Phaedra Eleftheriou

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 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.

Prediction of enzyme inhibition and mode of inhibitory action based on calculation of distances between hydrogen bond donor/acceptor groups of the molecule and docking analysis: An application on the discovery of novel effective PTP1B inhibitors

PTP1B is a protein tyrosine phosphatase involved in insulin receptor desensitization. PTP1B inhibition prolongs the activated state of the receptor, practically enhancing the effect of insulin. Thus PTP1B has become a drug target for the treatment of type II diabetes. PTP1b is an enzyme with multiple binding sites for competitive and allosteric inhibitors. Prediction of inhibitory action using docking analysis has limited success in case of enzymes with multiple binding sites, since the selection of the right crystal structure depends on the kind of inhibitor. In the present study, a two-step strategy for the prediction of PTP1b inhibitory action was applied to 12 compounds. Based on the study of known inhibitors, we isolated the structural characteristics required for binding to each binding site. As a first step, 3D-structures of the molecules were produced and their structural parameters were measured and used for prediction of the binding site of the compound. These results were used for the selection of the appropriate crystal structure for docking analysis of each compound, and the final prediction was based on the estimated binding energies. This strategy effectively predicted the activity of all compounds. A linear correlation was found between estimated binding energy and inhibition measured in vitro (r = –0.894).

Compounds against inflammation and oxidative insult as potential agents for neurodegenerative disorders

Amides of proline, a feature encountered in nootropics, via the carboxylic group of ibuprofen, indomethacin, ketoprofen and naproxen were prepared. Proline carboxylic group was amidated or esterified with potential antioxidant or neuroprotective compounds. Proline was replaced by 4-hydroxyproline, 2-pipecolic acid or omitted, for investigating the contribution of structure to activity. Anti-inflammatory activity was determined, and selected compounds were examined for anti-dyslipidemic action, protection against brain ischaemia/reperfusion and brain penetration.Graphical abstractAmides of proline and related structures with NSAIDs were synthesized. They were amidated or esterified with antioxidant or neuroprotective compounds. Activity against lipid peroxidation, inflammation and brain ischaemia was evaluated.

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/Hashimotos 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 Hashimotos 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/Hashimotos 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.

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.

Anti-HIV Agents: Current Status and Recent Trends

Human immunodeficiency virus is responsible for acquired immunodeficiency syndrome (AIDS), an infectious disease that consists a serious concern worldwide for more than three decades. By the end of 2013 UNAIDS estimated that there were 35 million (range 33.2–37.2 million) adults and children living with HIV/AIDS worldwide. Despite the introduction of highly active antiretroviral therapy (HAART), the need for new anti-HIV agents is extremely high because the existing medicines do not provide the complete curation and exhibit serious side effects, and their application leads to the appearance of resistant strains. This chapter explores the medicinal chemistry efforts that gave rise to currently launched drugs as well as investigational anti-HIV agents. Currently used and studied molecular targets of antiretrovirals and the main classes of HIV-1 inhibitors are presented. Among the future prospects, we discuss the efforts directed to overcome the latent HIV infection, utilization of natural products as potential anti-HIV agents, recent trends on development of biologics as potential anti-HIV medicines, and application of computer-aided methods in the discovery of new anti-HIV drugs.

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.