PTP1b is a protein tyrosine phosphatase involved in the inactivation of insulin receptor. Since inhibition of PTP1b may prolong the action of the receptor, PTP1b has become a drug target for the treatment of type II diabetes. In the present study, prediction of inhibition using docking analysis targeted specifically to the active or allosteric site was performed on 87 compounds structurally belonging to 10 different groups. Two groups, consisting of 15 thiomorpholine and 10 thiazolyl derivatives exhibiting the best prediction results, were selected for in vitro evaluation. All thiomorpholines showed inhibitory action (with IC = 4-45 μΜ, Ki = 2-23 μM), while only three thiazolyl derivatives showed low inhibition (best IC = 18 μΜ, Ki = 9 μΜ). However, free binding energy (E) was in accordance with the IC values only for some compounds. Docking analysis targeted to the whole enzyme revealed that the compounds exhibiting IC values higher than expected could bind to other peripheral sites with lower free energy, E, than when bound to the active/allosteric site. A prediction factor, E- (Σ × 0.16), which takes into account lower energy binding to peripheral sites, was proposed and was found to correlate well with the IC values following an asymmetrical sigmoidal equation with r = 0.9692.

A number of thiomorpholine derivatives that are structurally similar to some substituted morpholines possessing antioxidant and hypocholesterolemic activity were synthesized. The new compounds incorporate an antioxidant moiety as the thiomorpholine N-substituent. The derivatives were found to inhibit the ferrous/ascorbate-induced lipid peroxidation of microsomal membrane lipids, with IC50 values as low as 7.5 µΜ. In addition, these compounds demonstrate hypocholesterolemic and hypolipidemic action. The most active compound (5) decreases the triglyceride, total cholesterol, and low-density lipoprotein levels in the plasma of Triton WR-1339-induced hyperlipidemic rats, by 80, 78, and 76%, respectively, at 56 mmol/kg (i.p.). They may also act as squalene synthase inhibitors. The above results indicate that the new molecules may be useful as leads for the design of novel compounds as potentially antiatherogenic factors.

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The synthesised compounds, designed to exhibit two or more pharmacological actions, may be considered useful in the study of agents addressed to conditions involving inflammation and oxidative stress.

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Efforts, aiming to the development of safe non-steroidal anti-inflammatory agents, are evolving, however there are still several problems concerning gastro-protection to be efficiently solved, thus, design of effective and safe agents for the treatment of inflammatory conditions still remains a major challenge.

: Polymer-drug conjugates are polymers with drug molecules chemically attached to polymer side chains through a weak covalent bond (degradable bond) or a dynamic covalent bond. These systems are known as prodrugs in the inactive form of the drug passing into the blood circulation system. When the prodrug reaches to the target organ, tissue or cell, the drug is activated by cleavage of the bond between the drug and polymer under certain conditions existing in the target organ. The advantages of polymer-drug conjugates compared to other controlledrelease carriers and conventional pharmaceutical formulations are the increased drug loading capacity, the prolonged in vivo circulation time, the enhanced intercellular uptake, the better controlled release, the improved therapeutic efficacy and the enhanced permeability and retention effect. The aim of the present review is the investigation of polymer-drug conjugates bearing anticancer drugs. The polymer through its side chains is linked to the anticancer drugs via dynamic covalent bonds such as hydrazone/imine bonds, disulfide bonds and boronate esters. These dynamic covalent bonds are cleaved in conditions existing only in cancer cells and not in healthy ones. Thus, ensures the selective release of the drug to the targeted tissue, reducing in this way the frequent side effects of chemotherapy, leading to a more targeted application, despite the nature of the applied polymer, possessing the ability to aim selectively tumors via incorporation of a relative ligand.

Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%–93%). All the tested derivatives strongly decreased lipidemic indices in rat plasma after Triton induced hyperlipidaemia. They also reduced acute inflammation and a number of them demonstrated lipoxygenase inhibitory activity. Those compounds acquiring antioxidant moiety were inhibitors of lipid peroxidation and radical scavengers. Therefore, the synthesised compounds may add to the current knowledge about multifunctional agents acting against various disorders implicating inflammation, dyslipidaemia and oxidative stress.