In vitro inhibition of human erythrocyte hexokinase by various hyperglycemic drugs.

Hemolysis is the red blood cell abnormality most often associated with adverse effect of drug therapy. Drug-induced or drug-associated hyperglycemia could decrease the activity of hexokinase. The aim of this study was to investigate the inhibitory effects of some commonly used drugs that have hyperglycemic side effect on the human erythrocyte hexokinase enzyme in vitro. Hexokinase was purified from human erythrocytes using sequential chromatography, with a specific activity of 0.96 ± 0.18 U/g hemoglobin, and assayed in the presence of selected drugs that have hyperglycemic side effect. The IC50 were determined from the regression analysis graph. Correlation analysis showed that there was positive correlation between the hyperglycemic side effect of some of the tested drugs and decrease of hexokinase activity. This suggests that, at least in part, these drugs exert their hyperglycemic effect by inhibiting glucose phosphorylation by the hexokinase, which consequently causes the glucose accumulation.

Antilipolytic effects of 1,8-naphthyridine derivatives ß-adrenoceptor antagonists in rat white adipocytes.

The rat fat cell ß-adrenoceptors were investigated by studying the effects of new 1,8-naphthyridine derivatives synthesized starting from 7-amino-2-chloro-3-phenyl-1,8-naphthyridine on lipolysis induced by isoprenaline, and alprenolol. Lipolysis induced by isoprenaline agonist was competitively antagonized by the 1,8-naphthyridine analogue with a 7-hydroxy-2-(4'-methoxybenzylamine)-6-nitro-3-phenyl substituent designated as 3. In contrast, 10, 50, and 100 µm of 7-methoxy and 7-ethoxy derivatives did not modify the concentration-response curve of isoprenaline. A rightward shift of the curve was, however, observed with 50 µm of a 7-methoxy-2-(4'-methoxybenzylamine)-6-amino-3-phenyl substituent designated as 10. The selective ß1 -AR antagonist, 7-hydroxy-4-morpholinomethyl-2-piperazino-1,8-naphthyridine slightly reduced isoprenaline-induced lipolysis only at high doses. Alprenolol-mediated lipolytic effect was antagonized by derivative 3, 10 and the selective ß3 -AR antagonist SR 59,230A, but resistant to the selective ß1 -AR antagonist 7-hydroxy-4-morpholinomethyl-2-piperazino-1,8-naphthyridine. The results provide preliminary pharmacological evidence for the antilipolytic effect of the newly synthesized 1,8-naphthyridine derivatives on rat fat cells. The analogues designated as 3 and 10 were the most potent antagonists of this series.

Synthesis and beta-blocking activity of (R,S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and 2,3-dihydrothiopyrano[2,3-b]pyridine: identification of beta 3-antagonists.

Drugs acting on beta(1)- and beta(2)-adrenergic receptors are widely used for the clinical management of a large number of cardiovascular and respiratory pathologies. In the last decade, the discovery of the third subtype of beta receptors, the beta(3)-adrenoceptor, gave a further pharmacological target for the development of new selective drugs. Initially, a potential therapeutic use of beta(3)-selective agents seemed to be restricted to agonists, for the treatment of metabolic diseases, such as obesity, non-insulin-dependent diabetes, urinary frequency and incontinence. More recently, some interesting theories about a negative role played by the cardio-depressant activity of myocardial beta(3)-adrenoceptors in heart failure, seemed to justify a clinical use of beta(3)-antagonists in the last phases of this cardiac disease. Following the indications deriving from previous experimental work, the beta-antagonist properties of newly-synthesised (R,S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and of 2,3-dihydrothiopyrano[2,3-b]pyridine were evaluated, in order to identify some useful structure-activity relationships, which might account for selectivity towards the three beta-subtypes and, in particular, the beta(3)-adrenoceptor. Among the various observations regarding possible structure-activity relationships, able to explain the pharmacodynamic patterns of the synthesised compounds on the three subtypes of beta-adrenoceptors, the most significant data derived from the evaluation of the beta(3)-blocking properties of some oximeethers of 1,8-naphthyridine derivatives. In these molecules, although the presence of the large substituents in position 7, such as 4-chloro-phenoxy- or 4-t-butyl-phenoxy groups determined a dramatic decline in both the beta(1)- and beta(2)-activities, this structural characteristic had a modest influence on the beta(3)-affinity, which was only slightly lower. Hence, this last structural requirement of oximeethers of 1,8-naphthyridine derivatives seems to represent a useful expedient to induce an appreciable selectivity towards the beta(3)-receptor, through a markedly negative effect on the beta(1)- and beta(2)-activities rather than an increase in the beta(3)-affinity.

Synthesis of 3- or 4-phenyl-1,8-naphthyridine derivatives and evaluation of antimycobacterial and antimicrobial activity.

A series of 3- or 4-phenyl-1,8-naphthyridine derivatives variously substituted in the positions 2, 6 and 7 were synthesized and evaluated for in vitro evaluation for their antimycobacterial activity as part of a TAACF TB screening program under the direction of the US National Institute of Health, NIAID division. Several compounds showed an interesting activity when tested at a concentration of 6.25 microg/ml against Mycobacterium tuberculosis H(37)Rv and in particular compounds 2a, 4a,d, 8a,d and 8i, exhibit a % inhibition from 91 to 99. Among these, compounds 2a, 8a and 8d appeared to have a good activity with minimum inhibitory concentrations (MICs) of 6.25 microg/ml. On the basis of the biological results, the most effective substituent in position 2 or 7 seems to be the piperidinyl group. The introduction of a morpholinyl group either in position 2 or 7 of the heterocycle ring caused a decrease in activity. The 1,8-naphthyridine derivatives were also tested in vitro for their antimicrobial activity against Staphylococcus aureus as Gram-positive bacteria and Escherichia coli as Gram-negative bacteria.

Characterization of the biochemical effects of new 1, 8-naphthyridine derivatives, beta-receptor antagonists, in ventricular myocytes.

Novel derivatives of 1, 8-naphthyridine were synthesized from 7-amino-2-hydroxy-4-morpholinomethyl-1, 8-naphthyridine. The ability of the synthesized compounds to inhibit isoproterenol(ISO)-induced phosphorylation of phospholamban (PLB) was assessed. Their ability to block both beta(1) and beta(2) receptors almost completely abolished all ISO effects on phosphorylation of PLB. Analogues with either a 7-hydroxy-2-N-ethoxycarbonylpiperazine or a 7-hydroxy-2-piperazine substituent, designated as 6 and 9 respectively, showed a higher affinity for beta(1) receptor than that of the methoxy derivatives 12 and 13. However, treatment with 30 microM 9 and 1mM 13 lead to comparable levels of PLB phosphorylation. The reduction to 6-amino derivatives 10 and 17 led to compounds possessing beta(2) receptor blocking properties. The ability of the synthesized compounds to inhibit forskolin-stimulated cAMP production was also studied. Together, these results suggest that the 1, 8-naphthyridine parent structure can be modified, to produce compounds with increased activity whose effect in rat appears to be more clearly related to antagonism of beta(1)-rather than beta(2)-adrenergic receptors.

Synthesis of variously substituted 1,8-naphthyridine derivatives and evaluation of their antimycobacterial activity.

A series of 1,8-naphthyridine derivatives variously substituted in the 2, 3, 4 and 7 positions were synthesized for in vitro evaluation of antimycobacterial activity in accordance with an international program with the tuberculosis antimicrobial acquisition and coordinating facility (TAACF). Several compounds 4, 8, 12, 14, 19, 29 and 30, when tested at a concentration of 6.25 microg/ml against Mycobacterium tuberculosis H37Rv, showed an interesting activity with % inhibition in the range 38-96%. The most effective substituent in position 2, 4 or 7 of the 1,8-naphthyridine nucleus seem to be the piperidinyl group.