Synthesis and biological evaluation of novel 2,4-disubstituted-1,3-thiazoles as anti-Candida spp. agents.

A new series of [4-(4'-substituted-phenyl)thiazol-2-yl]hydrazine derivatives were synthesized in good yield (86-99%) and characterized by elemental analysis, IR, (1)H NMR, and mass spectral studies. The compounds were assayed for their in vitro broad-spectrum antifungal activity, compared to clotrimazole and fluconazole, against 20 clinical isolates of pathogenic Candida spp., representing five different species. The results showed that the presence of heterocyclic or bicyclic rings on hydrazone moiety in position C2 of thiazole revealed a promising selective inhibitory activity especially against Candida albicans and Candida glabrata.

Synthesis, stereochemical separation, and biological evaluation of selective inhibitors of human MAO-B: 1-(4-arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazines.

Novel 1-(4-arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazine derivatives have been investigated for their ability to inhibit selectively the activity of the human B isoform of monoamine oxidase. These compounds were obtained as racemates and (R)-enantiomers by a stereoconservative synthetic pattern in high yield and enantiomeric excess. The (S)-enantiomers of the most active derivatives have been separated by enantioselective HPLC. All compounds showed selective activity against hMAO-B with IC(50) ranging between 21.90 and 0.018 microM.

Investigations on the 2-thiazolylhydrazyne scaffold: synthesis and molecular modeling of selective human monoamine oxidase inhibitors.

A new series of [4-(3-methoxyphenyl)-thiazol-2-yl]hydrazyne derivatives were synthesized in good yield (71-99%) and characterized by elemental analysis and (1)H NMR studies. The compounds were assayed for their in vitro human monoamine oxidase (hMAO) inhibitory activity and selectivity and most of them showed IC(50) values in the nanomolar range, thus demonstrating our interest in this privileged scaffold. The most active and selective derivative (20), bearing a pyridine moiety on the CN, displayed IC(50)=3.81+/-0.12 nM and selectivity ratio=119 toward hMAO-B. Molecular modeling studies were carried out on recent and high resolution hMAO-A and hMAO-B crystallographic structures to better justify the enzyme-inhibitor interaction toward hMAO isoforms and to explain the structure-activity relationship of this kind of inhibitors.

Synthesis, selective anti-Helicobacter pylori activity, and cytotoxicity of novel N-substituted-2-oxo-2H-1-benzopyran-3-carboxamides.

N-substituted-3-carboxamido-coumarin derivatives were prepared and evaluated for selective antibacterial activity against 20 isolates of Helicobacter pylori clinical strains, including five metronidazole resistant ones. Some of them possessed the best activity against H. pylori metronidazole resistant strains with MIC values lower than the drug reference (metronidazole). Furthermore, anti-inflammatory activity through the inhibition of the IL-8 production was investigated.

Synthesis, semipreparative HPLC separation, biological evaluation, and 3D-QSAR of hydrazothiazole derivatives as human monoamine oxidase B inhibitors.

The present study reports on synthesis in high yields (70-99%), HPLC enantioseparation, inhibitory activity against human monoamino oxidases, and molecular modeling including 3D-QSAR studies, of a large series of (4-aryl-thiazol-2-yl)hydrazones (1-45). Most of the synthesized compounds proved to be potent and selective inhibitors of hMAO-B isoform in the micromolar or nanomolar range, thus demonstrating that hydrazothiazole could be considered a good pharmacophore to design new hMAO-B inhibitors. Due to the presence in some derivatives of a chiral center, we also performed a semipreparative chromatographic enantioseparation of these compounds obtained by a stereoconservative pattern. The separated enantiomers were submitted to in vitro biological evaluation to point out the stereorecognition of the active site of the enzyme towards these structures. Finally, a 3D-QSAR study was carried out using Comparative Molecular Field Analysis (CoMFA), aiming to deduce rational guidelines for the further structural modification of these lead compounds.

A new series of flavones, thioflavones, and flavanones as selective monoamine oxidase-B inhibitors.

A new series of synthetic flavones, thioflavones, and flavanones has been synthesized and evaluated as potential inhibitors of monoamine oxidase isoforms (MAO-A and -B). The most active series is the flavanone one with higher selective inhibitory activity against MAO-B. Some of these flavanones (mainly the most effective) have been separated and tested as single enantiomers. In order to investigate the MAOs recognition of the most active and selective compounds, a molecular modeling study has been performed using available Protein Data Bank (PDB) structures as receptor models for docking experiments.

Synthesis and inhibitory activity against human monoamine oxidase of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives.

A series of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives has been synthesized and assayed for their ability to inhibit the activity of the A and B isoforms of human monoamine oxidase (hMAO). Some of these compounds were endowed with a selective inhibitory activity against hMAO-B in the micromolar range. The most active of the series is the compound 13, N1-thiocarbamoyl-3-(fur-2'-yl)-5-(4'-fluoro-phenyl)-4,5-dihydro-(1H)-pyrazole, with IC(50) 2.75+/-0.81muM value and selectivity ratio of 25, which is the best candidate for further investigations.

Synthesis and evaluation of 4-acyl-2-thiazolylhydrazone derivatives for anti-Toxoplasma efficacy in vitro.

A new series of 4-acyl-2-thiazolylhydrazone derivatives was synthesized and screened for its in vitro activity against Toxoplasma gondii. We evaluated parasite growth inhibition and cytotoxicity, inhibition of replication, and inhibition of parasite invasion of host cells. The biological results indicated that some substances had an antiproliferative effect against intracellular T. gondii tachyzoites cultivated in vitro.

Chalcones: a valid scaffold for monoamine oxidases inhibitors.

A large series of substituted chalcones have been synthesized and tested in vitro for their ability to inhibit human monoamine oxidases A and B (hMAO-A and hMAO-B). While all the compounds showed hMAO-B selective activity in the micro- and nanomolar ranges, the best results were obtained in the presence of chlorine and hydroxyl or methoxyl substituents. To better understand the enzyme-inhibitor interaction and to explain the selectivity of the most active compounds toward hMAO-B, molecular modeling studies were carried out on new, high resolution, hMAO-B crystallographic structures. For the only compound that also showed activity against hMAO-A as well as low selectivity, the molecular modeling study was also performed on the hMAO-A crystallographic structure. The docking technique provided new insight on the inhibition mechanism and the rational drug design of more potent/selective hMAO inhibitors based on the chalcone scaffold.

Synthesis, molecular modeling, and selective inhibitory activity against human monoamine oxidases of 3-carboxamido-7-substituted coumarins.

A large series of 3-carboxamido-7-substituted coumarins have been synthesized and tested in vitro for their human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitory activity. Taking into account all the relevant structural information on MAOs reported in the literature, we made some changes in the coumarin nucleus and examined with particular attention the effect on activity and selectivity of substituting at position 3 with N-aryl or N-alkyl carboxamide and at position 7 with a benzyloxy or a 4'-F-benzyloxy group. Some of the assayed compounds proved to be potent, selective inhibitors of hMAO-B with IC(50) values in the micromolar range. To better understand the enzyme-inhibitor interaction and to explain the selectivity of the most active compounds toward hMAOs, molecular modeling studies were carried out on new, high resolution, hMAO-A and hMAO-B crystallographic structures.

A novel histone acetyltransferase inhibitor modulating Gcn5 network: cyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl)hydrazone.

Acetylation is a key modulator of genome accessibility through decondensation of the chromatin structure. The balance between acetylation and opposite deacetylation is, in fact, a prerequisite for several cell functions and differentiation. To find modulators of the histone acetyltransferase Gcn5p, we performed a phenotypic screening on a set of newly synthesized molecules derived from thiazole in budding yeast Saccharomyces cerevisiae. We selected compounds that induce growth inhibition in yeast strains deleted in genes encoding known histone acetyltransferases. A novel molecule CPTH2, cyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl)hydrazone, was selected based on its inhibitory effect on the growth of a gcn5Delta strain. We demonstrated a specific chemical-genetic interaction between CPTH2 and HAT Gcn5p, indicating that CPTH2 inhibits the Gcn5p dependent functional network. CPTH2 inhibited an in vitro HAT reaction, which is reverted by increasing concentration of histone H3. In vivo, it decreased acetylation of bulk histone H3 at the specific H3-AcK14 site. On the whole, our results demonstrate that CPTH2 is a novel HAT inhibitor modulating Gcn5p network in vitro and in vivo.

Synthesis, stereochemical identification, and selective inhibitory activity against human monoamine oxidase-B of 2-methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones.

A series of 2-methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones have been investigated for their ability to inhibit selectively the activity of the human A and B isoforms of monoamine oxidase (MAO). The target compounds, which present a stereogenic center on the cyclohexane ring, were obtained as pure (R) and (S) enantiomers by enantioselective HPLC. The absolute configuration of homochiral forms isolated on a semipreparative scale was obtained by a combined strategy based on chemical correlation and single-crystal X-ray diffraction. All compounds showed higher activity against the human MAO-B isoform with IC50 values ranging between 26.81 +/- 2.74 microM and 14.20 +/- 0.26 nM, and the assays carried out on the pure enantiomers showed higher activity for the (R) form. A computational study was performed by molecular mechanics, DFT-based quantomechanics, and docking techniques on the most active and human MAO-B selective inhibitor 8.

Synthesis, molecular modeling studies and selective inhibitory activity against MAO of N1-propanoyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives.

A series of N1-propanoyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives were synthesized and assayed as inhibitors of MAO-A and MAO-B isoforms. Most of the tested compounds showed inhibitory activity with micromolar values and MAO-A selectivity. In addition a computational work was carried out on the most selective compound 3b to highlight the most relevant interactions in the mechanism of recognition within both the MAO-A and the MAO-B enzyme active sites.

Synthesis and in vitro activity of 2-thiazolylhydrazone derivatives compared with the activity of clotrimazole against clinical isolates of Candida spp.

In this paper, we report on the synthesis of a novel series of 2-thiazolylhydrazone derivatives and the influence of the substituents on the thiazole ring on antifungal activity. All synthesized compounds were screened for their in vitro activities against 22 clinical isolates of Candida spp., representing six different species, compared to clotrimazole as a reference compound. Some of the tested compounds were found to possess significant antifungal activity when compared to clotrimazole, in particular compound 14 which exhibited higher potency against most of the Candida spp. considered. The compounds that were most active as anti-Candida agents were also submitted to cytotoxic screening by the Trypan Blue dye exclusion assay and in general they were shown to induce low cytotoxic effects.

A novel class of selective anti-Helicobacter pylori agents 2-oxo-2H-chromene-3-carboxamide derivatives.

A novel class of selective anti-Helicobacter pylori agents, 2-oxo-2H-chromene-3-carboxamide derivatives, were prepared and evaluated for their anti-bacterial activity. All synthesized compounds showed little or no activity against different species of Gram-positive and Gram-negative bacteria and against various strains of pathogenic fungi. Some of them exhibited a potent and specific inhibitory effect on the growth of H. pylori, including metronidazole-resistant strains, in the 0.0039-16 microg/mL MIC range. A cytotoxic screening by the Trypan blue dye exclusion assay was also carried out on the most active compounds as anti-H. pylori agents. Among the derivatives examined for their cytotoxic potential, a number of them induced low cytotoxic effects.

Monoamine oxidase isoform-dependent tautomeric influence in the recognition of 3,5-diaryl pyrazole inhibitors.

A series of 3,5-diaryl pyrazoles were prepared and assayed for their ability to inhibit reversibly monoamine oxidase-A (MAO-A) and monoamine oxidase B (MAO-B). Several compounds show inhibitory activity with concentration values in the nanomolar range. A computational work was carried out on the two most selective inhibitors that have tautomeric pyrazole forms. The binding free energies of these compounds for each MAO isoform were influenced by the tautomeric equilibria.

Selective inhibitory activity against MAO and molecular modeling studies of 2-thiazolylhydrazone derivatives.

A series of 2-thiazolylhydrazone derivatives have been investigated for the ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO) selectively. All of the compounds showed high activity against both the MAO-A and the MAO-B isoforms with pKi values ranging between 5.92 and 8.14 for the MAO-A and between 4.69 and 9.09 for the MAO-B isoforms. Both the MAO-A and the MAO-B isoforms, deposited in the Protein Data Bank as model 2BXR and 1GOS, respectively, were considered in a computational study performed with docking techniques on the most active and MAO-B-selective inhibitor, 18.

Synthesis, molecular modeling studies, and selective inhibitory activity against monoamine oxidase of N,N'-bis[2-oxo-2H-benzopyran]-3-carboxamides.

A novel series of N,N'-bis[2-oxo-2H-1-benzopyran]-3-carboxamide derivatives have been synthesized and investigated for the ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). Some of the synthesized compounds show good selective inhibitory activity against the MAO-A isoform. Both the MAO-A and -B isoforms, deposited in the Protein Data Bank as the 2BXR and 1GOS models, respectively, were considered in a computational study performed with docking techniques on the most active and selective inhibitors.

Quercetin as the active principle of Hypericum hircinum exerts a selective inhibitory activity against MAO-A: extraction, biological analysis, and computational study.

The methanol extract from Hypericum hircinum leaves exhibited in vitro inhibition of monoamine oxidases (MAO). Bioassay-guided fractionation led to the isolation of quercetin and five compounds identified for the first time from H. hircinum. Quercetin was the only compound with a selective inhibitory activity against MAO-A, with an IC50 value of 0.010 microM. To explain MAO selective inhibition at the molecular level, a computational study was carried out by conformational search and docking techniques using recently determined crystallographic models of both enzymatic isoforms. An in vivo study in mice was carried out using the forced swimming test in order to elucidate the behavioral effects of quercetin.

Synthesis, biological evaluation and 3D-QSAR of 1,3,5-trisubstituted-4,5-dihydro-(1H)-pyrazole derivatives as potent and highly selective monoamine oxidase A inhibitors.

The present report provides a extended study of the chemistry, the inhibitory activity against monoamino oxidases (MAO), and molecular modeling including the 3D-QSAR hypothesis of 1,3,5-trisubstituted-4,5-dihydro-(1H)-pyrazole derivatives. Four series of about eighty novel pyrazoline derivatives were prepared and investigated for their ability to inhibit the activity of the A and B isoforms of MAO selectively. Most of the new synthesized compounds proved more reversible, potent, and selective inhibitors of MAO-A than of MAO-B, and could be taken into account to develop the search further in this field, knowing that reversible and selective MAO-A inhibitors are used as antidepressant and antianxiety drug. The 30 most active compounds show inhibitory activity on MAO-A in the 8.6 x 10(-8) - 9.0 x 10(-9)M range. Moreover, it should be pointed out that for most of them a high IC(50) > or = 10(-9)M value is associated with a high A-selectivity (Selectivity Index MAO-B/MAO-A in the 10,000-16,250 range). Furthermore, due to the presence of a chiral centre at the C5 position of the pyrazole moiety, we performed the semi-preparative chromatographic enantioseparation of the most potent, selective, and chiral compounds. The separated enantiomers were then submitted to in vitro biological evaluation, and from the results of these experiments it has been possible to point out a difference in inhibiting the two isoforms selectively between the racemic mixture and the single enantiomers. The molecular modeling work was carried out combining the Glide docking approach with CoMFA with the aim to rationalize the structure-activity relationships of each pyrazoline inhibitor toward MAO-A and MAO-B isoforms and to derive a suitable selectivity model.