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Phosphodiesterase 4 (PDE4) is a key cAMP-metabolizing enzyme involved in the pathogenesis of inflammatory disease, and its pharmacological inhibition has been shown to exert therapeutic efficacy in chronic obstructive pulmonary disease (COPD). Herein, we describe a drug discovery program aiming at the identification of novel classes of potent PDE4 inhibitors suitable for pulmonary administration. Starting from a previous series of benzoic acid esters, we explored the chemical space in the solvent-exposed region of the enzyme catalytic binding pocket. Extensive structural modifications led to the discovery of a number of heterocycloalkyl esters as potent in vitro PDE4 inhibitors. (S*,S**)-18e and (S*,S**)-22e, in particular, exhibited optimal in vitro ADME and pharmacokinetics properties and dose-dependently counteracted acute lung eosinophilia in an experimental animal model. The optimal biological profile as well as the excellent solid-state properties suggest that both compounds have the potential to be effective topical agents for treating respiratory inflammatory diseases.

IC87114 [compound 1, (2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-(o-tolyl)quinazolin-4(3H)-one)] is a potent PI3K inhibitor selective for the δ isoform. As predicted by molecular modeling calculations, rotation around the bond connecting the quinazolin-4(3H)-one nucleus to the o-tolyl is sterically hampered, which leads to separable conformers with axial chirality (i.e., atropisomers). After verifying that the aS and aR isomers of compound 1 do not interconvert in solution, we investigated how biological activity is influenced by axial chirality and conformational equilibrium. The aS and aR atropisomers of 1 were equally active in the PI3Kδ assay. Conversely, the introduction of a methyl group at the methylene hinge connecting the 6-amino-9H-purin-9-yl pendant to the quinazolin-4(3H)-one nucleus of both aS and aR isomers of 1 had a critical effect on the inhibitory activity, indicating that modulation of the conformational space accessible for the two bonds departing from the central methylene considerably affects the binding of compound 1 analogues to PI3Kδ enzyme.

Two diastereoisomers CHF4226.01 (R, R) and CHF4232.01 (S, R), differing for a chiral center, have been studied to investigate their possible discrimination using NMR. 1D NMR and 2D NMR experiments, such as COSY, NOESY and ROESY, were performed on pure isomers and on the association complexes formed in the presence of the chiral reagent (S)-(-)-1-(2-napthyl)ethylamine (S-NEA). Moreover, computational studies, concerning conformational analysis and molecular dynamics, were started and supported the NMR results.

Synthesis and characterization of new thiosemicarbazones derived from natural aldehydes ( 1 – 9 ) have been investigated in order to develop a research program aimed at the development of compounds with antiviral, antibacterial, and antitumor properties. These substances contain both a chain with N and S nucleophilic centers with tuberculostatic activity, and an alkyl or terpenic moiety. In addition, a few nickel(II) and copper(II) complexes ( 10 – 18 ), derived also from the previously studied ligands, were synthesized and characterized by means of NMR and IR techniques. The trans -2-octenal N 1 -phenylthiosemicarbazone and its nickel complex were also characterized by X-ray diffractometry. Biological studies, performed with some of these compounds, have involved both inhibition of cell proliferation and apoptosis tests in vitro on human leukemia cell line U937 to deepen our knowledge on the way these substances interfere with biological processes in leukemic cells.

New thiosemicarbazone nickel complexes (1–7), derived from p-fluorobenzaldehyde and differently substituted thiosemicarbazides, were synthetized and characterized by means of NMR and IR techniques. The p-fluorobenzaldehyde 4-ethylthiosemicarbazone Et-Hfbt (1) and its complex [Ni(Et-fbt)2] (2) were also characterized by X-ray diffractometry. Molecule 1 consists of two units: the p-fluorobenzaldehyde residue and the thiosemicarbazonic chain. In the reaction of 1 with NiAc2·4H2O, complex 2 was afforded. The molecular structure of 2 consists of the neutral complexes [Ni(Et-fbt)2] with the metal not lying on a symmetry centre, with two consequently independent ligand molecules; the coordination results in a square planar geometry slightly twisted towards a tetrahedron, involving the sulfur and the hydrazine nitrogen atoms of the two ligands in a trans configuration.

As part of a research programme aimed at the synthesis of compounds with antiviral, antibacterial and antitumor properties and their spectroscopic characterization, new thiosemicarbazones deriving from natural aldehydes have been investigated. These substances contain in the same molecule both a chain with nucleophilic centres N, S with tubercolostatic activity, and a glycosidic or alkyl moiety (modified glycosides and nucleosides have recently received a great deal of attention in the fields of neoplastic diseases and viral infections). In this paper the synthesis and the characterization of these compounds by means of 1H NMR, IR, and MS techniques is reported. Biological studies have involved both inhibition of cell proliferation and apoptosis tests on human leukemia cell line U937.

Chiral porphyrins 1 and 2, bearing, respectively, four and two chains at the meso carbons, each one with a stereocentre at C-2 and a double bond at C-5, were functionalized to afford the corresponding thiosemicarbazonic derivatives 9–12 and the nickel(II) porphyrinato 13, compounds with potential antiviral, antibacterial and antitumour properties. To verify the biological activity of some of these products, assays of proliferation inhibition and apoptosis tests in vitro on human leukemic cell lines U937 were carried out for compounds 1, 6, 9 and 10.

The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.

Tetra- O -acetyl- d -ribose, penta- O -acetyl- d -glucose, 2,3;5,6-di- O -isopropylidene- d -mannofuranose, 2,3,5-tri- O -benzyl- d -arabinofuranose and 2,3,5,6-tetra- O -benzyl- d -glucose react with pyrrole and indole, in presence of Lewis acids, to afford C-glycosylpyrroles and indoles in position 2 and 3 respectively (acyclic C-nucleosides, 1–7 ). The crystal structure of 4 was determined by X-ray crystallography.

Chiral porphyrins 1 and 2, bearing, respectively, four and two chains at the meso carbons, each one with a stereocentre at C-2 and a double bond at C-5, were functionalized to afford the corresponding thiosemicarbazonic derivatives 9–12 and the nickel(II) porphyrinato 13, compounds with potential antiviral, antibacterial and antitumour properties. To verify the biological activity of some of these products, assays of proliferation inhibition and apoptosis tests in vitro on human leukemic cell lines U937 were carried out for compounds 1, 6, 9 and 10.

Two diastereoisomers CHF4226.01 (R, R) and CHF4232.01 (S, R), differing for a chiral center, have been studied to investigate their possible discrimination using NMR. 1D NMR and 2D NMR experiments, such as COSY, NOESY and ROESY, were performed on pure isomers and on the association complexes formed in the presence of the chiral reagent (S)-(-)-1-(2-napthyl)ethylamine (S-NEA). Moreover, computational studies, concerning conformational analysis and molecular dynamics, were started and supported the NMR results.

The reaction between pyrrolylmagnesiumbromide and (3 R )-(+)-citronellal produced porphyrin 1 with four chains at the meso carbons, each one bearing a stereogenic centre at C-2 and a double bond at C-5. 4′-Fluoro-phenyldipyrrylmethanebismagnesiumbromide 4 with (3 R )-(+)-citronellal gave rise to porphyrin 2 with two stereogenic chains.

The aim of this work was to organize chemical data in a client-server environment using Database Management System and Web fashion for the client interface. To solve this ancient problem (for us) merging text data, reaction schemes, tridimensional structures, and NMR, CD, and UV spectra images, we have based our implementation on a few fundamental points: no cost for the user, availability of data via the Internet, standard and freeware software, and a Web browser for the database inquiry. These functions are delivered in a platform-independent manner via the Internet and are used by computational experts and nonexperts alike. C-Glycosylporphyrins is the class of compounds chosen to test our applications. These results can be exportable for many other classes of chemical compounds.

The aim of this work was to organize chemical data in a client-server environment using Database Management System and Web fashion for the client interface. To solve this ancient problem (for us) merging text data, reaction schemes, tridimensional structures, and NMR, CD, and UV spectra images, we have based our implementation on a few fundamental points: no cost for the user, availability of data via the Internet, standard and freeware software, and a Web browser for the database inquiry. These functions are delivered in a platform-independent manner via the Internet and are used by computational experts and nonexperts alike. C-Glycosylporphyrins is the class of compounds chosen to test our applications. These results can be exportable for many other classes of chemical compounds.

New thiosemicarbazones ( 1 – 7 ), derived from p -fluorobenzaldehyde and differently substituted thiosemicarbazides, were synthetized and characterized by means of NMR and IR techniques. The p -fluorobenzaldehyde thiosemicarbazone Hfbt ( 1 ), the p -fluorobenzaldehyde 4-phenylthiosemicarbazone Ph-Hfbt ( 4 ) and complex [Ni(fbt) 2 ] ( 8 ) were also characterized by X-ray diffractometry. Molecules 1 and 4 consist of two units: the p -fluorobenzaldehyde residue and the thiosemicarbazonic chain. In the reaction of 1 with NiAc 2 ·4H 2 O, complex 8 was afforded. The molecular structure of 8 consists of the neutral molecules [Ni(fbt) 2 ] with the metal placed on a symmetry centre. The coordination results in a square planar configuration and involves the sulphur atom and the hydrazine nitrogen atom of the two ligands in a trans configuration. Moreover, for compounds 1 , 2 , 4 , and 8 , assays of proliferation inhibition and apoptosis tests in vitro on human leukemia cell line U937 were carried out.