LTB4 as marker of 5-LO inhibitory activity of two new N-omega-ethoxycarbonyl-4-quinolones.

The supposed 5-LO inhibitory activity of two N-omega-ethoxycarbonyl-4-quinolones was tested determining leukotriene B4 (LTB4) in RBL-1 cell cultures, pretreated with the two compounds of interest. LTB4, obtained by solid-phase extraction (SPE) from cell cultures supernatants, was determined by micellar electrokinetic chromatography (MEKC). The analysis was performed using an uncoated capillary, filled with borate buffer at pH 8.3, containing 12.5 mM SDS as micelles generator. Therefore, following the decreasing of LTB4 it was possible to verify the 5-LO inhibitory activity of two quinolone derivatives. To asses the suitability of the use of LTB4 as marker of the activity of the new compounds, the analysis was repeated using quercetin, a well known 5-LO inhibitor.

Synthesis and anti-human immunodeficiency virus type 1 integrase activity of hydroxybenzoic and hydroxycinnamic acid flavon-3-yl esters.

A series of new hydroxybenzoic and hydroxycinnamic acid flavon-3-yl esters were synthesized in order to obtain compounds targeting the human immunodeficiency virus (HIV) type 1 integrase (IN). The esters were tested for anti-IN and anti-reverse transcriptase (RT) activity in enzyme assays and for anti-HIV-1, anti-proliferative and anti-topoisomerase activity in cell-based assays. In enzyme assays, the two gallic acid flavon-3-yl esters showed a notable IN inhibition (IC50 values were 8.3 and 9.1 microM, respectively), while the two caffeic acid flavon-3-yl esters exhibited a modest activity (IC50 75 and 60 microM, respectively). Replacement of hydroxyl groups resulted in loss of potency. Caffeic acid 3',4'-dichloroflavon-3-yl ester also inhibited the RT activity whereas it was not active on human topoisomerases. It therefore represents an interesting example of a compound specifically targeting more than one step of the virus replication cycle.

N-omega-carbethoxypentyl-4-quinolones: a new class of leukotriene biosynthesis inhibitors.

6-[(4-Quinolinyl)oxy]hexanoic acids and the corresponding esters were designed and synthesized as inhibitors of the production of arachidonic acid metabolites. The inhibitory activities were assayed in vitro by evaluation of serum leukotriene B4 and thromboxane B2 production. While all 6-[(4-quinolinyl)oxy]hexanoic acids and their esters proved to be inactive, the N-alkyl-4-quinolones, obtained as by-products in their synthesis, were found to be a new class of leukotriene biosynthesis inhibitors.

Chiral discrimination and antipicornavirus activity of 6-oxazolinylisoflavan.

Racemic 6-oxazolinylisoflavan, a highly effective inhibitor of rhinovirus serotype 1B in vitro, was resolved by high-performance liquid chromatography on a chiral stationary phase in order to study the activity of the enantiomers against picornaviruses. The absolute configuration of the two isomers was determined by circular dichroism curves. The antipicornavirus activity of each isomer, separately collected, was evaluated in vitro against human rhinovirus serotype 1B, enterovirus 71, echovirus 6, coxsackievirus B4, and poliovirus type 2 by means of the plaque reduction assay. Both enantiomers were inhibitors of picornavirus replication with the degree of their activity depending on virus and isomer tested.

Synthesis of some guanylhydrazones and imidazolinylhydrazones as thromboxane-synthase and platelet aggregation inhibitors.

The imidazolinylhydrazones of (3-pyridinyloxy)-acetaldehyde and of 6-[3-(2-formyl-pyridinyl)oxy]hexanoic acid were synthesized as cyclic analogues of the corresponding guanylhydrazones which were found to be selective inhibitors of human thromboxane-synthase. The benzene isosters were also prepared in order to define the importance of the ring nitrogen for the activity. Moreover, the guanyl- and imidazolinyl-hydrazones of two 6-[(3-pyridinyl)oxy]hexanoic acids showing in the 2 position an alkyl chain with an alpha, beta-unsaturated ketonic function were prepared. Imidazolinylhydrazones 7 and 18 are selective inhibitors of thromboxane-synthase, while the two guanylhydrazones 14 and 15 which do not affect prostanoid biosynthesis seemed to be antagonists at the thromboxane receptor.

Synthesis and binding properties to GABA receptors of 3-hydroxypyridinyl- and 3-hydroxypiperidinyl-analogues of baclofen.

The synthesis of 3-(3-hydroxy-2-pyridinyl)propanoic acid, 3-(3-hydroxy-2-pyridinyl)-4-aminobutanoic acid, their corresponding piperidine compounds, and of some cyclized derivatives is described. In in vitro assays none of the new compounds shows any noteworthy affinity for GABAA or GABAB receptors; only (R,S)-3-(3-hydroxy-2-pyridinyl)-4-aminobutanoic acid and its lactam inhibited in some degree [3H]GABA binding, at 10(-4) M concentration, with low specificity as regards the two receptors.

Synthesis of guanylhydrazones derived from 3-pyridinol and evaluation of their effect on serum thromboxane B2 and prostaglandin E2 production.

3-Pyridyloxyacetaldehyde guanylhydrazone and the guanylhydrazones of pyridine-2- and -4-aldehydes substituted at the 3-position with the omega-carboxypentyloxy chain were synthesized in order to evaluate their activity as thromboxane synthase inhibitors in vitro. The tested compounds inhibit thromboxane B2 biosynthesis in human serum. The first appears to be a selective inhibitor of thromboxane synthase, since there was a concomitant rise in Prostaglandin E2 (PGE2) level. The derivative of 4-pyridinealdehyde was the more active one of the other two compounds but it also markedly lowered PGE2 biosynthesis proving to be an inhibitor of cyclooxygenase.