Cesare Pellerano

Synthesis and anti-tubercular evaluation of 4-quinolylhydrazones

A series of 4-quinolylhydrazones were synthesized and tested against Mycobacterium tuberculosis H37Rv. Preparation of the title compounds was achieved by reaction of 4-quinolylhydrazine and aryl- or heteroaryl-carboxaldehyde. For the most of derivatives interesting antitubercular properties were showed; two compounds (3(2) and 3(25)), identified as the most active, were tested also against Mycobacterium avium.

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.

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.

High affinity central benzodiazepine receptor ligands. Part 3: insights into the pharmacophore and pattern recognition study of intrinsic activities of pyrazolo[4,3-c]quinolin-3-ones

Novel 2-phenyl-2,5-dihydropyrazolo[4,3-c]quinolin-3-(3H)-ones (PQs) endowed with high affinity for central benzodiazepine receptor (BzR) were synthesized. In particular, 9-fluoro-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (2(2)) showed binding affinity in the subnanomolar concentration range and proved to be in vitro a potent antagonist. This finding allowed the nature of the hydrogen bonding receptor site H(2) to be established, as located between the N-1 nitrogen of the PQ nucleus and the ortho position of the N-2-aryl group. [35S]tert-Butylbicyclophosphorothionate ([35S]TBPS) binding assays and electrophysiological measurements of the effects on GABA-evoked Cl(-) currents at recombinant human alpha(1)beta(2)gamma(2)(L) GABA(A) receptors, expressed in Xenopus laevis oocytes, were used to assess the intrinsic activities of a large series of PQs. With the aim of extracting discriminant information and distinguishing BzR ligands with different profiles of efficacy, 51 PQ derivatives, including full and partial agonists, antagonists, and inverse agonists, were analyzed in a multidimensional chemical descriptor space, defined by the lipophilicity parameter CLOG P and 3-D molecular WHIM descriptors, by means of principal component analysis, k-nearest neighbors (k-NN) method, and linear discriminant analysis (LDA). The classification methods were applied to subsets of pairs of efficacy classes, and lipophilicity and 3-D size descriptors were detected as the discriminant variables by a stepwise linear discriminant analysis. LDA proved to be superior to k-NN, especially in classifying PQ ligands (60-84% of success in prediction ability) into categories of efficacies which were contiguous and quite overlapped in the hyperspace of variables.

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.

Chelating agents as potential antitumorals. 2-quinolylhydrazones and bis-2-quinolylhydrazones. I

Summary A number of pyruvic acid, methylpyruvate and pyruvic carboxaldehyde 2-quinolylhydrazones have been synthesized. Some bis-2-quinolylhydrazones were also obtained during the reaction with pyruvic carboxaldehyde. All these compounds have been evaluated for cytotoxicity and most display a significant in vitro activity against a variety of cell lines.

Chelating properties of new series of heterocyclichydrazones. X-ray crystallography and mass spectrometry of their metal complexes

Abstract The chelating properties of a new series of α-N-heterocyclichydrazones (heterocycle=substituted quinoline, benzothiazole, phthalazine) have been studied. Nickel complexes have been synthesized and structurally characterized in the gas phase by mass spectrometry and tandem mass spectrometry, and in the solid state by x-ray crystallography. Each ligand (LH) acts as tridentate and it undergoes a deprotonation in the complex formation. The complexes are neutral species and they can be formulated as [ML2]. The crystal structure of bis[N-(2-benzothiazolyl)-N′-(methlymethoxycarbonyl)hydrazine]nickel(II)×0.5 H2O has been determined. The metal shows a pseudo-octahedral polyhedron and it is coordinated to two nitrogen and to oxygen atoms in the equatorial plane, and to two hydrazone nitrogen atoms in the axial positions.

On the isomerism/tautomerism of hydrazones. Crystal structures, study in solution and theoretical calculations of new series of α-N-heterocyclic hydrazones

The isomerism/tautomerism of new series of α-N-heterocyclic hydrazones with chelating properties towards metal ions and potential biological activity have been studied in the solid state by X-ray crystallography and in solution by nuclear magnetic resonance. Among possible syn-Z/anti-E isomers and different tautomeric structures, the molecular structures of dimethylquinolylhydrazone 5 and its phthalazinyl analogue 6 have shown that both are anti-E isomers. In 5 the mobile proton resides on the hydrazone nitrogen, but in the phthalazine derivative 6 it is located on one endocyclic nitrogen. The same isomeric structures are also confirmed in the solution by NMR experiments. While for 6 no other isomer is detected, the quinoline derivatives 1–5 show chemical equilibrium between the imino and amino tautomers in the solution, the latter being present in a very high amount (>90%). The study has also been extended to potential energy calculations of isolated molecules and of molecules in the crystal lattice.