Novel and potent tacrine-related hetero- and homobivalent ligands for acetylcholinesterase and butyrylcholinesterase.

Based upon synthetic and biochemical results, a novel and potent tacrine analogue and heterobivalent analogues of tacrine, were designed. The role played by the amino groups of homo- and heterobivalent ligands in the interaction with the peripheral and catalytic sites of AChE and BuChE were investigated. The syntheses of these materials together with the results of AChE/BuChE inhibition assays are detailed.

High affinity central benzodiazepine receptor ligands. Part 2: quantitative structure-activity relationships and comparative molecular field analysis of pyrazolo[4,3-c]quinolin-3-ones.

A large series of 2-aryl(heteroaryl)-2,5-dihydropyrazolo[4,3-c]quinolin-3(3H)-ones (PQ, 106 compounds), carrying appropriate substituents at the quinoline and N2-phenyl rings, were designed, prepared and tested as central benzodiazepine receptor ligands. Compounds with an affinity significantly higher than the parent compound CGS-8216 were obtained, the most active ligand showing a pIC50 = 10.35. Hansch and comparative molecular field analyses gave coherent results suggesting the main structural requirements of high receptor binding affinity. The possible formation of a three-centred hydrogen bond (HB) at the HB donor site H2, as a key interaction for high receptor binding affinity, was assessed by the calculation and comparison of the molecular electrostatic potentials of a series of selected ligands.

Synthesis and pharmacological activity of 1,2,4-triazolo[4,3-a]quinolines.

The synthesis of a series of 1,2,4-triazolo[4,3-a]quinoline derivatives is described; their structures were assigned by 1H NMR and analytical data. The new compounds were tested in vivo for their antiinflammatory and analgesic activities, as well as for their ulcerogenic action. Some of the tested triazoles showed an analgesic activity in the acetic acid writhing test and antiinflammatory properties on carrageenan paw edema assay.

High affinity central benzodiazepine receptor ligands: synthesis and structure-activity relationship studies of a new series of pyrazolo[4,3-c]quinolin-3-ones.

A large series of 2-aryl(heteroaryl)-2,5-dihydropyrazolo[4,3-c]quinolin- 3-(3H)-ones, carrying appropriate substituents at the quinoline and N2-phenyl rings, were prepared and tested as central benzodiazepine receptor ligands. Results from structure-affinity relationship studies were in full agreement with previously proposed pharmacophore models and, in addition, quantitative structure-activity analysis gave further significant insight into the main molecular determinants of high benzodiazepine receptor affinity. The intrinsic activity of some active ligands was also determined and preliminary discussed.

Chelating agents as potential antitumorals: alpha-(N)-heterocyclic hydrazones and bis-alpha-(N)-heterocyclic hydrazones.

A number of pyruvic acid and methylpyruvate alpha-(N)-heterocyclic hydrazones has been synthesized. Bis-heterocyclic hydrazones were obtained from reaction with pyruvic carboxaldehyde. Some complexes of Ni(II) were prepared and characterized as neutral complexes. All these compounds have been evaluated for cytotoxicity against P388 and HL-60 leukemia.

New 1-[quinolyl(4)]-1,2,3-triazoles: synthesis and evaluation of antiinflammatory and analgesic properties. II.

Several 1-[quinolyl(4)]-1,2,3-triazoles were synthesized by 1,3-dipolar cycloaddition of 4-azidoquinolines with activated methylene compounds. The synthesized compounds, tested for antiinflammatory and analgesic activities, resulted moderately active as antiinflammatories, but with a very interesting analgesic activity, sometimes higher than that of indomethacin, used as reference drug. Some of the triazole derivatives were evaluated also as antimicrobial, but none of them exhibited activity.

New 1-[quinolyl(4)]-1,2,3-triazoles: synthesis and evaluation of antiinflammatory and analgesic properties. I.

The synthesis of new 1-[quinolyl(4)]-1,2,3-triazoles is reported. These have been obtained by reacting 4-azidoquinolines with ethyl p-nitrobenzoylacetate. The synthesized compounds, tested for antiinflammatory and analgesic activities, results moderately active as antiinflammatories, but with a very interesting analgesic activity, sometimes higher than that of indomethacin, used as reference drug.

Pyrazolo[4,3-c]quinolines, synthesis and specific inhibition of benzodiazepine receptor binding. Note II.

Two new series of 2-arylpyrazolo[4,3-c]quinolin-3-ones (6,8-difluoro- and 7,9-dichloro-derivatives) have been synthesized and tested for their ability to displace [3H]flunitrazepam from rat brain membranes. Several compounds possess comparable and sometimes higher affinity for central benzodiazepine receptors than that of diazepam. Some selected compounds were also tested in vivo in the anti-pentylenetetrazol test; some anticonvulsant activity resulted for the 6,8-difluoroderivatives only.

New quinoline derivatives: synthesis and evaluation for antiinflammatory and analgesic properties--Note II.

The synthesis of new halogenated series of 4-anilinoquinoline-3-carboxylic acids, N-[3-carboxyquinolyl(4)]anthranilic acids and their corresponding esters is reported. These have been obtained by reacting 4-chloro-3-carbethoxy-quinolines with variously substituted anilines and methyl anthranilate respectively. The synthesized compounds were tested for antiinflammatory and analgesic activities; some of them showed a good analgesic activity, sometimes higher than that of indomethacin, used as reference drug.

Synthesis of 4-quinolylazide derivatives and evaluation of their antitumor and antimicrobial activity.

Synthesis and pharmacological evaluation of a series of 4-quinolylazide derivatives are reported. These were screened against P388 lymphocitic leukemia in mice, but they resulted inactive. All the compounds were also tested for their antimicrobial activity against gram-positive, gram-negative strains and fungi; only three derivatives exhibited poor activity.

Pyrazolo [4,3-c] quinolines synthesis and specific inhibition of benzodiazepine receptor binding (Note I).

A series of 2-arylpyrazolo[4,3-c] quinolin-3-one derivatives, bearing different substituents in the two aromatic rings, were prepared and tested for their ability to displace [3H] flunitrazepam from rat brain membranes. Some compounds have shown an affinity for receptors comparable and sometimes higher than that of CGS series.

Quinolinehydrazones as inhibitors of retroviral reverse transcriptase.

The inhibitory activity of a series of 2- and 4-quinolinehydrazones on retroviral reverse transcriptase has been studied on enzymes from M-MuLV, RAV-2, and on a crude lysate of HIV-1, assuming the first two enzymes as potential models of the third. The highest activity is mainly found in lipophilic, water soluble 4-quinolinehydrazones. The inhibitory activity of these compounds decreases in changing from the M-MuLV to the RAV-2, and HIV-1 enzymes, in this order.

New quinoline derivatives: synthesis and evaluation for antiinflammatory and analgesic properties--Note I.

New 4-anilinoquinoline-3-carboxylic acids, N-[3-carboxyquinolyl (4)]anthranilic acids and their corresponding esters were synthetized by reacting 4-chloro-3-carbethoxyquinolines with substituted anilines and methyl anthranilate respectively. All the compounds were tested for antiinflammatory and analgesic activities. Some derivatives showed a significant antiinflammatory activity comparable to that of indomethacin.

[Tridentate N-N-N chelating systems as potential antitumor agents]. / Sistemi chelanti tridentati N-N-N quali potenziali agenti antitumorali.

Tridentate chelating agents, as potential antitumor agents, were prepared by condensing 2-quinolylhydrazines, 2-pyridylhydrazine and 2-benzothiazolylhydrazine with pyridine-2-aldehyde, 6-methylpyridine-2-aldehyde, 2-acetylpyridine and 2-benzoylpyridine. All compounds were tested against Lymphocytic leukemia P388. The active pyridine-2-aldehyde-4-methyl-2-quinolylhydrazone [1-(4'-methyl-2'-quinolyl)-3-(2'-pyridyl)-1,2-diaza-2-propene] (I d) was also tested against other experimental tumors and proved inactive.

[Quinolylhydrazones with potential antimicrobial and antiparasitic activity]. / Chinolilidrazoni a potenziale attività antimicrobica ed antiparassitaria.

Quinolinehydrazones prepared by condensation of hydrazinoquinolines with 1-phenyl-2,5-dimethyl-3-pyrrolcarboxaldehyde, 2-chloro-4-dimethylaminobenzaldehyde and 2,6-dichlorobenzaldehyde are described. All compounds were tested in vitro for antimicrobial activity, the results obtained are shown and discussed. The quinolinehydrazones of the 1-phenyl-2,5-dimethyl-3-pyrrolcarboxaldehyde were tested in vivo against Hymenolepis nana and Taenia taeniaeformis and proved inactive.

[Synthesis of potential antitumor agents: nitrogen mustards based on quinoline]. / Sintesi di potenziali agenti antitumorali: mostarde azotate a supporto chinolinico.

Benzaldehyde nitrogen mustard derivatives of hydrazinoquinolines, 9-hydrazinoacridine and 1,2,3,4-tetrahydro-9-hydrazinoacridine were synthesized; all compounds were tested against lymphocytic leukemia P388 and proved inactive.

[Synthesis and biological activity of new compounds with the 1,3-dioxol(4,5-g)quinoline structure]. / Sintesi ed attività biologica di nuovi composti a struttura 1,3-diossol[4,5-g]chinolinica.

The synthesis of some 1,3-dioxol[4,5-g]quinoline derivatives is described. The compounds show appreciable activity in vitro against some gram-positive bacteria and do not show any significant activity against P388 lymphocytic leukemia. Microbiological and antitumor results are presented.

Anticestode quinolinehydrazones.

One hundred and seven 4-quinolinehydrazones were synthesized and tested in vivo against the tapeworm Hymenolepis nana. Twenty-five derivatives showed significant cestocidal activity; structure-activity correlations were performed using Free-Wilson methodology. Two compounds, 2,6-dimethyl-4-[(3-pyridinylmethylene)hydrazino]quinoline and 2,6-dimethyl-4-[2p][(6-methyl)pyridinylmethylene]hydrazino)quinoline, predicted to be maximally active, effected 100% reduction of H. nana in mice at 200 mg/kg, p.o.