Synthesis and biological activity of new donepezil-hydrazinonicotinamide hybrids.

Currently available treatment used in Alzheimer's disease is based on acetylcholinesterase inhibitors, e. g. donepezil, tacrine, galantamine, and rivastigmine. In the present study some derivatives of donepezil were synthesized, and their potential anticholinesterase properties were investigated using the colorimetric Ellman's method. These compounds were synthesized by condensation between indanone derivatives and the hydrazine nicotinated moiety (Hynic). For received derivatives, the selectivity and the IC50 values for acetylcholinesterase and butyrylcholinesterase were calculated. All the tested compounds exhibited lower affinity for AChE than donepezil and higher affinity for BChE than donepezil. Compound 33 showed the most selectivity for AChE among the obtained indanone derivatives.

Synthesis, biological activity and molecular modeling of 4-fluoro-N-[ω-(1,2,3,4-tetrahydroacridin-9-ylamino)-alkyl]-benzamide derivatives as cholinesterase inhibitors.

The aim of this study was to synthesize and determine the biological activity of new derivatives of 4-fluorobenzoic acid and tetrahydroacridine towards inhibition of cholinesterases. Compounds were synthesized in condensation reaction between 9-aminoalkyl-tetrahydroacridines and the activated 4-fluorobenzoic acid. Properties towards inhibition of acetyl- and butyrylcholinesterase were estimated according to Ellman's spectrophotometric method. Among synthesized compounds the most active were compounds 4a and 4d. These compounds, in comparison with tacrine, were characterized by the similar values of IC50. Among all obtained compounds, 4d presented the highest selectivity towards inhibition of acetylcholinesterase. Molecular modeling studies revealed that all derivatives presented similar extended conformation in the gorge of acetylcholinesterase, however, there were 2 main conformations in the active center of butyrylcholinesterase: bent and extended conformation.

Design, synthesis and biological evaluation of new 2-benzoxazolinone derivatives as potential cholinesterase inhibitors for therapy of alzheimer's disease.

Currently acetylcholinesterase inhibitor (AChEI) therapy is one of the most frequently used methods in the treatment of Alzheimer's disease; tacrine, donepezil, rivastygmine and galantamine are applied in different stages of AD. In the present study, we propose a new series of 2-benzoxazolinone derivatives as potential cholinesterase inhibitors. These compounds were synthesized by condensation of 6-chloro acetyl-2-benzoxa zolinone with the corresponding amine and evaluated as acetylcholinesterase inhibitors using the colorimetric Ellman's method. Selectivity and the IC50 values were determined for the received derivatives. All tested compounds exhibited the inhibitory activity towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compound 3e showed stronger activity than the standard tacrine, and compound 3a showed activity similar to that of tacrine for AChE. Compounds 3a, 3b, 3c, and 3e showed stronger activity than the standard donepezil towards the inhibition of BChE, and the compound 3e showed stronger activity than donepezil towards AChE.

HPLC method for determination of the purity of a mebrofenin-ligand for 99mTc-complexes.

A reversed-phase HPLC method has been developed for the estimation of purity and quantitative determination of mebrofenin UV detection at 205 nm was used. The stability of mebrofenin alone and in the presence of stannous chloride at 25 degrees C was studied. No decomposition product was found and there was no influence of SnCl2 on the stability of mebrofenin.

New tacrine-hydrazinonicotinamide hybrids as acetylcholinesterase inhibitors of potential interest for the early diagnostics of Alzheimer's disease.

The syntheses and the preliminary results of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition by an affinity series of tacrine-hydrazinonicotinamide hybrids are described. These molecules were prepared by condensation of tacrine analogues with the hydrazine nicotinate moiety (HYNIC). Derivatives 6a and 6b showed lower activity than the model tacrine, while compounds 6c and 6d showed the strongest affinity to AChE. All the tested compounds exhibited lower affinity for BChE than tacrine. Alzheimer disease (AD) is characterised by a deficit of acetylcholinesterase, and these new compounds, as ligands for 99mTc complexes, are potential radiopharmaceuticals for an early diagnosis of Alzheimer's disease.

New derivatives of 2-(N-arylmethylideneamine) benzophenone oxime as potential radiopharmaceuticals for brain imaging.

BACKGROUND: The aim of this work was the development of a sufficient method for synthesis and radiolabelling with technetium- 99m a new class of compounds as potential ligands for brain imaging. METHODS: The synthesis of new ligands with the structure of 2-(N-arylmethylideneamine) benzophenone oxime (6-10) based on the cyclocondensation of appropriate 2-aminobenzophenone oxime 1-2 with respective aldehydes 3-4 or ketone 5 in acidic conditions. During our experiments in dependencies from the reaction conditions, compounds with the structure of Schiff's bases (6-10) or 3N-oxides 1,2-dihrydroquinazoline derivatives were obtained. Labelling of compounds 6 or 7 with technetium- 99m was done by stannous chloride reduction according to two methods (in ethyl alcohol or in chloroform) following the radiolabelling method of HM-PAO. The complex (99m)Tc-HM-PAO was the leading compound in our computational calculations with geometrical optimisation of a molecule. Using molecular modelling (semi-empirical method ZINDO) we have determined the electrostatic potential for the obtained ligands. Additionally we have calculated total energy,binding energy, heat of formation and several 3D-QSAR parameters for theoretically possible complexes of (99m)Tc with the obtained ligands. RESULTS: As a result of our experiments a method of a synthesis of new compounds 6 and 7 has been developed. Computational calculations were performed using the HyperChem 4.5 program. These calculations confirmed our hypothesis that only ligand 7 is able to form a complex with (99m)Tc and this complex possesses lipophilic properties. CONCLUSIONS: Complex (99m)Tc-7, due to its lipophilic properties, is a potential radiopharmaceutical for the brain imaging.

New analogues of ACPD with selective activity for group II metabotropic glutamate receptors.

In this study we have determined the pharmacology of a series of 1-aminocyclopentane-1,3-dicarboxylic acid (1,3-ACPD) analogues at cloned metabotropic glutamic acid (mGlu) receptors. The new analogues comprise the four possible stereoisomers of 1-amino-1-carboxycyclopentane-3-acetic acid (1,3-homo-ACPD) and the racemic mixture of (1RS,2RS)-1-amino-1-carboxycyclopentane-2-acetic acid (1RS,2RS-homo-ACPD), (1RS,2RS)-Homo-ACPD was shown to be a competitive mGlu2 receptor antagonist with a KB of 391 microM. (1S,3R)-Homo-ACPD and (1R,3R)-homo-ACPD were both shown to be mGlu2 receptor agonists with EC50 values of 122 and 105 microM, respectively. Compared to (S)-Glu both compounds displayed partial agonism with intrinsic activities of 79% and 47%, respectively. (1S,3S)-Homo-ACPD was also found to be a partial mGlu2 receptor agonist with an intrinsic activity of 27% compared to (S)-Glu. None of the compounds tested showed any activity at mGlu1a or mGlu4a receptors. These homo-ACPD's show a higher degree of subtype selectivity than the parent compound (1SR,3RS)-ACPD. In addition none of the compounds demonstrated any activity at ionotropic Glu receptors.

Synthesis of new derivatives of 4-acylquinoxalin-2-ones with potential pharmacological activity.

Some of new derivatives of 4-acylquinoxalin-2-one obtained in the reaction of N,N'-bis(chloroacetyl)-4,5-dimethyl-o-phenylenediamine with primary amines are described. Compounds were tested for their anti-HIV activity and as ligands for 99mTc.

Comparison in rabbits of chole-scintigraphic properties of several 99mTc-IDA derivatives.

Pathways and kinetics of excretion were compared to four 99mTc-IDA derivatives in healthy rabbits of both sexes. Assessment of differences between the compounds was based upon: plasma clearance, characteristics of time-activity curves measured scintigraphically over the liver (time of the peak Tmax; time for decline of activity to half the peak value-T50%), and hepatocytic mean transit time (MTT) as derived after deconvolution of the hepatic time-activity curve. Hepatocyte transit time was short and similar to 99mTc-complexes of Mebrofenin, 2,4-diethyl IDA (HEPIDA) and 3-iodo-2,6-diethylphenylcarbamoylmethyliminodiacetic acid (JODIDA); it was evidently longer for 99mTc-p-butyl-IDA (BIDA). 99mTc-HEPIDA displayed significant urinary elimination; the remaining three compounds were excreted practically completely via the biliary route. It is concluded that optimal parameters were displayed by 99mTc-Mebrofenin and 99mTc-JODIDA.

New derivatives of hexahydroazepine, hexahydro(1,4,5)oxadiazepine and hexahydro(1,4,5)oxadiazocine with expected pharmacological activity.

New derivatives with the expected pharmacological activity of heterocyclic systems mentioned above having ether (1-6) and ester (7-10) groups were obtained.