversibly inhibited by nonvitamin K antagonist oral anticoagulants (NOACs) such as apixaban, betrixaban, edoxaban, and rivaroxaban. Thrombosis is extremely common and is one of the leading causes of death in developed countries. In previous studies, novel thiourea and oxime ether isosteviol derivatives as FXa inhibitors were designed through a combination of QSAR studies and molecular docking. In the present contribution, molecular dynamics (MD) simulations were performed for 100 ns to assess binding structures previously predicted by docking and furnish additional information. Moreover, three thiourea- and six oxime ether-designed isosteviol analogs were then examined for their drug-like and ADMET properties. MD simulations demonstrated that four out of the nine investigated isosteviol derivatives, i.e., one thiourea and three oxime ether ISV analogs, form stable complexes with FXa. These derivatives interact with FXa in a manner similar to Food and Drug Administration (FDA)-approved drugs like edoxaban and betrixaban, indicating their potential to inhibit factor Xa activity. One of these derivatives, E24, displays favorable pharmacokinetic properties, positioning it as the most promising drug candidate. This, along with the other three derivatives, can undergo further chemical synthesis and bioassessment.

Lipophilic Studies and In Silico ADME Profiling of Biologically Active 2-Aminothiazol-4(5H)-one Derivatives.

Pseudothiohydantoin derivatives have a wide range of biological activities and are widely used in the development of new pharmaceuticals. Lipophilicity is a basic, but very important parameter in the design of potential drugs, as it determines solubility in lipids, nonpolar solvents, and makes it possible to predict the ADME profile. The aim of this study was to evaluate the lipophilicity of 28 pseudothiohydantoin derivatives showing the inhibition of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) using chromatographic methods. Experimentally, lipophilicity was determined by reverse phase thin layer chromatography (RP-TLC) and reverse phase high-performance liquid chromatography (RP-HPLC). In both methods, methanol was used as the organic modifier of the mobile phase. For each 2-aminothiazol-4(5H)-one derivative, a relationship was observed between the structure of the compound and the values of the lipophilicity parameters (log kw, RM0). Experimental lipophilicity values were compared with computer calculated partition coefficient (logP) values. A total of 27 of the 28 tested compounds had a lipophilicity value < 5, which therefore met the condition of Lipinski's rule. In addition, the in silico ADME assay showed favorable absorption, distribution, metabolism, and excretion parameters for most of the pseudothiohydantoin derivatives tested. The study of lipophilicity and the ADME analysis indicate that the tested compounds are good potential drug candidates.

Novel Isosteviol-Based FXa Inhibitors: Molecular Modeling, In Silico Design and Docking Simulation.

Direct oral anticoagulants are an important and relatively new class of synthetic anticoagulant drugs commonly used for the pharmacotherapy of thromboembolic disorders. However, they still have some limitations and serious side effects, which continuously encourage medicinal chemists to search for new active compounds acting as human-activated coagulation factor X (FXa) inhibitors. Isosteviol is a nontoxic hydrolysis product of naturally occurring stevioside and possesses a wide range of therapeutic properties, including anticoagulant activity. The present contribution describes the in silico design of novel oxime ether isosteviol derivatives as well as a molecular modeling approach based on QSAR analysis and a docking simulation for searching for novel isosteviol-based compounds as potential FXa inhibitors. The elaborated ANN model, encompassing topological and geometrical information, exhibited a significant correlation with FXa-inhibitory activity. Moreover, the docking simulation indicated six of the most promising isosteviol-like compounds for further investigation. Analysis showed that the most promising derivatives contain heterocyclic, aromatic, five-membered moieties, with substituents containing chlorine or fluorine atoms. It is anticipated that the findings reported in the present work may provide useful information for designing effective FXa inhibitors as anticoagulant agents.

A Review of Biologically Active Oxime Ethers.

Oxime ethers are a class of compounds containing the >C=N-O-R moiety. The presence of this moiety affects the biological activity of the compounds. In this review, the structures of oxime ethers with specific biological activity have been collected and presented, and bactericidal, fungicidal, antidepressant, anticancer and herbicidal activities, among others, are described. The review includes both those substances that are currently used as drugs (e.g., fluvoxamine, mayzent, ridogrel, oxiconazole), as well as non-drug structures for which various biological activity studies have been conducted. To the best of our knowledge, this is the first review of the biological activity of compounds containing such a moiety. The authors hope that this review will inspire scientists to take a greater interest in this group of compounds, as it constitutes an interesting research area.

Synthesis of Novel 2-(Cyclopentylamino)thiazol-4(5H)-one Derivatives with Potential Anticancer, Antioxidant, and 11ß-HSD Inhibitory Activities.

In this study, a series of nine new 2-(cyclopentylamino)thiazol-4(5H)-one derivatives were synthesized, and their anticancer, antioxidant, and 11ß-hydroxysteroid dehydrogenase (11ß-HSD) inhibitory activities were tested. Anticancer activity has been assessed using the MTS (MTS: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay against human colon carcinoma (Caco-2), human pancreatic carcinoma (PANC-1), glioma (U-118 MG), human breast carcinoma (MDA-MB-231), and skin melanoma (SK-MEL-30) cancer cell lines. Cell viability reductions, especially in the case of Caco-2, MDA-MB-231, and SK-MEL-30 lines, were observed for most compounds. In addition, the redox status was investigated and oxidative, but nitrosative stress was not noted at a concentration of 500 µM compounds tested. At the same time, a low level of reduced glutathione was observed in all cell lines when treated with compound 3g (5-(4-bromophenyl)-2-(cyclopentylamino)thiazol-4(5H)-one) that most inhibited tumor cell proliferation. However, the most interesting results were obtained in the study of inhibitory activity towards two 11ß-HSD isoforms. Many compounds at a concentration of 10 µM showed significant inhibitory activity against 11ß-HSD1 (11ß-hydroxysteroid dehydrogenase type 1). The compound 3h (2-(cyclopentylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one) showed the strongest 11ß-HSD1 inhibitory effect (IC50 = 0.07 µM) and was more selective than carbenoxolone. Therefore, it was selected as a candidate for further research.

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

Glucocorticoids (GCs) belong to the group of steroid hormones. Their representative in humans is cortisol. GCs are involved in most physiological processes of the body and play a significant role in important biological processes, including reproduction, growth, immune responses, metabolism, maintenance of water and electrolyte balance, functioning of the central nervous system and the cardiovascular system. The availability of cortisol to the glucocorticoid receptor is locally controlled by the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). Evidence of changes in intracellular GC metabolism in the pathogenesis of obesity, metabolic syndrome (MetS) and cardiovascular complications highlights the role of selective 11ß-HSD1 inhibition in the pharmacotherapy of these diseases. This paper discusses the role of 11ß-HSD1 in MetS and its cardiovascular complications and the importance of selective inhibition of 11ß-HSD1.

A Review of the Biological Activity of Amidrazone Derivatives.

Amidrazones are widely used in chemical synthesis, industry and agriculture. We compiled some of the most important findings on the biological activities of amidrazones described in the years 2010-2022. The data were obtained using the ScienceDirect, Reaxys and Google Scholar search engines with keywords (amidrazone, carbohydrazonamide, carboximidohydrazide, aminoguanidine) and structure strategies. Compounds with significant biological activities were included in the review. The described structures derived from amidrazones include: amidrazone derivatives; aminoguanidine derivatives; complexes obtained using amidrazones as ligands; and some cyclic compounds obtained from amidrazones and/or containing an amidrazone moiety in their structures. This review includes chapters based on compound activities, including: tuberculostatic, antibacterial, antifungal, antiparasitic, antiviral, anti-inflammatory, cytoprotective, and antitumor compounds, as well as furin and acetylocholinesterase inhibitors. Detailed information on the compounds tested in vivo, along the mechanisms of action and toxicity of the selected amidrazone derivatives, are described. We describe examples of compounds that have a chance of becoming drugs due to promising preclinical or clinical research, as well as old drugs with new therapeutic targets (repositioning) which have the potential to be used in the treatment of other diseases. The described examples prove that amidrazone derivatives are a potential source of new therapeutic substances and deserve further research.

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

Glucocorticoids (GCs), which are secreted by the adrenal cortex, are important regulators in the metabolism of carbohydrates, lipids, and proteins. For the proper functioning of the body, strict control of their release is necessary, as increased GCs levels may contribute to the development of obesity, type 2 diabetes mellitus, hypertension, cardiovascular diseases, and other pathological conditions contributing to the development of metabolic syndrome. 11ß-hydroxysteroid dehydrogenase type I (11ß-HSD1) locally controls the availability of the active glucocorticoid, namely cortisol and corticosterone, for the glucocorticoid receptor. Therefore, the participation of 11ß-HSD1 in the development of metabolic diseases makes both this enzyme and its inhibitors attractive targets in the pharmacotherapy of the above-mentioned diseases.

Assessment of the concentration of selected metalloproteinases (MMP-2, MMP-3, MMP-9 and MMP-13) in patients with ulcers as a complication of type 2 diabetes.

Introduction: Impaired chronic wound healing is a great challenge for modern medicine. This process causes ulceration especially in the course of diseases such as type II diabetes mellitus. Aim: This study assesses the concentration of selected matrix metalloproteinases in the example of metalloproteinase 2, 3, 9, 13 in patients with impaired healing of chronic wounds as a complication of type 2 diabetes. Material and methods: Nineteen people took part in the assessment of wound healing in patients with type 2 diabetes. The control group consisted of 21 healthy people. In the blood serum the concentration of MMP-2, MMP-3, MMP-9 and MMP-13 was determined. Results: The concentrations of MMP-2 and MMP-3 in the group of patients with ulcers were significantly higher (61% and 84% accordingly) compared to those in the control group without chronic wounds. No statistically significant differences in MMP-9 and MMP-13 concentrations were observed between the study and control groups. Conclusions: The increase in MMP-2 concentration, which is particularly active in the degradation of type IV collagen, which is the main component of the basal membranes, in patients with type 2 diabetes may impede and delay the healing of chronic wounds and thus contribute to the intensification of vascular complications. In turn, the increase in MMP-3 concentration, which plays a significant role in vascular diseases, in patients with type 2 diabetes may lead to intensification of atherosclerotic changes involving the arteries of the lower extremities and ulceration.

The Oxime Ethers with Heterocyclic, Alicyclic and Aromatic Moiety as Potential Anti-Cancer Agents.

Chemotherapy is one of the most commonly used methods of cancer disease treatment. Due to the acquisition of drug resistance and the possibility of cancer recurrence, there is an urgent need to search for new molecules that would be more effective in destroying cancer cells. In this study, 1-(benzofuran-2-yl)ethan-1-one oxime and 26 oxime ethers containing heterocyclic, alicyclic or aromatic moiety were screened for their cytotoxicity against HeLa cancer cell line. The most promising derivatives with potential antitumor activity were 2-(cyclohexylideneaminoxy)acetic acid (18) and (E)-acetophenone O-2-morpholinoethyl oxime (22), which reduced the viability of HeLa cells below 20% of control at concentrations of 100-250 µg/mL. Some oxime ethers, namely thiazole and benzothiophene derivatives (24-27), also reduced HeLa cell viability at similar concentrations but with lower efficiency. Further cytotoxicity evaluation confirmed the specific toxicity of (E)-acetophenone O-2-morpholinoethyl oxime (22) against A-549, Caco-2, and HeLa cancer cells, with an EC50 around 7 µg/mL (30 µM). The most potent and specific compound was (E)-1-(benzothiophene-2-yl)ethanone O-4-methoxybenzyl oxime (27), which was selective for Caco-2 (with EC50 116 µg/mL) and HeLa (with EC50 28 µg/mL) cells. Considering the bioavailability parameters, the tested derivatives meet the criteria for good absorption and permeation. The presented results allow us to conclude that oxime ethers deserve more scientific attention and further research on their chemotherapeutic activity.

Concentration of proinflammatory cytokines in patients with ulcers as a complication of type 2 diabetes mellitus.

INTRODUCTION: Difficult healing of chronic wounds is a serious problem for modern medicine. It leads to ulceration, especially in conditions such as diabetic foot syndrome or chronic venous insufficiency. This may be a result of chemical, physical, thermal or biological factors, among others. Analysis of mediators and molecular factors released by the abovementioned structure helps to better understand the mechanism of healing of chronic wounds and the formation of ulcers. AIM: To assess excretion of selected cytokines in patients with ulcerations as a complication of diabetes mellitus type 2. MATERIAL AND METHODS: Seventeen patients aged 68-87 took part in the assessment of wound healing in patients with ulceration in the course of diabetes mellitus type 2. The control group consisted of 21 healthy patients aged 32-62. In the blood serum bFGF, TNF-α, IL-4, TGF-ß1, TGF-ß2 and TGF-ß3 were determined. RESULTS: A significant difference was found in bFGF, IL-4, TGF-ß1, TGF-ß2, and TGF-ß3 levels. Concentration of bFGF was 12% lower in patients with ulcers than in the non-ulcerated control group (p = 0.013). IL-4 concentration was 46% lower in patients with ulcers than in the non-ulcerated control group (p = 0.002). TGF-ß1, TGF-ß2 and TGF-ß3 concentrations were also lower in the group of patients with ulcers compared to those in the non-ulcerated control group. CONCLUSIONS: Reduced concentrations of selected cytokines and growth factors may indicate abnormal activity of the cells that secrete them and affect the healing process of chronic wounds, hindering and delaying the healing process.

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

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 11ß-HSD1. Inhibition of 11ß-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 11ß-HSD isoforms. For most of them, over 50% inhibition of 11ß-HSD1 and less than 45% inhibition of 11ß-HSD2 activity at the concentration of 10 µM was observed. The binding energies found during docking simulations for 11ß-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.

A Novel N-Tert-Butyl Derivatives of Pseudothiohydantoin as Potential Target in Anti-Cancer Therapy.

Tumors are currently more and more common all over the world; hence, attempts are being made to explain the biochemical processes underlying their development. The search for new therapeutic pathways, with particular emphasis on enzymatic activity and its modulation regulating the level of glucocorticosteroids, may contribute to the development and implementation of new therapeutic options in the treatment process. Our research focuses on understanding the role of 11ß-HSD1 and 11ß-HSD2 as factors involved in the differentiation and proliferation of neoplastic cells. In this work, we obtained the 9 novel N-tert-butyl substituted 2-aminothiazol-4(5H)-one (pseudothiohydantoin) derivatives, differing in the substituents at C-5 of the thiazole ring. The inhibitory activity and selectivity of the obtained derivatives in relation to two isoforms of 11ß-HSD were evaluated. The highest inhibitory activity for 11ß-HSD1 showed compound 3h, containing the cyclohexane substituent at the 5-position of the thiazole ring in the spiro system (82.5% at a conc. 10 µM). On the other hand, the derivative 3f with the phenyl substituent at C-5 showed the highest inhibition of 11ß-HSD2 (53.57% at a conc. of 10 µM). A low selectivity in the inhibition of 11ß-HSD2 was observed but, unlike 18ß-glycyrrhetinic acid, these compounds were found to inhibit the activity of 11ß-HSD2 to a greater extent than 11ß-HSD1, which makes them attractive for further research on their anti-cancer activity.

Microbial Synthesis of (S)- and (R)-Benzoin in Enantioselective Desymmetrization and Deracemization Catalyzed by Aureobasidium pullulans Included in the Blossom Protect™ Agent.

In this study, we examined the Aureobasidium pullulans strains DSM 14940 and DSM 14941 included in the Blossom Protect™ agent to be used in the bioreduction reaction of a symmetrical dicarbonyl compound. Both chiral 2-hydroxy-1,2-diphenylethanone antipodes were obtained with a high enantiomeric purity. Mild conditions (phosphate buffer [pH 7.0, 7.2], 30 °C) were successfully employed in the synthesis of (S)-benzoin using two different methodologies: benzyl desymmetrization and rac-benzoin deracemization. Bioreduction carried out with higher reagent concentrations, lower pH values and prolonged reaction time, and in the presence of additives, enabled enrichment of the reaction mixture with (R)-benzoin. The described procedure is a potentially useful tool in the synthesis of chiral building blocks with a defined configuration in a simple and economical process with a lower environmental impact, enabling one-pot biotransformation.

Synthesis of Novel 2-(Isopropylamino)thiazol-4(5H)-one Derivatives and Their Inhibitory Activity of 11ß-HSD1 and 11ß-HSD2 in Aspect of Carcinogenesis Prevention.

Glucocorticoid metabolism at the tissue level is regulated by two isoenzymes 11ß-hydroxysteroid dehydrogenase (11ß-HSD), which mutually convert biologically active cortisol and inactive cortisone. Recent research is focused on the role of 11ß-HSD1 and 11ß-HSD2 as autocrine factors of tumor cell proliferation and differentiation. Herein, we report the synthesis of novel 2-(isopropylamino)thiazol-4(5H)-one derivatives and their inhibitory activity for 11ß-HSD1 and 11ß-HSD2. The derivative containing the spiro system of thiazole and cyclohexane rings shows the highest degree of 11ß-HSD1 inhibition (54.53% at 10 µM) and is the most selective inhibitor of this enzyme among the tested compounds. In turn, derivatives containing ethyl and n-propyl group at C-5 of thiazole ring inhibit the activity of 11ß-HSD2 to a high degree (47.08 and 54.59% at 10 µM respectively) and are completely selective. Inhibition of the activity of these enzymes may have a significant impact on the process of formation and course of tumors. Therefore, these compounds can be considered as potential pharmaceuticals supporting anti-cancer therapy.

Effect of chemical structure of benzofuran derivatives and reaction conditions on enantioselective properties of Aureobasidium pullulans microorganism contained in Boni Protect antifungal agent.

Bioorganic asymmetric reduction of carbonyl compounds is one of the most important fundamental and practical reactions for producing chiral alcohols. The stereoselective bioreduction of prochiral ketones of benzofuran derivatives in the presence of yeast-like fungus Aureobasidium pullulans contained in the antifungal Boni Protect agent was studied. Biotransformations were carried out under moderate conditions in an aqueous and two-phase system and without multiplication of the bioreagent. Despite similar chemical structure, each of the used ketone has been reduced with varying efficiency and selectivity. One of the reasons for these results is the presence of a whole set of oxidoreductases in A. pullulans cells that are sensitive to the smallest changes in the structure of prochiral substrate. The unsymmetrical methyl ketones were biotransformed with the highest selectivity. Aureobasidium pullulans microorganism is less effective in the reduction of unsymmetrical halomethyl ketones. The presence of a heteroatom in the alkyl group significantly decreases the selectivity of the process. Finally, as a result of the preferred hydride ion transfer from the dihydropyridine ring of the cofactor to the carbonyl double bond on the re side, secondary alcohols of the S and R configuration were obtained with moderate to high enantioselectivity (55-99%).

The application of safe for humans and the environment Polyversum antifungal agent containing living cells of Pythium oligandrum for biotransformation of prochiral ketones.

This report presents the whole-cell biotransformation of benzofuranyl-methyl ketone derivatives with the application of Polyversum antifungal agent containing Pythium oligandrum microorganism. Stereochemistry of the reduction of prochiral substrates was modified by the bioconversion conditions (concentration of reagents, a source of the carbon atom, biotransformation medium). In optimized conditions enantioselective process was noted. Secondary alcohols with excellent enantiomeric purity and high yields were obtained. The enantiomeric excess and conversion degree of 1-(benzofuran-2-yl)ethanol, 1-(7-ethylbenzofuran-2-yl)ethanol and 1-(3,7-dimethylbenzofuran-2-yl)ethanol were 99%/98.1%, 94%/94.4% and 99%/72.6%, respectively. In the presence of P. oligandrum, one of the enantiotopic hydrides of the dihydropyridine ring coenzyme is selectively transferred to a re side of the prochiral carbonyl group to give products with S configuration. This study demonstrates an inexpensive, eco-friendly approach in synthesis of optically pure benzofuran derivatives and can be an interesting alternative to organocatalysis. Furthermore, this method can be used in biotechnology processes due to its good chemical performance and a high degree of product isolation.

Application of ELISA Technique and Human Microsomes in the Search for 11ß-Hydroxysteroid Dehydrogenase Inhibitors.

The metabolic syndrome is defined by impaired carbohydrate metabolism and lipid disorders and often accompanied by hypertension, all of which will lead to obesity and insulin resistance. Glucocorticoids play a regulatory role in the metabolism of proteins, lipids, and carbohydrates. There is growing evidence for a role of glucocorticoids in the development of the metabolic syndrome. The most important factor that regulates the access of endogenous glucocorticoids to receptors after release of glucocorticoids and their diffusion into the cytoplasm of target cells is the steroid metabolism involving a microsomal enzyme, 11ß-hydroxysteroid dehydrogenase (11ß-HSD). The changes in intracellular glucocorticoid metabolism in the pathogenesis of obesity indicate the participation of modulation by 11ß-HSD1, which may represent a new therapeutic target for the treatment of diseases such as type 2 diabetes, visceral obesity, or atherosclerosis. The aim of our study was to determine the fast and effective method to assess inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase. The material for this study was human liver and kidney microsomes. In this study we used ELISA technique using 96-well microplates coated with antibodies which were specific for analyzed enzymes. The method can quickly and efficiently measure the inhibition of both 11ß-HSD1 and 11ß-HSD2. This method can be used to search for and determine inhibitors of this enzyme. Cortisone and cortisol were used as the substrates for corresponding enzyme assays. Furthermore, 3-N-allyl-2-thiouracil derivatives were used by us for comparison purposes in developing the method, although, due to their structure, those derivatives have not previously been considered as potential inhibitors of 11ß-HSD1. 3-N-Allyl-2-thiouracil derivatives are a group worth considering, because by modifying their structure (e.g., by introducing other substituents into the pyrimidine ring) it will be possible to obtain an increase in the activity of compounds in this regard. In conclusion, this study shows an efficient and fast method of determining inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase.

Synthesis of the N-methyl Derivatives of 2-Aminothiazol-4(5H)-one and Their Interactions with 11ßHSD1-Molecular Modeling and in Vitro Studies.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is an enzyme that affects the body's cortisol levels. The inhibition of its activity can be used in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes. In this study, we synthesized new derivatives of 2-(methylamino)thiazol-4(5H)-one and tested their activity towards inhibition of 11ß-HSD1 and its isoform - 11ß-HSD2. The results were compared with the previously tested allyl derivatives. We found out that methyl derivatives are weaker inhibitors of 11ß-HSD1 in comparison to their allyl analogs. Due to significant differences in the activity of the compounds, molecular modeling was performed, which was aimed at comparing the interactions between 11ß-HSD1 and ligands differing by substituent at the amine group (allyl vs. methyl). Modeling showed that the absence of the allyl group can lead to the rotation of whole ligand molecule which affects its interaction with the enzyme.

Thiazolo[3,2-a]pyrimidin-5-one derivatives as a novel class of 11ß-hydroxysteroid dehydrogenase inhibitors.

11ß-hydroxysteroid type 1 dehydrogenase (11ß-HSD1) is an enzyme that increases tissue concentrations of cortisol. Selective inhibitors of this enzyme regulate the level of cortisol and thus play a key role in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes. In this study the inhibitory activity of 29 thiazolo[3,2-a]pyrimidin-5-one derivatives on 11ß-HSD1 were investigated. Studies were carried out with pooled human liver microsomes. A lot of analyzed compounds show activity for inhibiting 11ß-HSD1 (up to 59.15% at concentration 10 µmol/l). Molecular docking simulation show that the molecule of the most active compound: 7-(cyclohexylmethyl)-2-iodomethyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-one forms hydrogen bonds with Ala172, Leu171, Leu215 or Tyr177. In addition, the cycloalkane moiety can create the hydrophobic contacts with NADP+. For this compound also the most favourable Docking Score value was obtained. The most active compound only in the slight degree inhibits 11ß-HSD2 activity and is a selective inhibitor of 11ß-hydroxysteroid dehydrogenase type 1. Consequently it can have a real effect on the regulation of the cortisol level in the body.