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).

Thiazoles and thiazolidinones as antioxidants.

Antioxidants are of great interest because of their involvement in important biological and industrial processes. According to Halliwell antioxidants are substances that at low concentration significantly delay or prevent oxidation. Chemically, oxidation is a process in which a loss of electrons occurs. Oxidants play a significant role in the pathogenesis of a number of disorders leading to oxidative stress. Oxidative stress may be defined as an imbalance between cellular production of reactive oxygen species and antioxidant defense mechanisms. ROS (e.g., superoxide radical, peroxynitryl, hydroxyl radical and hydrogen peroxide) are constantly produced as a result of metabolic reactions in living systems. Oxidative damage caused by ROS is responsible for many degenerative diseases such as cancer, atherosclerosis, diabetes, cirrhosis, Alzheimer's and inflammatory diseases. The aim of this review is to describe recent developments in the study of the antioxidant activity of thiazole and thiazolidinone derivatives, which are the core structure in a variety of pharmaceuticals with a broad spectrum of biological activity and their role in preventing the formation of ROS.

Synthesis and biological evaluation of some 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones as dual anti-inflammatory/antimicrobial agents.

As a part of our ongoing studies in developing new derivatives as dual antimicrobial/anti-inflammatory agents we describe the synthesis of novel 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones. All newly synthesized compounds were tested for their anti-inflammatory activity using carrageenan mouse paw edema bioassay. Their COX-1/LOX inhibitory activities were also determined. Moreover, all compounds were evaluated for their antimicrobial and antifungal activities against a panel of Gram positive, Gram negative bacteria and moulds. All tested compounds exhibited better antimicrobial activity than commercial drugs, bifonazole, ketoconazole, ampicillin and streptomycin.

Novel (E)-1-(4-methyl-2-(alkylamino)thiazol-5-yl)-3-arylprop-2-en-1-ones as potent antimicrobial agents.

New (E)-1-(4-methyl-2-(alkylamino)thiazol-5-yl)-3-arylprop-2-en-1-ones, unsubstituted or carrying fluoro, bromo, methoxy, nitro, methyl and chloro groups on the benzene ring, were synthesized and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria and fungi. The compounds were very potent towards all tested microorganisms and in most cases their activity was better than that of reference drugs.

Thiazole-based chalcones as potent antimicrobial agents. Synthesis and biological evaluation.

As part of ongoing studies in developing new antimicrobials, we report the synthesis of a new class of structurally novel derivatives, that incorporate two known bioactive structures a thiazole and chalcone, to yield a class of compounds with interesting antimicrobial properties. Evaluation of antibacterial activity showed that almost all the compounds exhibited greater activity than reference drugs and thus could be promising novel drug candidates.