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In order to further explore the antiproliferative properties of O-phenoxyethyl and O-adamantyl acylthiocarbamates (ATCs), a series of 14 derivatives was prepared by a parallel adaptation of a highly convergent one-pot three-step procedure. Ten acylthiocarbamates were selected by the National Cancer Institute drug evaluation program and screened against a panel of 55 to 58 cell lines derived from nine different types of human cancers. In general, the tested compounds showed a widespread micromolar activity with some specificity against leukemia, renal UO-31, central nervous system (CNS) SNB-75, and non-small cell lung HOP-92 cancer cell lines. Bioinformatic COMPARE analyses were carried out to identify possible mechanism(s) of action for acylthiocarbamate antiproliferative activity.

Et3N-mediated condensation of preformed or in situ generated indole iminium salts with active methylene reagents provides stereoselectively Knoevenagel-type indoles in moderate to good yields.

The potassium salt 2 of 1,3,3-trimethyl-N-nitro-2-oxabicyclo[2.2.2]octan-6-imine 1 reacted with bromine in acetic acid solution to give (1S,4S,5S)-5-bromo-1,3,3-trimethyl-N-nitro-2-oxa-bicyclo[2.2.2]octan-6-imine 3. Bromination of the salt 2 in methanolic potassium hydroxide afforded a mixture of (1S,4S)-5,5-dibromo-1,3,3-trimethyl-N-nitro-2-oxabicyclo[2.2.2]octan-6E-and -6Z-imine 4 and 5, whose X-ray crystal-structure determinations allowed their absolute configurations to be established. Bromination of monobromide 3 under different conditions gave the dibromide 4, which was converted into isomer 5 by storage in chloroform solution. Nitrimine 3 reacted with hydroxylamine hydrochloride and sodium hydroxide or piperidine to give (1S,4S,5S)-5-bromo- and -5-hydroxyamino-N-hydroxy-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-6-imine or (1S,4S,5S)-N-hydroxy-1,3,3-trimethyl-5-(piperidin-1-yl)-2-oxabicyclo[2.2.2]octan-6-imine. Reaction of compound 3 with aliphatic and aromatic primary amines afforded N-substituted (1S,4S,5S)-5-bromo-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-6-imines. Reduction of compound 3 with sodium cyanoborohydride gave (1S,4S,5S)-5-bromo-1,3,3-trimethyl-N-mtro-2-oxabicyclo[2.2.2]octan-6-amine, whereas consecutive treatment with potassium hydroxide and aq. hydrochloric acid afforded the less stable isomer (1S,4S)-5-bromo-1,3,3-trimethyl-N-nitro-2-oxabicyclo[2.2.2]oct-5-en-6-amine.

The synthesis of 3-(arylamino)-6,7-dihydro-6-methylpyrano[4,3-c]pyrazol-4(1H or 2H)-ones by reaction of N-aryl-5,6-dihydro-4-hydroxy-6-methyl-2-oxo- 2H-pyrano-3-carbothioamides with hydrazine is described. Some compounds showed remarkable antipyretic, analgesic, antiarrhythmic and hypotensive activity in rats or mice, as well as weak antiinflammatory, local anesthetic and in vitro platelet antiaggregating activity.

The synthesis of 5-[[omega-(dialkylamino)alkoxy]methylene]-1,3,3-trimethyl-2- oxabicyclo[2.2.2]octan-6-ones by reaction of (+)-5-(hydroxymethylene)-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan- 6-one with a series of omega-(chloroalkyl)dialkylamines in the presence of potassium carbonate is described. Some compounds showed strong hypotensive, local anesthetic and antiarrhythmic activity in rats and mice, as well as moderate analgesic, antipyretic and in vitro platelet antiaggregating activity.

The synthesis in excellent yields of 2,3-dihydro-6-mercapto-1,3,5-triphenyl-2-thioxo-4(3H)-pyrimidinone 3 and 5-ethoxycarbonyl-2,3-dihydro-6-mercapto-1,3-diphenyl-2-thioxo-4(3H )- pyrimidinone 4 by reaction of methyl phenylacetate or diethyl malonate, respectively, with phenyl isothiocyanate (3 molar equivalents) and sodium hydride (2 molar equivalents) in DMF solution is described. Acylation of 3 and 4 with acyl chlorides gave, generally in satisfactory yields, 6-acylthio derivatives 13 and 14. Some of the above compounds showed a platelet antiaggregating activity in vitro superior or comparable to that of acetylsalicylic acid, as well as remarkable antiinflammatory, antiarrhythmic, local anesthetic and antihyperlipidemic activities in rats and in mice. Weak anticonvulsant and hypoglycemic activities were also detected.

The synthesis of novel 2-aryl-3-phenylamino-4,5-dihydro-2H-benz[g]indazoles 4a-f, starting from N-phenyl-3,4-dihydro-1(2H)-oxonaphthalene-2-carbothioamide and the proper arylhydrazines, is described. Title compounds were evaluated for antiinflammatory, analgesic, antipyretic, antiarrhythmic, hypotensive, local anaesthetic and platelet antiaggregating activities; some of them showed an appreciable antiarrhythmic activity in rats and a good level of infiltration anaesthesia in mice.

The title compounds were synthesized by cyclizing 3-dimethylaminomethylene-4-chromanone with creatine to give the acid 2 that was successively converted into the corresponding amides 3a-f via diphenylphosphorylazide and the relevant amines. The free acid 2 and some of 3a-f showed antiinflammatory, hypotensive and antiarrhythmic properties.

A series of 2-aryl-6-methyl-3-phenylamino-6,7-dihydropyrano[4,3-c]pyrazol-4(2H )-ones were prepared and tested for antiinflammatory, analgesic, antipyretic, antiarrhythmic, antihypertensive and platelet antiaggregating activities. All of them showed an appreciable level of analgesic activity in mice.

The synthesis of 6-thiosubstituted 5-ethoxycarbonyl-1,3-diphenyl-2-thioxo-2,3-dihydropyrimidin- 4(1H)-ones 3, and of 6-substituted 5-hydroxy-1,3-diphenyl-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-ones 5 and their esters 6 is described. These derivatives were prepared in order to evaluate the influence on the pharmacological profile of alkyl substituents bearing polar/hydrophilic functionalities at an enethiol substructure as in compounds 3 or to assess the effects arising from the incorporation of the sulfur atom in a thiophene moiety as in thienopyrimidinones 5 and 6 in comparison with a series of 5-substituted 6-acylthio-1,3-diphenyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones 1c,d, previously described. Preliminary screenings suggest that all tested compounds maintained or even increased the local anesthetic activity, but failed in the platelet antiaggregating activity; on the other hand, antiarrhythmic and antiinflammatory activity was preserved in some esters 6.

A series of 1,3,4-thiadiazol-2(3H)-ones (2a–j) with a nicotinoyl/isonicotinoyl group in position 3 and an aroylamino substituent in position 5 of the ring was prepared and evaluated for antipyretic and anti-inflammatory activities. All the title compounds and in particular 2e, 2i and 2j exhibited anti-inflammatory activity and were devoid of antipyretic properties.

A series of N -methyl- N -pyrimidin-2-yl glycines 2a–e , having the pyrimidine ring fused with a cyclohexane [ N -methyl- N -(5,6,7,8-tetrahydroquinazolin-2-yl)glycine], cyclohexene [ N -methyl- N -(5,6-dihydroquinazolin-2-yl)glycine], 1,2,3,4-tetrahydronaphthalene [ N -methyl- N -(5,6-dihydrobenzo[e]quinazolin-2-yl)glycine], benzopyrane [ N -methyl- N -(5-phenyl-5 H -[1]benzopyrano[4,3- d ]pyrimidin-2-yl)glycine] and benzothiopyrane [ N -methyl- N -(5 H -[1]benzothiopyrano[4,3- d ]pyrimidin-2-yl)glycine] ring, was prepared and tested for antiinflammatory activity. With the same purpose a number of N -5 H -[1]benzopyrano[4,3- d ]pyrimidin-2-yl substituted amino acids 3a–e , having a different chain length and branching were also synthesized and tested. All the described products 2 and 3 showed an appreciable antiphlogistic activity, particularly 2b and 2c .

A series of new 2,5-cycloamino-5 H -[1]benzopyrano[4,3- d ]pyrimidines 3a – i have been synthesized and tested in vivo for the anti-inflammatory/analgesic/antipyretic effects and in vitro to evaluate the antiplatelet activity on guinea-pig platelet-rich plasma aggregated by collagen, adenosine-5′-diphosphate (ADP) and arachidonic acid (AA). Title compounds were ineffective in vivo; however, the pyrrolidino derivatives 3a and 3c exhibited an antiplatelet activity against all the aggregants differing from that of acetylsalicylic acid (ASA) while the 5-morpholino derivatives 3g – i showed the most potent ASA-like antiplatelet activity.

The synthesis of a new family of A1-adenosine receptor (A1AR) ligands 3a–n has been performed in a straightforward way. Affinity data at A1AR, A2AAR and A3AR in bovine membranes show that these new compounds bind the A1AR in a selective way over A2AAR and A3AR and one of them (3j) presents a very high affinity, probably due to the phenethylamine substituent at C-4.

In several non-infectious human diseases, such as ulcerous colitis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), the extravasal recruitment of neutrophils plays a crucial role in the development of tissue damage, which, when persistent, can lead to the irreversible organ dysfunction. The neutrophil activation is controlled by a number of intracellular pathways, particularly by a cAMP-dependent protein kinase A (PKA) which also acts on phosphodiesterase IV (PDE4) gene stimulating the synthesis of this enzyme, able to transform cAMP to inactive AMP. PDE4 inhibitors enhance intracellular cAMP and decrease inflammatory cell activation. Several 3-cyclopentyloxy-4-methoxybenzaldehyde and 3-cyclopentyloxy-4-methoxybenzoic acid derivatives were synthesized and studied by us to evaluate their ability to inhibit the superoxide anion production in human neutrophils. These compounds were found able to inhibit the neutrophil activation and some of them increased the cAMP level on tumor necrosis factor-alpha-stimulated neutrophils. Moreover, they also inhibited selectively the human PDE4 enzyme, although they are less potent than the reference compound Rolipram. We report here synthesis, biological studies and some SAR considerations concerning the above mentioned compounds.

A novel series of O-[2-hydroxy-3-(dialkylamino)propyl]ethers of (+)-camphor oxime was prepared and tested for its cardiovascular, analgesic and anti-inflammatory properties. No significant anti-inflammatory and hypotensive activities were displayed by any of the compounds, whereas several of them are reasonably active as antiarrhythmic and analgesic agents.