Design, synthesis, and in vitro antitumor activity of new 1,4-diarylimidazole-2-ones and their 2-thione analogues.

A series of new 1,4-diarylimidazol-2(3H)-one derivatives and their 2-thione analogues has been prepared and evaluated in vitro for antitumor activity against the NCI human cancer cell panel. Compounds bearing a 3,4,5-trimethoxyphenyl ring linked to either N-1 or C-4 position of the imidazole core demonstrated an interesting profile of cytotoxicity with preferential activity against leukemic cell lines. Compound 13 exhibited a potent antitumor activity against MOLT-4 (GI(50)=20 nM) and SR (GI(50)=32 nM) cell lines.

Inhibition of fatty acid amide hydrolase, a key endocannabinoid metabolizing enzyme, by analogues of ibuprofen and indomethacin.

There is evidence in the literature that the nonsteroidal anti-inflammatory drugs indomethacin and ibuprofen can interact with the cannabinoid system both in vitro and in vivo. In the present study, a series of analogues of ibuprofen and indomethacin have been investigated with respect to their ability to inhibit fatty acid amide hydrolase, the enzyme responsible for the hydrolysis of the endogenous cannabinoid anandamide. Of the fourteen compounds tested, the 6-methyl-pyridin-2-yl analogue of ibuprofen ("ibu-am5") was selected for further study. This compound inhibited rat brain anandamide hydrolysis in a non-competitive manner, with IC50 values of 4.7 and 2.5 microM being found at pH 6 and 8, respectively. By comparison, the IC50 values for ibuprofen were 130 and 750 microM at pH 6 and 8, respectively. There was no measurable N-acylethanolamine hydrolyzing acid amidase activity in rat brain membrane preparations. In intact C6 glioma cells, ibu-am5 inhibited the hydrolysis of anandamide with an IC50 value of 1.2 microM. There was little difference in the potencies of ibu-am5 and ibuprofen towards cyclooxygenase-1 and -2 enzymes, and neither compound inhibited the activity of monoacylglycerol lipase. Ibu-am5 inhibited the binding of [3H]-CP55,940 to rat brain CB1 and human CB2 cannabinoid receptors more potently than ibuprofen, but the increase in potency was less than the corresponding increase in potency seen for inhibition of FAAH activity. It is concluded that ibu-am5 is an analogue of ibuprofen with a greater potency towards fatty acid amide hydrolase but with a similar cyclooxygenase inhibitory profile, and may be useful for the study of the therapeutic potential of combined fatty acid amide hydrolase-cyclooxygenase inhibitors.

Synthesis, characterisation and insulin-mimetic activity of oxovanadium(IV) complexes with amidrazone derivatives.

The complexation of VO(2+) ion by ten acetamidrazone and 2-phenylacetamidrazone derivatives (L) was studied. Sixteen novel VO(2+) complexes were synthesised and characterised through the combined application of analytical and spectroscopic (EPR (electron paramagnetic resonance), FT-IR and diffuse reflectance electronic absorption) techniques. Eight are 1:2 species of composition [VOL(2)]SO(4) x xH(2)O and eight are 1:1 species with formula [VOL(SO(4))](n) x xH(2)O. The experimental data suggest a bidentate coordination mode for L with the donor set formed by the imine nitrogen and the carbonyl oxygen. EPR spectra indicate a square-pyramidal geometry for the 1:1 complexes and a penta-coordinated geometry intermediate between the square-pyramid and the trigonal-bipyramid for the 1:2 species. The hyperfine coupling constant along z axis, A(z), of the 1:2 complexes exhibits a marked reduction with respect to the predicted value (approximately 148x10(-4)cm(-1) vs. approximately 170x10(-4)cm(-1)). IR spectroscopic evidence supports the presence of sulphate as a counter-ion in the 1:2, and as a bridging bidentate ligand in the 1:1 complexes. Insulin-mimetic tests on modified fibroblasts, based on a modified MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazoliumbromide) assay, performed on three of the bis-chelated and eight of the mono-chelated derivatives, indicate that they are biologically active. The similar hydro/lipophilicity and the lack of ligand substituents recognizable by cell membrane receptors prevent substantial differentiation in the insulin-mimetic action.

Amidrazones as precursors of biologically active compounds--synthesis of diaminopyrazoles for evaluation of anticancer activity.

The regioselectivity of coupling phenyl isocyanate to 3-(2-acylhydrazino)-3-aminopropenenitriles and ethyl 3-(2-acylhydrazino)-3-aminopropenoates as simple access to aminopyrazole derivatives, endowed with potential antitumoral activity, is reported. 3-(2-Acylhydrazino)-3-aminopropenenitriles react with phenyl isocyanate to afford 3-amino-3-(2-acylhydrazino)-2-phenylaminocarbonyl-2-propenenitriles. These key intermediates were cyclized into 3,5-diaminopyrazole-4-carboxamide derivatives. Preliminary results of poor antiproliferative activities of these compounds are also reported.

New potential anticancer agents based on the anthranilic acid scaffold: synthesis and evaluation of biological activity.

The synthesis and anticancer activity of new compounds designed on the anthranilic acid scaffold are reported. The antiproliferative activity was assayed by the National Cancer Institute in established in vitro and in vivo anticancer experimental models. Structural variations based on the flufenamic acid motif afforded a series of (hetero)aryl esters of N-(2-(trifluoromethyl)pyridin-4-yl)anthranilic acid, which showed in vitro growth inhibitory properties against human tumor cell lines in nanomolar to low micromolar concentrations. The pyridinyl ester 25 exhibited very potent in vitro antiproliferative efficacy, with a chemosensitive profile showing a number of GI(50) values at concentrations lower than 10(-7) M in the full panel of human tumor cell lines. Compound 25 was also tested in vivo as a potential anticancer agent in the hollow fiber assay and in human tumor xenografts, showing moderate inhibitory properties. Analysis of biological activities and the COMPARE procedure was utilized to support putative biochemical mechanisms implicated with the antiproliferative activity.

Synthesis and antiproliferative activity of 2,6-dibenzylamino-3,5-dicyanopyridines on human cancer cell lines.

A new series of 2,6-dibenzylamino-3,5-dicyanopyridines were synthesized and evaluated for their in vitro anticancer activity toward cell lines of nine different types of human cancer. Some of newly prepared compounds demonstrated remarkable anticancer activity against most of the tested subpanel tumor cell lines.

From the potent and selective mu opioid receptor agonist H-Dmt-d-Arg-Phe-Lys-NH(2) to the potent delta antagonist H-Dmt-Tic-Phe-Lys(Z)-OH.

H-Dmt-d-Arg-Phe-Lys-NH(2) ([Dmt(1)]DALDA) binds with high affinity and selectivity to the mu opioid receptor and is a potent and long-acting analgesic. Substitution of d-Arg in position 2 with Tic and masking of the lysine amine side chain by Z protection and of the C-terminal carboxylic function instead of the amide function transform a potent and selective mu agonist into a potent and selective delta antagonist H-Dmt-Tic-Phe-Lys(Z)-OH. Such a delta antagonist could be used as a pharmacological tool.

In vitro antimycobacterial activity of newly synthesised S-alkylisothiosemicarbazone derivatives and synergistic interactions in combination with rifamycins against Mycobacterium avium.

The antimycobacterial activities of two new S-alkylisothiosemicarbazone derivatives (1i and 1f) against 32 Mycobacterium avium isolates were investigated. The minimum inhibitory concentrations (MICs) were significantly lower than those of rifampicin and other reference drugs. The two derivatives also showed excellent intracellular activity against M. avium residing in the macrophage-like J774 cells. Interestingly, the combination of subinhibitory concentrations of 1i and rifabutin or rifampicin induced a potent synergistic effect, as determined by the fractional inhibitory concentration indexes (FICIs) ranging between 0.103 and 0.412. Such synergistic effect resulted in a 81-fold and 139-fold reduction of the MICs of rifabutin and rifampicin, respectively. Enhancement of intracellular activity of rifabutin by the S-alkylisothiosemicarbazone derivative 1i was also observed. Results indicate that S-alkylisothiosemicarbazones can be useful in the therapy and prophylaxis of M. avium infections and can represent a template for the development of novel antimycobacterial drugs. Furthermore, as a consequence of their ability to enhance the activity of rifamycins, a reduction of drug interactions following the co-administration of protease inhibitors could be achieved by lower doses of rifampicin and rifabutin.

Synthesis of ibuprofen heterocyclic amides and investigation of their analgesic and toxicological properties.

A series of amides of ibuprofen with heteroaromatic amines was synthesized and assayed in vivo for their analgesic properties by means of writhing test in rats. When compared to parent ibuprofen some of the new amides exhibited a comparable or improved analgesic activity and a lower ulcerogenic effect.

New bis(pyridyl)methane derivatives from 4-hydroxy-2-pyridones: synthesis and antitumoral activity.

Bis(pyridyl)methane derivatives 5-40 were obtained from the reaction of 4-hydroxy-2-pyridones 3 and 4 with aldehydes. Compounds 5-40 were evaluated for cytotoxic activity against a panel of 60 human cancer cell lines by the National Cancer Institute and some of them demonstrated inhibitory effects on the growth of a wide range of cancer cell lines generally at 10(-5) M level and in some case at 10(-7) M concentrations.

Synthesis and antimycobacterial activity of new S-alkylisothiosemicarbazone derivatives.

A new series of S-alkylisothiosemicarbazones of 3- and 4-pyridincarboxaldehyde and 4-fluoro- and 4-trifluoromethylbenzaldehyde was synthesized and evaluated for biological activity against various Mycobacterium strains. Inhibitory activity against Mycobacterium tuberculosis H37Rv ATCC 27294 and INH-R ATCC 35822 was compared with activity against clinical isolated Mycobacteria as well as against MOTT. Some of newly prepared compounds showed best inhibitory values against clinical isolated Mycobacteria, besides to low citotoxicity values.

Activity of a new class of isonicotinoylhydrazones used alone and in combination with isoniazid, rifampicin, ethambutol, para-aminosalicylic acid and clofazimine against Mycobacterium tuberculosis.

The activities of six derivatives of a new class of isonicotinoylhydrazones were investigated in vitro against Mycobacterium tuberculosis H37Rv ATCC 27294, isoniazid-resistant M. tuberculosis ATCC 35822, rifampicin-resistant ATCC 35838, pyrazinamide-resistant ATCC 35828, streptomycin-resistant ATCC 35820 and 16 clinical isolates of M. tuberculosis. Several compounds showed interesting antimycobacterial activity against both ATCC strains and clinical isolates, but were less active against isoniazid-resistant M. tuberculosis. Combinations of five isonicotinoylhydrazone derivatives and rifampicin, ethambutol, para-aminosalicylic acid, isoniazid and clofazimine were also investigated against M. tuberculosis H37Rv ATCC 27294 and against ATCC drug-resistant strains. Addition of sub-MICs of some isonicotinoylhydrazone derivatives resulted in a four- to 16-fold reduction in MICs of ethambutol, para-aminosalicylic acid and rifampicin with fractional inhibitory concentrations (FICs) ranging between 0.17 and 0.37, suggesting a synergic interaction against M. tuberculosis H37Rv. Increased activity was also observed with other combinations (FICs 0.53-0.75), including isoniazid, and a synergic interaction between one of the isonicotinoylhydrazone derivatives and isoniazid (FIC 0.26) was shown against isoniazid-resistant M. tuberculosis ATCC 35822, whereas no effects were observed on combining the isonicotinoylhydrazones with clofazimine. The ability of isonicotinoylhydrazones to inhibit specifically the growth of M. tuberculosis, the high selectivity index and their ability to enhance the activity of standard antituberculous drugs in vitro indicate that they may serve as promising lead compounds for future drug development for the treatment of M. tuberculosis infections.