New Substituted 5-Benzylideno-2-Adamantylthiazol[3,2-b][1,2,4]Triazol-6(5H)ones as Possible Anti-Inflammatory Agents.

BACKGROUND: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs act as cyclooxygenase inhibitors. However, almost all of them have undesired side effects. METHODS: Prediction of the anti-inflammatory action of the compounds was performed using PASS Program. The anti-inflammatory activity was evaluated by the carrageenan paw edema test. COX and LOX inhibitory actions were tested using ovine COX-1, human recombinant COX-2 and soybean LOX-1, respectively. Docking analysis was performed using Autodock. RESULTS: All designed derivatives had good prediction results according to PASS and were synthesized and experimentally evaluated. The compounds exhibited in vivo anti-inflammatory action with eleven being equal or better than indomethacin. Although, some of them had no or low inhibitory effect on COX-1/2 or LOX, certain compounds exhibited COX-1 inhibition much higher than naproxen and COX-2 inhibition, well explained by Docking analysis. CONCLUSIONS: A number of compounds with good anti-inflammatory action were obtained. Although, some exhibited remarkable COX inhibitory action this activity did not follow the anti-inflammatory results, indicating the implication of other mechanisms.

In Silico Evaluation of the Effectivity of Approved Protease Inhibitors against the Main Protease of the Novel SARS-CoV-2 Virus.

The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has 79.5% sequence identity with SARS-CoV-1 and the same strategy for host cell invasion through the ACE-2 surface protein. Since the development of novel drugs is a long-lasting process, researchers look for effective substances among drugs already approved or developed for other purposes. The 3D structure of the SARS-CoV-2 main protease was compared with the 3D structures of seven proteases, which are drug targets, and docking analysis to the SARS-CoV-2 protease structure of thirty four approved and on-trial protease inhibitors was performed. Increased 3D structural similarity between the SARS-CoV-2 main protease, the HCV protease and α-thrombin was found. According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than -8.00 kcal/mol and better prediction results than reference compounds. Since some of the compounds are well-tolerated drugs, the promising in silico results may warrant further evaluation for viral anticipation. DPP-4 inhibitors with anti-viral action may be more useful for infected patients with diabetes, while anti-coagulant treatment is proposed in severe SARS-CoV-2 induced pneumonia.

Rational Use of Heterogeneous Data in Quantitative Structure-Activity Relationship (QSAR) Modeling of Cyclooxygenase/Lipoxygenase Inhibitors.

Numerous studies have been published in recent years with acceptable quantitative structure-activity relationship (QSAR) modeling based on heterogeneous data. In many cases, the training sets for QSAR modeling were constructed from compounds tested by different biological assays, contradicting the opinion that QSAR modeling should be based on the data measured by a single protocol. We attempted to develop approaches that help to determine how heterogeneous data should be used for the creation of QSAR models on the basis of different sets of compounds tested by different experimental methods for the same target and the same endpoint. To this end, more than 100 QSAR models for the IC50 values of ligands interacting with cyclooxygenase 1,2 (COX) and seed lipoxygenase (LOX), obtained from ChEMBL database were created using the GUSAR software. The QSAR models were tested on the external set, including 26 new thiazolidinone derivatives, which were experimentally tested for COX-1,2/LOX inhibition. The IC50 values of the derivatives varied from 89 µM to 26 µM for LOX, from 200 µM to 0.018 µM for COX-1, and from 210 µM to 1 µM for COX-2. This study showed that the accuracy of the models is dependent on the distribution of IC50 values of low activity compounds in the training sets. In the most cases, QSAR models created based on the combined training sets had advantages in comparison with QSAR models, based on a single publication. We introduced a new method of combination of quantitative data from different experimental studies based on the data of reference compounds, which was called "scaling".

Novel Thiazolidin-4-ones as Potential Non-nucleoside Inhibitors of HIV-1 Reverse Transcriptase.

BACKGROUND: HIV is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), an infectious disease with increasing incidence worldwide. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in the treatment of AIDS. Although, many compounds are already being used as anti-HIV drugs, research for the development of new inhibitors continues as the virus develops resistant strains. METHODS: The best features of available NNRTIs were taken into account for the design of novel inhibitors. PASS (Prediction of activity spectra for substances) prediction program and molecular docking studies for the selection of designed compounds were used for the synthesis. Compounds were synthesized using conventional and microwave irradiation methods and HIV RT inhibitory action was evaluated by colorimetric photometric immunoassay. RESULTS: The evaluation of HIV-1 RT inhibitory activity revealed that seven compounds have significantly lower ΙC50 values than nevirapine (0.3 µΜ). It was observed that the activity of compounds depends not only on the nature of substituent and it position in benzothiazole ring but also on the nature and position of substituents in benzene ring. CONCLUSION: Twenty four of the tested compounds exhibited inhibitory action lower than 4 µΜ. Seven of them showed better activity than nevirapine, while three of the compounds exhibited IC50 values lower than 5 nM. Two compounds 9 and 10 exhibited very good inhibitory activity with IC50 1 nM.

4,5-Diaryl 3(2H)Furanones: Anti-Inflammatory Activity and Influence on Cancer Growth.

Apart from their anti-inflammatory action, COX inhibitors have gathered the interest of many scientists due to their potential use for the treatment and prevention of cancer. It has been shown that cyclooxygenase inhibitors restrict cancer cell growth and are able to interact with known antitumor drugs, enhancing their in vitro and in vivo cytotoxicity. The permutation of hydrophilic and hydrophobic aryl groups in COX inhibitors leads to cardinal changes in the biological activity of the compounds. In the present study, thirteen heterocyclic coxib-like 4,5-diarylfuran-3(2H)-ones and their annelated derivatives-phenanthro[9,10-b]furan-3-ones-were synthesized and studied for anti-inflammatory and COX-1/2 inhibitory action and for their cytotoxic activity on the breast cancer (MCF-7) and squamous cell carcinoma (HSC-3) cell lines. The F-derivative of the -SOMe substituted furan-3(2H)-ones exhibited the best activity (COX-1 IC50 = 2.8 µM, anti-inflammatory activity (by carrageenan paw edema model) of 54% (dose 0.01 mmol/kg), and MCF-7 and HSC-3 cytotoxicity with IC50 values of 10 µM and 7.5 µM, respectively). A cytotoxic effect related to the COX-1 inhibitory action was observed and a synergistic effect with the anti-neoplastic drugs gefitinib and 5-fluorouracil was found. A phenanthrene derivative exhibited the best synergistic effect with gefitinib.

5-Adamantan thiadiazole-based thiazolidinones as antimicrobial agents. Design, synthesis, molecular docking and evaluation.

In continuation of our efforts to develop new compounds with antimicrobial properties we describe design, synthesis, molecular docking study and evaluation of antimicrobial activity of seventeen novel 2-{[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-imino}-5-arylidene-1,3-thiazolidin-4-ones. All compounds showed antibacterial activity against eight Gram positive and Gram negative bacterial species. Twelve out of seventeen compounds were more potent than streptomycin and all compounds exhibited higher potency than ampicillin. Compounds were also tested against three resistant bacterial strains: MRSA, P. aeruginosa and E. coli. The best antibacterial potential against ATCC and resistant strains was observed for compound 8 (2-{[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-imino}-5-(4-nitrobenzylidene)-1,3thiazolidin-4-one). The most sensitive bacterium appeared to be S. typhimirium, followed by B. cereus while L. monocitogenes and M. flavus were the most resistant. Compounds were also tested for their antifungal activity against eight fungal species. All compounds exhibited antifungal activity better than the reference drugs bifonazole and ketokonazole (3-115 times). It was found that compound 8 appeared again to be the most potent. Molecular docking studies on E. coli MurB, MurA as well as C. albicans CYP 51 and dihydrofolate reductase were used for the prediction of mechanism of antibacterial and antifungal activities confirming the experimental results.

Application of Docking Analysis in the Prediction and Biological Evaluation of the Lipoxygenase Inhibitory Action of Thiazolyl Derivatives of Mycophenolic Acid.

5-LOX inhibition is among the desired characteristics of anti-inflammatory drugs, while 15-LOX has also been considered as a drug target. Similarity in inhibition behavior between soybean LOX-1 and human 5-LOX has been observed and soybean LOX (sLOX) type 1b has been used for the evaluation of LOX inhibition in drug screening for years. After prediction of LOX inhibition by PASS and docking as well as toxicity by PROTOX and ToxPredict sixteen (E)-N-(thiazol-2-yl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide derivatives with lengths varying from about 15⁻20 Å were evaluated in vitro for LOX inhibitory action using the soybean lipoxygenase sLOX 1b. Docking analysis was performed using soybean LOX L-1 (1YGE), soybean LOX-3 (1JNQ), human 5-LOX (3O8Y and 3V99) and mammalian 15-LOX (1LOX) structures. Different dimensions of target center and docking boxes and a cavity prediction algorithm were used. The compounds exhibited inhibitory action between 2.5 µΜ and 165 µΜ. Substituents with an electronegative atom at two-bond proximity to position 4 of the thiazole led to enhanced activity. Docking results indicated that the LOX structures 1JNQ, 3V99 and 1LOX can effectively be used for estimation of LOX inhibition and amino acid interactions of these compounds.

Study of the lipidemic profile of diabetic patients. Negative correlation of cholesterol levels of diabetes type I patients with serum amylase concentration.

Diabetes Mellitus type I (DM1) and II (DM2) share the common characteristic of high blood glucose concentration and the health complications resulting from uncontrolled hyperglycemia such as hyperlipidemia, cardiovascular problems, stroke, ketoacidosis, kidney failure and blindness but have different etiology. DM1 is practically an autoimmune disease. Genetic susceptibility together with environmental factors leads to disease development. The main characteristics of Diabetes type II (DM2) is insulin resistance in muscle and liver cells accompanied by loss of ß-cell function. However, adipose tissue, gastro-intestinal tract, pancreatic a-cell activity, may be involved in disease development. In parallel to the impairment of endocrine pancreatic function, a reduction in exocrine function has also been observed in all types of Diabetes Mellitus. A decrease in amylase and lipase activity has been mentioned by many authors, although cases with elevated amylase have been referred. Most recently a trend for positive correlation between HDL cholesterol and amylase in Diabetes type II patients was shown. In the present study we evaluated the lipidemic profile and related factors such as cortisol, total serum antioxidant capacity (TAC) and amylase in patients suffering from diabetes type I and II. The relationship between different parameters was examined. Blood serum from 20 DM1 patients and 45 DM2 patients was used. Serum from 50 healthy individuals was used as control. Total cholesterol and triglycerides were measured using an enzymatic colorimetric method. Serum cortisol, auto-antibodies and anti-Neu5Gc antibodies were measured using immunoenzyme assays and TAC measurement was made using the ABTS method. Mean total cholesterol was 245.5mg/dL in Diabetes I patients and was significantly elevated compared to healthy individuals as well as Diabetes II patients (168.71±76.0mg/dL). The observed difference was statistically significant (P=0.0004). On the contrary, triglyceride values were within normal range in both cases (123.7±63.2mg/dL in DM1 and 168.1±76.0mg/dL in DM2 patients). Cortisol levels were elevated in both cases with higher values observed in Diabetes type I (280.5±162.9ng/mL in DM1 and 248.5±100.1ng/mL in DM2), while total antioxidant capacity was significantly reduced compared to healthy individuals, 1.470mM, with lower values observed in Diabetes type I (0.680±0.116mM in DM1 and 0.849±0.126mM in DM2). Amylase determination revealed a mean amylase value, 81.7U/ml, within normal range and a negative correlation between cholesterol levels and amylase (r=-0.770) in DM1 patients. No correlation was observed between the determined values or the presence of autoantibodies and antibodies against Neu5Gc in the samples. In conlusion, the lipidemic profile and overall atherogenic and cardiovascular risk factors were worse in Diabetes I compared to Diabetes II patients. Most interestingly, cholesterol levels exhibited a negative correlation with serum amylase values. Since, amylase is not known to be involved in lipid metabolism, cholesterol levels and serum amylase activity may have a common modulator related to Diabetes development.

Synthesis and HIV-1 RT inhibitory action of novel (4/6-substituted benzo[d]thiazol -2-yl)thiazolidin-4-ones. Divergence from the non-competitive inhibition mechanism.

Reverse transcriptase (RT) inhibitors play a major role in the therapy of human immunodeficiency virus type 1 (HIV-1) infection. Although, many compounds are already used as anti-HIV drugs, research on development of novel inhibitors continues, since drug resistant strains appear because of prolonged therapy. In this paper, we present the synthesis and evaluation of HIV-1 RT inhibitory action of eighteen novel (4/6-halogen/MeO/EtO-substituted benzo[d]thiazol-2-yl)thiazolidin-4-ones. The two more active compounds (IC50 : 0.04 µM and 0.25 µM) exhibited better inhibitory action than the reference compound, nevirapine. Docking analysis supports a stable binding of the most active derivative to the allosteric centre of RT. Kinetic analysis of two of the most active compounds indicate an uncompetitive inhibition mode. This is a desired characteristic, since mutations that affect activity of traditional non-competitive NNRTIs may not affect activity of compounds of this series. Interestingly, the less active derivatives (IC50 > 40 µM) exhibit a competitive mode of action.

Vitamin D Status in Osteoporotic and Diabetic Patients and Athletic Healthy Individuals from Northern Greece.

Background: Vitamin D deficiency is recognised as a pandemic in the developed world. However, the importance of prudent sun exposure tends to be overlooked, which is responsible for this pandemic. Methods: We investigated the vitamin D status in 326 adults, 165 females and 161 males: 99 Osteoporosis patients, 53 Type 1 Diabetes patients, 51 Type 2 Diabetes patients, and 123 Athletic Healthy individuals, from Northern Greece, through the measurement of total calcidiol in winter and summer by immunoenzymatic assay. Results: In the Whole Sample 23.31% had severe deficiency, 13.50% mild deficiency, 17.48% insufficiency, and 45.71% adequacy at the end of winter. Mean concentrations differed significantly (p <0.001) between males and females. The prevalence of deficiency in the young was significantly lower than in the middle-aged (p = 0.004) and in the elderly (p <0.001), while it was significantly lower (p = 0.014) in the middle-aged than in the elderly. The best vitamin D status was found in the Athletic Healthy individuals, followed by the Type 1 and Type 2 Diabetic patients, while Osteoporotic patients had the poorest status. The difference in mean concentrations between winter and summer was significant (p <0.001). Conclusions: Vitamin D status deteriorated with increasing age and it was better in males than in females. Our findings suggest that outdoor physical activity in a Mediterranean country can cover the vitamin D needs of the young and the middle-aged, but not of the elderly, without the need for dietary supplements.

Substituted 6,7-dimethoxy-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole- 3-1,1-dioxide Derivatives with Antimicrobial Activity and Docking Assisted Prediction of the Mechanism of their Antibacterial and Antifungal Properties.

BACKGROUND: Although a great number of the targets of antimicrobial therapy have been achieved, it remains among the first fields of pharmaceutical research, mainly because of the development of resistant strains. Docking analysis may be an important tool in the research for the development of more effective agents against specific drug targets or multi-target agents 1-3. METHODS: In the present study, based on docking analysis, ten tetrahydrothiazolo[2,3-a]isoindole derivatives were chosen for the evaluation of the antimicrobial activity. RESULTS: All compounds showed antibacterial activity against eight Gram-positive and Gram-negative bacterial species being, in some cases, more potent than ampicillin and streptomycin against all species. The most sensitive bacteria appeared to be S. aureus and En. Cloacae, while M. flavus, E. coli and P. aeruginosa were the most resistant ones. The compounds were also tested for their antifungal activity against eight fungal species. All compounds exhibited good antifungal activity better than reference drugs bifonazole (1.4 - 41 folds) and ketoconazole (1.1 - 406 folds) against all fungal species. In order to elucidate the mechanism of action, docking studies on different antimicrobial targets were performed. CONCLUSION: According to docking analysis, the antifungal activity can be explained by the inhibition of the CYP51 enzyme for most compounds with a better correlation of the results obtained for the P.v.c. strain (linear regression between estimated binding Energy and log(1/MIC) with R 2 =0.867 and p=0.000091 or R 2 = 0.924, p= 0.000036, when compound 3 is excluded.

3-Amino-5-(indol-3-yl)methylene-4-oxo-2-thioxothiazolidine Derivatives as Antimicrobial Agents: Synthesis, Computational and Biological Evaluation.

Herein we report the design, synthesis, computational, and experimental evaluation of the antimicrobial activity of fourteen new 3-amino-5-(indol-3-yl) methylene-4-oxo-2-thioxothiazolidine derivatives. The structures were designed, and their antimicrobial activity and toxicity were predicted in silico. All synthesized compounds exhibited antibacterial activity against eight Gram-positive and Gram-negative bacteria. Their activity exceeded those of ampicillin and (for the majority of compounds) streptomycin. The most sensitive bacterium was S. aureus (American Type Culture Collection ATCC 6538), while L. monocytogenes (NCTC 7973) was the most resistant. The best antibacterial activity was observed for compound 5d (Z)-N-(5-((1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-4-hydroxybenzamide (Minimal inhibitory concentration, MIC at 37.9-113.8 µM, and Minimal bactericidal concentration MBC at 57.8-118.3 µM). Three most active compounds 5d, 5g, and 5k being evaluated against three resistant strains, Methicillin resistant Staphilococcus aureus (MRSA), P. aeruginosa, and E. coli, were more potent against MRSA than ampicillin (MIC at 248-372 µM, MBC at 372-1240 µM). At the same time, streptomycin (MIC at 43-172 µM, MBC at 86-344 µM) did not show bactericidal activity at all. The compound 5d was also more active than ampicillin towards resistant P. aeruginosa strain. Antifungal activity of all compounds exceeded those of the reference antifungal agents bifonazole (MIC at 480-640 µM, and MFC at 640-800 µM) and ketoconazole (MIC 285-475 µM and MFC 380-950 µM). The best activity was exhibited by compound 5g. The most sensitive fungal was T. viride (IAM 5061), while A. fumigatus (human isolate) was the most resistant. Low cytotoxicity against HEK-293 human embryonic kidney cell line and reasonable selectivity indices were shown for the most active compounds 5d, 5g, 5k, 7c using thiazolyl blue tetrazolium bromide MTT assay. The docking studies indicated a probable involvement of E. coli Mur B inhibition in the antibacterial action, while CYP51 inhibition is likely responsible for the antifungal activity of the tested compounds.

PTP1b Inhibition, A Promising Approach for the Treatment of Diabetes Type II.

BACKGROUND: Diabetes Mellitus (DM), is a metabolic disorder characterized by high blood glucose levels. The main types of diabetes mellitus are Diabetes mellitus type I, Diabetes mellitus type II, gestational diabetes and Diabetes of other etiology. Diabetes type II, the Non Insulin Dependent Type (NIDDM) is the most common type, characterized by the impairment in activation of the intracellular mechanism leading to the insertion and usage of glucose after interaction of insulin with its receptor, known as insulin resistance. Although, a number of drugs have been developed for the treatment of diabetes type II, their ability to reduce blood glucose levels is limited, while several side effects are also observed. Furthermore, none of the market drugs targets the enhancement of the action of the intracellular part of insulin receptor or recuperation of the glucose transport mechanism in GLUT4 dependent cells. The Protein Tyrosine Phosphatase (PTP1b) is the main enzyme involved in insulin receptor desensitization and has become a drug target for the treatment of Diabetes type II. Several PTP1b inhibitors have already been found, interacting with the binding site of the enzyme, surrounding the catalytic amino acid Cys215 and the neighboring area or with the allosteric site of the enzyme, placed at a distance of 20 Å from the active site, around Phe280. However, the research continues for finding more potent inhibitors with increased cell permeability and specificity. OBJECTIVE: The aim of this review is to show the attempts made in developing of Protein Tyrosine Phosphatase (PTP1b) inhibitors with high potency, selectivity and bioavailability and to sum up the indications for favorable structural characteristics of effective PTP1b inhibitors. METHODS: The methods used include a literature survey and the use of Protein Structure Databanks such as PuBMed Structure and RCSB and the tools they provide. CONCLUSION: The research for finding PTP1b inhibitors started with the design of molecules mimicking the Tyrosine substrate of the enzyme. The study revealed that an aromatic ring connected to a polar group, which preferably enables hydrogen bond formation, is the minimum requirement for small inhibitors binding to the active site surrounding Cys215. Molecules bearing two hydrogen bond donor/acceptor (Hb d/a) groups at a distance of 8.5-11.5 Å may form more stable complexes, interacting simultaneously with a secondary area A2. Longer molecules with two Hb d/a groups at a distance of 17 Å or 19 Å may enable additional interactions with secondary sites (B and C) that confer stability as well as specificity. An aromatic ring linked to polar or Hb d/a moieties is also required for allosteric inhibitors. A lower distance between Hb d/a moieties, around 7.5 Å may favor allosteric interaction. Permanent inhibition of the enzyme by oxidation of the catalytic Cys215 has also been referred. Moreover, covalent modification of Cys121, placed near but not inside the catalytic pocket has been associated with permanent inhibition of the enzyme.

Docking Assisted Prediction and Biological Evaluation of Sideritis L. Components with PTP1b Inhibitory Action and Probable Anti-Diabetic Properties.

BACKGROUND: The main characteristic of Diabetes type II is the impaired activation of intracellular mechanisms triggered by the action of insulin. PTP1b is a Protein Tyrosine Phosphatase that dephosphorylates insulin receptor causing its desensitization. Since inhibition of PTP1b may prolong insulin receptor activity, PTP1b has become a drug target for the treatment of Diabetes II. Although a number of inhibitors have been synthesized during the last decades, the research still continues for the development of more effective and selective compounds. Moreover, several constituents of plants and edible algae with PTP1b inhibitory action have been found, adding this extra activity at the pallet of properties of the specific natural products. OBJECTIVE: Sideritis L. (Lamiaceae) is a herbal plant growing around the Mediterranean sea which is included in the Mediterranean diet for centuries. The present study is the continuation of a previous work where the antioxidant and anti-inflammatory activities of the components of Sideritis L. were evaluated and aimed to investigate the potential of some sideritis's components to act as PTP1b inhibitors, thus exhibiting the beneficial effect in the treatment of diabetes II. METHODS: Docking analysis was done to predict PTP1b inhibitory action. Human recombinant PTP1b enzyme was used for the evaluation of the PTP1b inhibitory action, while inhibition of the human LAR and human T-cell PTP was tested for the estimation of the selectivity of the compounds. CONCLUSION: Docking analysis effectively predicted inhibition and mode of inhibitory action. According to the experimental results, four of the components exhibited PTP1b inhibitory action. The most active ones were acetoside, which acted as a competitive inhibitor, with an IC50 of 4 µM and lavandufolioside, which acted as an uncompetitive inhibitor, with an IC50 of 9.3 µM. All four compounds exhibited increased selectivity against PTP1b.

Design, Synthesis, Evaluation of Antimicrobial Activity and Docking Studies of New Thiazole-based Chalcones.

BACKGROUND: Thiazole derivates as well as chalcones, are very important scaffold for medicinal chemistry. Literature survey revealed that they possess wide spectrum of biological activities among which are anti-inflammatory and antimicrobial. OBJECTIVES: The current studies describe the synthesis and evaluation of antimicrobial activity of twenty eight novel thiazole-based chalcones. METHODS: The designed compounds were synthesized using classical methods of organic synthesis. The in vivo evaluation of antimicrobial activity was performed by microdilution method. RESULTS: All compounds have shown antibacterial properties better than that of ampicillin and in many cases better than streptomycin. As far as the antifungal activity is concerned, all compounds possess much higher activity than reference drugs bifonazole and ketoconazole. The most sensitive bacterial species was B. cereus (MIC 6.5-28.4 µmol × 10-2/mL and MBC 14.2-105.0 µmol × 10-2/mL) while the most resistant ones were L. monocytogenes (MIC 21.4-113.6 µmol × 10-2/mL) and E. coli (MIC 10.7- 113.6 µmol × 10-2/mL) and MBC at 42.7-358.6 µmol × 10-2/mL and 21.4-247.2 µmol × 10-2/mL, respectively. All the compounds exhibited antibacterial activity against the three resistant strains, MRSA, P. aeruginosa and E.coli. with MIC and MBC in the range of 0.65-11.00 µmol/mL × 10-2 and 1.30-16.50 µmol/mL × 10-2. Docking studies were performed. CONCLUSION: Twenty-eight novel thiazole-based chalcones were designed, synthesized and evaluated for antimicrobial activity. The results showed that these derivatives could be lead compounds in search of new potent antimicrobial agents. Docking studies indicated that DNA gyrase, GyrB and MurA inhibition may explain the antibacterial activity.

Chromenone derivatives as a versatile scaffold with dual mode of inhibition of HIV-1 reverse transcriptase-associated Ribonuclease H function and integrase activity.

A number of compounds targeting different processes of the Human Immunodeficiency Virus type 1 (HIV-1) life cycle have been developed in the continuing fight against AIDS. Coumarin-based molecules already proved to act as HIV-1 Protease (PR) or Integrase (IN) inhibitors and also to target HIV-1 reverse transcriptase (RT), blocking the DNA-dependent DNA-polymerase activity or the RNA-dependent DNA-polymerase activity working as common NNRTIs. In the present study, with the aim to exploit a coumarin-based scaffold to achieve the inhibition of multiple viral coded enzymatic functions, novel 4-hydroxy-2H, 5H-pyrano (3, 2-c) chromene-2, 5-dione derivatives were synthesized. The modeling studies calculated the theoretical binding affinity of the synthesized compounds on both HIV-1 IN and RT-associated Ribonuclease H (RNase H) active sites, which was confirmed by biological assays. Our results provide a basis for the identification of dual HIV-1 IN and RT RNase H inhibitors compounds.

Computer-aided discovery of anti-inflammatory thiazolidinones with dual cyclooxygenase/lipoxygenase inhibition.

New anti-inflammatory agents possessing dual cyclooxygenase/lipoxygenase (COX/LOX) inhibition were discovered by computer-aided prediction of biological activity for 573 virtually designed chemical compounds. Prediction of biological activity was performed by PASS, and prediction results were analyzed with PharmaExpert software. Nine 2-(thiazole-2-ylamino)-5-phenylidene-4-thiazolidinone derivatives differing by the phenyl group substitution were selected for synthesis and experimental testing as potential COX/LOX inhibitors. Eight tested compounds exhibited anti-inflammatory activity in the carrageenin-induced paw edema. It was shown that seven tested compounds (77.8%) were LOX inhibitors, seven compounds were COX inhibitors (77.8%), and six tested compounds (66.7%) were dual COX/LOX inhibitors. Analysis of lipophilicity of the compounds showed a negative correlation with inhibition of edema formation. The binding modes of the most active compounds of this series (2-(thiazole-2-ylamino)-5-( m-chlorophenylidene)-4-thiazolidinone for COX-1 and COX-2, and 2-(thiazole-2-ylamino)-5-( m-nitrophenylidene)-4-thiazolidinone for 15-LOX) were proposed on the basis of docking studies.

Synthesis and in silico biological activity evaluation of new N-substituted pyrazolo-oxazin-2-one systems.

Cyclisation of pyrazolo-beta-enaminones 3 readily obtained from 4-aceto acetyl pyrazol 2 with triphosgene led to the formation of N-substituted pyrazolo-1,3-oxazin-2-ones 4 in good yields. Estimation of pharmacotherapeutic potential, possible molecule mechanisms of action, toxic/side effects and interaction with drug-metabolizing enzymes were made for synthesised compounds on the basis of prediction of activity spectra for substances (PASS) prediction results and their analysis by PharmaExpert software. COX inhibition predicted by PASS was confirmed by experimental evaluation.

New N-(2-phenyl-4-oxo-1,3-thiazolidin-3-yl)-1,2-benzothiazole-3-carboxamides and acetamides as antimicrobial agents.

A series of 21 novel N-[2-phenyl-4-oxo-1,3-thiazolidin-3-yl]-1,2-benzothiazole-3-carboxamides/acetamides (4a-4p) as well as a series of N'-(halophenylmethylidene)-1,2-benzothiazole-3-acetohydrazides (3h-3p) have been synthesized and evaluated for their antimicrobial activity against eight bacterial and eight fungal species, among them plant, animal and human pathogens and food contaminating species. All compounds appeared to be potent and the best activity was exhibited by compound 4d with MIC in the range of 10.7-21.4 µmol mL-1 × 10-2 and MBC of 21.4-40.2 µmol mL-1 × 10-2. The best antifungal activity was observed for compounds 4p and 3h. Elucidation of the relationship between the antimicrobial activity and molecular properties of the synthesized compounds was also performed. Synthetic intermediates were also tested with several exhibiting good antimicrobial activities. Docking studies for some compounds were performed.

Prevalence of anti-Neu5Gc antibodies in patients with hypothyroidism.

BACKGROUND: N-Glycolylneuraminic acid (Neu5Gc) is a sialic acid synthesized by animals, but not by humans or birds. However, it can be incorporated in human cells and can trigger immune response. In the present study, we detected anti-Neu5Gc antibodies in samples of the general population and of patients suffering from hypothyroidism/Hashimoto's disease, which is known to have autoimmune origin. METHODS: Antibodies were measured using enzyme-immunosorbent techniques. RESULTS: Serum anti-Neu5Gc IgG antibodies were higher in patients with hypothyroidism (mean: 14.8 ± 15.9 µg/mL, median: 10.0 µg/mL, P = 0.0003, Mann-Whitney) and even higher in the group with Hashimoto's thyroiditis (mean: 31.1 ± 16.3 µg/mL, median: 27.2 µg/mL, P = 0.0000, Mann-Whitney) compared to the general population (mean: 5.3 ± 4.7 µg/mL, median : 4 µg/mL). All anti-TPO positive samples had anti-Neu5Gc antibody concentration higher than the mean value of the general population while anti-TPO concentration was increased as anti-Neu5Gc concentration increased. Low concentrations of IgA and IgM antibodies were measured in both general population and patient groups. CONCLUSION: The increased values of anti-Neu5Gc antibodies in patients with hypothyroidism/Hashimoto's disease and the correlation of anti-TPO incidence with increased anti-Neu5Gc concentration raise the possibility of an association between anti-Neu5Gc antibody development and autoimmune hypothyroidism.