Pier Luigi Ferrarini

Synthesis and β-blocking activity of (R, S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and 2,3-dihydrothiopyrano[2,3-b]pyridine : potential antihypertensive agents - Part IX

The synthesis of oximeethers of 2,3-dihydro-1,8-naphthyridine and 2, 3-dihydrothiopyrano[2,3-b]pyridine is described. These compounds exhibit a selective beta-blocking activity, with a selectivity towards beta(2)-receptors. Groups in the N(1) position giving rise to a considerable steric hindrance led to a higher beta(2)-blocking selectivity, whereas groups creating a moderate hindrance caused a weak but significant decrease in beta(2)-antagonist potency. Substitution of the N(1)-R group with a sulfur atom led to compounds possessing beta(1)-, beta(2)- and beta(3)-blocking properties. Compounds 9c(1) and 10a(1) showed a beta(3)-antagonist activity slightly lower than that of propranolol.

Synthesis of 1,8-naphthyridine derivatives: potential antihypertensive agents – Part VIII

A series of 2-(carbethoxypiperazinyl)- and 2-piperazinyl-1,8-naphthyridine derivatives, variously substituted, have been synthesized and pharmacologically investigated for their antihypertensive activity. Some of them exhibited a significant and prolonged decrease of the mean arterial pressure (MAP) on spontaneously hypertensive rats. For this series of compounds, on the basis of the pharmacological results obtained, no structure-activity relationship can be deduced at this time. Moreover, the most active and representative compounds 11b, 12a and 16b were investigated by means of in vitro pharmacological functional studies and in vivo, as diuretic agents, to determine a possible mechanism of the antihypertensive activity, which is unknown for the moment.

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

Some 4-phenyl-1,8-naphthyridine derivatives with a piperazino group in the 2- and/or 7-position have been synthesized and evaluated for their tuberculostatic activity. The compounds 1, 6, 10, 17b,c and 19i showed a marked activity against Mycobacterium tuberculosis H37Rv. For this series of compounds, submitted to biological screening, no structure-activity relationship can be deduced.

Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists.

The CB(2) receptor activation can be exploited for the treatment of diseases such as chronic pain and tumors of immune origin, devoid of psychotropic activity. On the basis of our already reported 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the human CB(1) and CB(2) cannabinoid receptors. Some of the reported compounds showed a subnanomolar CB(2) affinity with a CB(1)/CB(2) selectivity ratio greater than 200 (compounds 6, 12, cis-12, 13, and cis-13). Further studies revealed that compound 12, which presented benzyl and carboxy-4-methylcyclohexylamide substituents bound in the 1 and 3 positions, exerted a CB(2)-mediated inhibitory action on immunological human basophil activation. On the human T cell leukemia line Jurkat the same derivative induced a concentration-dependent decrease of cell viability. The obtained results suggest that 1,8-naphthyridin-2(1H)-on-3-carboxamides represent a new scaffold very suitable for the development of new promising CB(2) agonists.

Synthesis and antiplatelet activity of some 2,7-di(N-cycloamino)-3-phenyl-1,8-naphthyridine derivatives

Several 2,7-di(N-cycloamino)-3-phenyl-1,8-naphthyridine derivatives were synthesized and tested for their ability to inhibit human platelet aggregation in vitro induced by arachidonic acid, collagen and ADP. Only five compounds showed any appreciable activity, and the results of all the active derivatives were similar to those of papaverine in the test with arachidonic acid and collagen. Moreover, the most active compounds were investigated in the test with ADP and again showed a significant activity. The tested compounds that possessed the best activity were also shown to increase the c-AMP level significantly without involving the adenylyl cyclase system.

Reinvestigation of reductive butylation of aminophthalimides: new compounds with local anesthetic activity

A careful reinvestigation on reductive butylation of N-β-diethylaminoethyl aminophthalimides showed that this reaction yields the corresponding butylaminophthalimides together with the 1-hydroxy butylaminophthalimidines. The same reaction carried out on N-β-diethylaminoethyl aminophthalimides hydrochlorides gave the corresponding butylamino phthalimidines. The 1-hydroxy butylaminophthalimidines 5 and 6, tested for their local anesthetic properties, exhibited interesting activity comparable to that of Novesine, showing hence a potential therapeutic efficacy.

Synthesis and evaluation of antihypertensive activity of 1,8-naphthyridine derivatives. Part X

A series of 4-(N-methylencycloalkylamino)-1,8-naphthyridine derivatives variously substituted in positions 2 and 7 were synthesized and pharmacologically investigated for possible antihypertensive activity. These compounds were tested to determine a possible vasodilator mechanism of action. Compounds 22, 23, 27-29, 47 and 48 showed satisfactory levels of potency (pIC(50)>5), which in one case (compound 23) reached a really interesting value (pIC(50) 6.92). Furthermore, for some selected compounds (19, 22, 23, 26, 28, 29, 47), the vasorelaxing activity was also evaluated in the presence of the guanylate cyclase blocker ODQ or of the adenylate cyclase blocker SQ 22536, and some of these can be considered as possible guanylate-cyclase inhibitors. Finally, compounds 19, 22 and 23 were also tested in the presence of the ATP-sensitive potassium channel blocker glybenclamide and seem to possess activating properties on these potassium channels.

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.

Synthesis and antiplatelet activity of some 3-phenyl-1,8-naphthyridine derivatives.

A series of 2-cycloalkylamino-3-phenyl-1,8-naphthyridine derivatives, variously substituted in the 6- and 7-positions were synthesized and tested for their ability to inhibit human platelet aggregation in vitro induced by arachidonate, collagen and ADP. Compounds 5a,b, 7a,b, 8a and 10c,d showed a remarkable activity similar to that of indomethacin in the test with arachidonate and collagen. In the test with ADP only compound 8a showed a significant activity. The presence of a morpholinyl or piperidinyl group in position 2 and of a chloro or methoxy group in position 7 of the 1,8-naphthyridine nucleus seem to favour a higher activity. However on the basis of the pharmacological results, no structure-activity relationship can be deduced. Compounds 5b and 7b, which possess the best activity in the arachidonate test, were also shown to increase the c-AMP level significantly, without involving the adenylyl cyclase system.

4-[6-(Dansylamino)hexylamino]-7-methyl-2-phenyl-1,8-naphthyridine as a new potential fluorescent probe for studying A1-adenosine receptor.

A new fluorescent ligand for adenosine receptors, obtained by the insertion of a dansylamino-moiety with a linear hexyl spacer in the N4 position of a 1,8-naphthyridine adenosine receptor ligand, proved to possess a high affinity and selectivity for the A1 receptor subtype.