UV-vis and FTIR-ATR characterization of 9-fluorenon-2-carboxyester/(2-hydroxypropyl)-beta-cyclodextrin inclusion complex.

In this work, the usefulness of (2-hydroxypropyl)-beta-cyclodextrin (HP-beta-CyD) as a tool to form an inclusion complex with 9-fluorenonic derivative (AG11) has been investigated, in pure water, by UV absorption. Phase-solubility diagrams allowed the determination of the association constant between AG11 and HP-beta-CyD. At the same time, solid binary systems between AG11 and HP-beta-CyD have been prepared in 1:1 stoichiometry by co-precipitation method. In order to confirm the complexation, FTIR spectroscopy in ATR geometry measurements have been performed and the results have been compared with the free compounds and the corresponding physical mixture in the same molar ratio. The nature of the interactions between AG11 and HP-beta-CyD has been elucidated also by applying mathematical procedures such as deconvolution and curve fitting. Improvement of the aqueous solubility is expected to improve the bioavailability of the drug in oral administration.

Design and synthesis of DNA-intercalating 9-fluoren-beta-O-glycosides as potential IFN-inducers, and antiviral and cytostatic agents.

Novel 9-fluoren-beta-O-glycosides, designed as DNA-intercalating agents in structural correlation with antiviral tilorone and anticancer anthracyclines, have been prepared with yields in beta-anomers ranging between 25 and 63%. They have been screened for antiproliferative, immunostimulating and antiviral properties against HSV-1 and HSV-2 viruses. Compounds displaying significant antiviral activity against HSV-2 are acetylated 1 and deprotected 6 9-fluorenyl-O-d-arabinopyranoses, whereas 9-fluorenyl-O-d-glucopyranose 3 is the most effective on HSV-1 replication, followed by 1 and 6. The conformational properties of these compounds have been evaluated by molecular modelling techniques.

Chiral 3,3'-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones] with anti-inflammatory activity. Part 11: evaluation of COX-2 selectivity and modelling.

Anti-inflammatory/analgesic 3,3'-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones] 1, obtained as racemic mixtures (a) and mesoforms (b), have two equivalent stereogenic centres (C-2 and C-2') and exist as RR, SS and RS isomers. The enantioseparation of 1a provided the single enantiomers that displayed different in vitro cyclooxygenase-1/cyclooxygenase-2 selectivity ratios. In particular the dextrorotatory compound is a highly selective COX-2 inhibitor and the levorotatory one is moderately selective. Instead, RS-meso isomer (1b) exhibited similar levels of inhibitory activity on both COX isozymes. The diastereo- and enantioselectivity has been explained by molecular modelling of RR, SS and RS compounds into COX-1 and COX-2 binding sites. Theoretical results indicated SS>RS>RR affinity order towards COX-2 isoenzyme, in agreement with in vitro and previous in vivo pharmacological results.

Synthesis and aldose reductase inhibitory activity of 5-arylidene-2,4-thiazolidinediones.

Several (Z)-5-arylidene-2,4-thiazolidinediones were synthesized and tested as aldose reductase inhibitors (ARIs). The most active of the N-unsubstituted derivatives (2) exerted the same inhibitory activity of Sorbinil. The introduction of an acetic side chain on N-3 of the thiazolidinedione moiety led to a marked increase in lending inhibitory activity, conducting to the discovery of a very potent ARI (4c), whose activity level (IC50=0.13 microM) was in the same range of Tolrestat. Moreover, the corresponding methyl esters (3), devoid of any acidic functionality, showed appreciable inhibitory activity similar to that of the N-unsubstituted compounds. It was also found that the substitution pattern on the 5-benzylidene moiety markedly influenced the activity of N-unsubstituted 2,4-thiazolidinediones 2, compounds with substituents at the meta position being generally more effective than the para-substituted ones; however, this SAR was not evidenced in acetates 3 and acids 4.

Synthesis and antiinflammatory, analgesic activity of 3,3'-(1,2-ethanediyl)-bis[2-aryl-4-thiazolidinone] chiral compounds. Part 10.

In this note, the synthesis and structure-activity relationships of a new series of 2R,2'R/2S,2'S and 2R,2'S-meso 3,3'-(1,2-ethanediyl)-bis[2-aryl-4-thiazolidinones] are described. Antiinflammatory activity was investigated by the carrageenin-induced paw edema test and analgesic activity by acetic acid writhing and hot plate tests in rats. All compounds displayed ulcerogenic effects and acute toxicity much lower than indomethacin and phenylbutazone. Meso isomers (b) showed better pharmacological profiles than corresponding racemates (a). Methoxy substitution patterns of the aryls on stereogenic carbons are generally the most favorable on the pharmacological profile.

Nickel(II) 2,6-diacetylpyridine bis(isonicotinoylhydrazonate) and bis(benzoylhydrazonate) complexes: structure and antimycobacterial evaluation. Part XI.

The reaction of 2,6-diacetylpyridine (dap) and isonicotinoyl- or benzoylhydrazide leads to bishydrazones H(2)dapin (1a) and H(2)dapb (1b), respectively. The condensation can either take place as a bimolecular kinetic process between the two reactants or as a monomolecular metal-templated synthesis in the presence of nickel(II) ions. In the latter case the reaction products are charged 2,6-diacetylpyridine bis(hydrazone) nickel(II) complexes, which can be easily deprotonated to neutral hydrazonates. Diffractometric analysis of one of these [Ni(dapb)](2) (8b) has shown a binuclear structure with two octahedral nickel(II) ions bridged by two helicoidal dap (bishydrazonates) in a spheroidal structure of C(2V) symmetry. The synthesized complexes 8 are promising as antimycobacterial agents against M. tuberculosis H37Rv. In particular, 8b displays significant activity (MIC=0.025 microg/mL) 10-fold higher than rifampin and equal to isoniazid, while its ligand is ineffective. Compound 8b is also capable of reducing HIV-induced cytopathogenic effect in human T(4 )lymphocytes.

Antimycobacterial in vitro activity of cobalt(II) isonicotinoylhydrazone complexes. Part 10.

Octahedral cobalt(II) complexes of isonicotinoylhydrazones, which were obtained from the primary antituberculous agent isoniazid, have been synthesised and characterised. Their antimycobacterial in vitro activity has been evaluated against Mycobacterium tuberculosis H37Rv: they exhibit MIC values ranging from < 0.1 to 0.39 microg/mL, showing them to be generally more active than previously reported analogous Cu(II) and Ni(II) complexes.

Isoniazid-related copper(II) and nickel(II) complexes with antimycobacterial in vitro activity. Part 9.

Isonicotinoylhydrazones 1, obtained by the primary antituberculous agent Isoniazid, have been used as monoanionic ligands (L) to prepare copper(II) 2 and nickel(II) 3 octahedral complexes of stoichiometry [MeL2(H2O)2]. Their antimycobacterial in vitro activity was evaluated against Mycobacterium tuberculosis H37Rv in comparison with the ligands. Complexes 2a, 2b, 2f, 3b, 3d and 3g displayed MIC values < or = 0.2 microg/mL.

Synthesis and in vitro antimicrobial and antitumoral screening of novel lipophilic isoniazid analogues. VI.

Various kinds of lipophilic analogues of isonicotinic acid hydrazide (Isoniazid) were synthesized and in vitro explored in a search for antimycobacterial agents with extended activity spectrum against pathogens responsible for the AIDS-associated diseases. The primary in vitro screening showed that a) isonicotinoylhydrazones 1a, 1b, 1d, 1e are more active than the parent drug against non-tubercular mycobacteria (MIC ranging between 0.5 and 4 micrograms/ml), b) isonicotinohydrazides 6b and 6e display interesting antibacterial activity on some Gram + and Gram-strains, and c) trifluoromethyl-containing compounds 1a and 2c inhibit the growth of several human tumor cell lines at doses between 10(-5) and 10(-6) M. On the contrary, none of the tested analogues significantly counteracts the cytopathogenicity induced by HIV and HSV viruses.

3,3'-Bi(1,3-thiazolidin-4-one) system. VIII. 3,3'-(1,2-Ethanediyl) derivatives and corresponding 1,1'-disulfones: synthesis, stereochemistry and antiinflammatory activity.

To deeply investigate the influence of lipophilicity, phenyl substitution patterns and stereo-chemistry on pharmacological profiles of chiral bisarylthiazolidinones, frequently endowed with stereoselective antiinflammatory, analgesic, antihistaminic activities, we synthesized and explored some 3,3'-(1,2-ethanediyl) analogues 1-4, along with their S-oxidized derivatives 5-8. Each derivative can be isolated as 2R, 2'R/2S, 2'S (a) and 2R, 2'S- or 2S, 2'R- meso (b) diastereomers, which were explored by means of carrageenin edema test, acetic acid writhing and hot plate tests, and also tested for gastrolesive potential and LD50. Independently of lipophilic and electronic features, disulfides 3b, 4b and disulfones 7a, 8a, 8b displayed interesting activity levels which appear to be mainly linked to the disubstitution pattern on benzenic rings.

Halogenated isoniazid derivatives VI. Evaluation of anti-HSV-1 and anti-HIV-1 in vitro activities of fluorinated analogues.

The synthesis and evaluation of antiviral in vitro activity are reported of some 2'-(1-arylethyl)isonicotinohydrazides (5a-d) and N-(1-arylethyl)isonicotinohydrazonic acids (6a-d), obtained by reducing fluorinated acetophenone isonicotinoylhydrazones (2a-d) with sodium cyanoborohydride. These INH analogues, along with other ones previously prepared, i.e. benzaldehyde isonicotinoylhydrazones 1, 4-aryl-1-methoxyl-1-(4-pyridyl)-2,3-diaza-1,3-butadienes 3 and 5-aryl-4-methyl-2-(4-pyridyl)-delta 2-1,3,4-oxadiazolines 4, were assayed for anti-HSV-1 activity on the monoblastoid cell line U937. Only some compounds (1b, 1d, 4d and 4e) displayed a moderate antiherpetic activity. In addition, the reduced compounds 5 and 6, submitted to the anti-HIV-1 screening, did not display significant effects in reducing virus-induced cytopathogenicity. The cytotoxicity of all compounds has been assayed on Vero cells and some considerations in correlation with structure are discussed.

2-(4-Pyridyl)-delta 2-1,3,4-oxadiazolines from isonicotinoylhydrazones and diazomethane as potential antimycobacterial and anti-HIV agents. V.

The 5-aryl-4-methyl-2-(4-pyridyl)-delta 2-1,3,4-oxadiazolines 3, previously synthesized along with isomer 4-aryl-1-methoxy-1-(4-pyridyl)-2,3-diaza-1,3-butadienes 2 from benzaldehyde isonicotinoylhydrazones and diazomethane, were tested for in vitro activity against both M. tuberculosis and some atypical mycobacterial strains as well as against human immunodeficiency virus (HIV-1). Some halophenyl derivatives, 3e, 3g, 3i, 3j, were found to display MIC ranges from 1 to 10 (micrograms/ml against H 37 Rv and a clinical isolate tubercular strain, whereas against M. avium (MAC) the MICs were higher than 20 micrograms/ml. When the combinations of oxadiazolines with ethambutol, acting as inhibitor of cell wall synthesis, were assayed on MAC strain a synergistic effect was demonstrated for 3g and 3h trifluoromethyl derivatives. The antimycobacterial profiles of 2 and 3 analogues are compared and discussed. As shown by compounds 2, no substantial anti-HIV in vitro activity was found in selected delta 2-oxadiazolines; a moderate cytotoxicity, however, appears to be a common property.

Halogenated isoniazid derivatives as possible antimycobacterial and anti-HIV agents--III.

As part of a research directed to the synthesis of novel isoniazid derivatives with potential activity on mycobacteria and HIV virus, the acetophenone-isonicotinoylhydrazones 3 and the 4-aryl-1-methoxy-1-(4-pyridyl)- 2,3-diaza-1,3-butadienes 5, obtained by reaction between isonicotinoylhydrazones and diazomethane, have been prepared and tested for such activities. Both classes of derivatives showed interesting growth inhibitory activity on non-tubercular mycobacteria, including the emerging M. avium. Such activity appears to be linked to fluorine and/or chlorine presence on benzene rings. In contrast, none of the compounds submitted to the anti-AIDS in vitro screening, displayed any protection against HIV-1 virus-induced cytopathic effect in T4-lymphocyte cell lines.

Aminopyrazinyl derivatives: synthesis and evaluation of antiinflammatory and related activities.

Some amides, 1-substituted methylenediamines and 2-substituted thiazolidin-4-ones, all containing the aminopyrazinyl moiety, were synthesized and tested in the experimental models of acute and chronic inflammations and as potential analgesic agents. The first series of compounds are inactive, whereas the N,N'-di-(2-pyrazinyl)-methylene-diamines and the 3-(2'-pyrazinyl)-thiazolidinones 6, 7, 11, 12 and even more 16 and 17 were found to be endowed with antiinflammatory and analgesic properties and low acute toxicity, the two latter being the most interesting.

Trifluoromethylcontaining sulfanilamides. I. Synthesis and in vitro antibacterial activity.

In a wider research directed to improve pharmacological profiles of known anti-infective agents by introducing fluorine or trifluoromethyl groups, some sulfanilamides trifluoromethylsubstituted on N1 ring, were synthesized and examined for their in vitro activity against gram-positive and gram-negative bacteria. Two N1-trifluoromethylphenyl-sulfanilamides, 1 and 4, exhibited MIC values, against all tested bacteria, similar or lower than those of the "classical" sulfanilamides, assayed in comparison. The new sulfanilamide 4 appears to be the more interesting: in fact, the presence of p-aminobenzoic acid (PABA) in culture medium did not influence its MIC values and no synergy was observed with trimethoprim, suggesting mechanism of action different from that of known sulfanilamides.