Background. The need of iron-chelating agents as orally active alternatives to desferal for the treatment of iron overload in thalassaemic patients, has stimulated considerable research efforts in the synthesis of new metal chelators. One of the member of hydroxypyridinones (2,3- dimethyl-3- ) hydroxypyridinones has so far received the most attention. This compound is rapidly glucuronidated into a non-chelating metabolite, which partly explains why high doses of the compound has to be used in order to achieve negative balance. This metabolic behavior has led the medicinal chemists to design compounds such as N-hydroxyalkyl derivatives which do not undergo extensive metabolism. The objective of the present work was to further synthesis and design new derivatives of hydroxypyridinones (N- acetonitril and N-ethylamine derivatives) Methods. The synthesis route involves the benzylation of hydroxyl group of maltol (ethyl maltol) using benzyl chloride conversion of the benazylated maltol (ethyl maltol) to the N-acetonitril bezylated pyridinone derivatives by introducing the aminoacetonitril in pyridine solvent and cleavage of benzyl group by hydrogenation method or using the bromodimethyl borane to form the N-acetonitril or N- ethylamine- 3- hydroxypyridinones respectively.Results. In this work three final compounds such as 1- (2- aminoethyl)- 2- methyl- 3-hydroxypyridin- 4- one, 1- (2- aminoethyl)- 2- ethyl- 3- hydroxypyridin-4- one and 1- cyanomethyl -2- methyl- 3- hydroxypyridin- 4- one were synthesized.Discussion. Identification and structural elucidation of compounds were achieved by IH NMR and Mass spectra, elemental analysis and through physical constants. The biological effects of compounds will be studied in the near future.

Hydroxypyridinone iron chelators are currently the main candidates for development of orally active iron chelating alternatives to desferrioxamine (DFO). In the present study, the relative efficacy and liver toxicity of a bidentate chelator, 2-methyl-3-hydroxypyridin-4-one (MHPO), was studied in iron overloaded rats and compared with those of DFO. For iron overloading, rats received i.p. injections of 100 mg/kg of iron-dextran twice a week for 4 consecutive weeks. They were allowed for equilibration of iron after overloading for 15 days. Then the rats received i.p. injections of 200 mg/kg/day of either MHPO or DFO for 15 days. At the end of this period, blood samples were taken and the iron and ferritin concentrations and the total iron binding capacity (TIBC) were determined. The activities of SGOT, SGPT and ALP were analyzed by standard colorimetric kits. Serum values for iron, TIBC and ferritin were shown to have no significant differences after the administration of either MHPO or DFO in treated rats. SGOT and SGPT values were significantly reduced after the administration of MHPO. DFO, however, was only able to reduce SGPT with the same dose. There were no significant differences between two chelators with regards to ALP. After the administration of MHPO, skin rashes were observed in a way that rats could not move. In conclusion, this study confirms that MHPO is at least as effectives as DFO at mobilizing iron, and reduces liver toxicity, however, with regard to other side effects such as its skin toxicity, further studies are required.

Transfusion-dependent patients such as those suffering from β-thalassaemia develop a fatal secondary haemosiderosis and consequently a selective iron chelator must be used to relieve such iron overload. 3- Hydroxypyridin-4-ones are selective for iron(III) under most biological conditions, but unlike desferrioxamine, are efficiently absorbed when administered orally. In this study, the synthesis and determination of partition coefficients (Kpart) of a range of 1-substituted-2-ethyl-3-hydroxypyridin-4-ones, as orally active iron chelators, are described. All of the 1-substituted-2-ethyl-3-hydroxypyridin-4-ones were synthesized via a three step synthetic pathway. The commercially available 2-ethyl-3-hydroxypyran-4-one (ethyl maltol) was benzylated in aqueous methanol. The reaction product of the benzylated ethyl maltol with an excess of the suitable primary aryl amines was heated in a thick-walled sealed glass tube at 150-160°C to give 1-aryl-2-ethyl-3-benzyloxypyridin-4-one derivatives which were isolated as the free-bases. Removal of the benzyl group under acidic conditions was performed by catalytic hydrogenation to yield the bidentate chelators as HCl salt in good yield. In this work, final following compounds of 1-phenyl-2-ethyl-3- hydroxypyridin-4-one, 1-(4-methylphenyl)-2-ethyl-3-hydroxypyridin-4-one, 1-(4-methoxylphenyl)-2-ethyl- 3-hydroxypyridin-4-one, and 1-(4-nitrophenyl)-2-ethyl-3-hydroxypyridin-4-one were synthesized. Identifcation and structural elucidation of ligands were achieved by 1HNMR, IR, elemental analysis, mass spectra and through physical experiments. The Kpart values of the compounds were also determined in an aqueous/octanol system using an automated continuous flow method (a filter probe method).

Zinc sulphate is currently used for treatment of zinc deficiency. Its uptake by the body is poor, necessitating the administration of high doses. This leads to a range of unpleasant side effects. In order to increase the bioavailability of zinc, several zinc complexes have been designed and synthesized using bidentate ligands of hydroxypyranones and hydroxypyridinones. Elemental analysis in each zinc complex was consistent with the formulations of ZnL2 species L: bidentate ligand) with 1.5 or 7 water molecules per zinc and the water molecules were removed by heating in a vacuum oven to yield anhydrous zinc complexes. The partition coefficients (Kpart) of the complexes were also determined in 1-octanol/buffer (at pH 7.40) system by using shake-flask method. It was found that, the complexes with hydroxypyranone ligands possess higher Kpart values than those with hydroxypyidinone ligands. Therefore, the comparison of the complexes highlights the hydroxypyranone zinc complexes as the most promising candidates for using in zinc deficiency. Since it was anticipated that this type of complexes probably possesses suitable lipophilicity to facilitate their penetration into the gastrointestinal tract.

A series ofortho -hydroxypyridine-4-ones were prepared in high yields and evaluated for antioxidant and iron chelating activities. N1-H hydroxypyridinones Va, Vb, and Ve were the best radical scavengers in DPPH free radical scavenging assay. CompoundVb was proved to be the most potent compound in hydrogen peroxide scavenging assay. All of the synthesized compounds had very close chelating ability, compounds containing N1-CH3 hydroxypyridinone ring were stronger chelating agents.

Background: Leishmaniasis infection threatens millions of people in under developing and developing countries. Treatment of this neglected disease is very complicated. Subjects and Methods: A novel series of antimony (V) complexes using bidentate ligands of hydroxypyranones and hydroxypyridinones have been designed and synthesized. For the synthesis of the complexes, SbCl5 in water was added to the solution of each ligand at 60° C and the pH of mixture was adjusted to 8 using aqueous NaOH. After 24 h stirring, extraction of produced compound into acetone gave the desired complex. The structure of complexes was achieved by using FTIR, 1HNMR, and electron spin ionization mass spectroscopic techniques. All compounds were evaluated for in vitro anti amastogote form of Leishmania major. Results and Conclusion: The most potent antimony complexes against amastigotes were 5b (after 48 and 72 h) and 5a (after 72 h) with IC50 values of 24. 4, 16. 3, and 30. 1 µ g/mL, respectively. Furthermore, antimony and iron complexes were used together for in vitro anti amastigote form of L. major activity. These compounds were toxic for macrophages and destroyed them.

Recently, it has been shown that a number of hydroxypyridinones such as 1,2-dimethy 1-3- hydroxypyridin-4-one (L1) are useful for the treatment of iron overload in place of desferrioxamine in thalassaemic patients. In this study, the intestinal absorption (I.A.) of L1 and one of its analogues namely 2-methy-3-hydroxypyridin-4-one (L2), which possesses a higher partition coefficient (Kpart) than L1, have been determined.The ligands L1 and L2, used in the present study, were synthesized from maltol and methylamine or ammonia, respectively in a three step reaction method. Identification and purity of compounds were achieved by spectroscopy and elemental analysis. The I.A. of drugs was determined using the Everted Gut Sac method at different concentrations and time intervals. The concentrations of samples were measured by a DVMs spectrophotometer (lmax=280 nm).The results showed that the rate and I.A. of L2 are not statistically different from those of L1. At a concentration of 60 mg/lit, and after 45 min, the absorption reached a maximum for both ligands. It is clear that for the prediction of I.A. of a new drug a simple measurement of Kpart is not sufficient and other factors such as the number of hydrogen bonds between drug molecules and the surrounding molecules should also be taken into account due to their possible interferences. It could be concluded that from the point of I.A, the drug L2 has no advantage over the L1.