Reductive Oligomerization of Nitroaniline Catalyzed by Fe3O4 Spheres Decorated with Group 11 Metal Nanoparticles.

The present work demonstrates a simple and sustainable method for forming azo oligomers from low-value compounds such as nitroaniline. The reductive oligomerization of 4-nitroaniline was achieved via azo bonding using nanometric Fe3O4 spheres doped with metallic nanoparticles (Cu NPs, Ag NPs, and Au NPs), which were characterized by different analytical methods. The magnetic saturation (M s) of the samples showed that they are magnetically recoverable from aqueous environments. The effective reduction of nitroaniline followed pseudo-first-order kinetics, reaching a maximum conversion of about 97%. Fe3O4-Au is the best catalyst, its a reaction rate (k Fe3O4-Au = 0.416 mM L-1 min-1) is about 20 times higher than that of bare Fe3O4 (k Fe3O4 = 0.018 mM L-1 min-1). The formation of the two main products was determined by high-performance liquid chromatography-mass spectrometry (HPLC-MS), evidencing the effective oligomerization of NA through N = N azo linkage. It is consistent with the total carbon balance and the structural analysis by density functional theory (DFT)-based total energy. The first product, a six-unit azo oligomer, was formed at the beginning of the reaction through a shorter, two-unit molecule. The nitroaniline reduction is controllable and thermodynamically viable, as shown in the computational studies.

Larvicidal isoxazoles: Synthesis and their effective susceptibility towards Aedes aegypti larvae.

Twenty 3,5-disubstituted isoxazoles have been synthesized and tested against fourth instar Aedes aegypti larvae. In the synthesis of title compounds, modifications have been made in the C-5 side-chain with a view to test their larvicidal activity. These isoxazoles have been obtained by 1,3-dipolar cycloaddition of arylnitrile oxides to terminal alkynes which furnished the desired products in 20% to 79% yields. A comparative study of the larvicidal activity between 3-(3-aryl-isoxazol-5-yl)-propan-1-ols and 3-(3-aryl-isoxazol-5-yl)-propionic acids clearly demonstrated that the latter compounds possess much better larvicidal activity than the former. We also tested two esters, viz., methyl 3-[3-(phenyl)-isoxazole-5-yl] propionate and methyl 3-[3-(4-chlorophenyl)-isoxazole-5-yl] propionate, where the latter presented an excellent larvicidal profile.

Structural investigation of anti-Trypanosoma cruzi 2-iminothiazolidin-4-ones allows the identification of agents with efficacy in infected mice.

We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds 6-24. Compounds with a phenyl at position N3, 15-19, 22-24, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one 5. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one 18, which inhibited the activity of cruzain and the proliferation of epimastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles 26-45 and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease.

Synthesis of 1,2,3-triazole derivatives and in vitro antifungal evaluation on Candida strains.

1,2,3-Triazoles have been extensively studied as compounds possessing important biological activities. In this work, we describe the synthesis of ten 2-(1-aryl-1H-1,2,3-triazol-4-yl)propan-2-ols via copper catalyzed azide alkyne cycloaddition (CuAAc or click chemistry). Next the in vitro antifungal activity of these ten compounds was evaluated using the microdilution broth method against 42 isolates of four different Candida species. Among all tested compounds, the halogen substituted triazole 2-[1-(4-chlorophenyl)-1H-(1,2,3)triazol-4-yl]propan-2-ol, revealed the best antifungal profile, showing that further modifications could be done in the structure to obtain a better drug candidate in the future.

Comparative computational studies of 3,4-dihydro-2,6-diaryl-4-oxo-pyrimidine-5-carbonitrile derivatives as potential antinociceptive agents.

In this study, the antinociceptive properties of 3,4-dihydro-2,6-diaryl-4-oxo-pyrimidine-5-carbonitrile derivatives 5a-i at doses of 25 and 50 mg/kg were evaluated in mice, using the abdominal constriction test. Molecular modeling studies were also performed using density functional theory calculations. These data provided information about the electrostatic and ionization potentials and were used to compare the antinociceptive activity of the title compounds. The most active compounds were 3,4-dihydro-2-(4-chlorophenyl)-6-(4-methoxyphenyl)-4-oxo-pyrimidine-5-carbonitrile (5b) and 3,4-dihydro-2,6-diphenyl-4-oxo-pyrimidine-5-carbonitrile (5i), which inhibited the number of abdominal constrictions, at 50 mg/kg dose, in 88.6% and 88% of the sample, respectively. A preliminary SAR study demonstrated that halogen replacement in the phenyl rings of the compounds under study reduces the antinociceptive activity. DFT calculations showed that there is a high correlation between the ionization potentials and the analgesic properties of the compounds. It was found that compounds with a positive ionization potential (compounds 5b and 5i) were found to be the best analgesic drugs in this series.

Improved microwave-mediated synthesis of 3-(3-aryl-1,2,4-oxadiazol-5-yl)propionic acids and their larvicidal and fungal growth inhibitory properties.

The synthesis of 3-(3-aryl-1,2,4-oxadiazol-5-yl)propionic acids from arylamidoximes and succinic anhydride under focused microwave irradiation conditions is described. The new synthetic method furnished the desired products in 2-3 min and good yields. Furthermore, the previously complicated purification procedure has been simplified in a manner which is quick, eco-friendly and cost-effective. Larvicidal bioassay and fungal growth inhibitory tests were performed using several 3-(3-aryl-1,2,4-oxadiazol-5-yl)propionic acids. These acids presented strong larvicidal activity against L4 larvae of Aedes aegypti. The results suggest that larvicidal activity might be correlated with the presence of electron-withdrawing substituents in the para position of the phenyl ring except the fluorine atom. The alterations observed in the larvae spiracular valves of the siphon and anal papillae by 1,2,4-oxadiazoles in the larvicidal bioassay are responsible for larvae's death. Furthermore, all acids inhibited the fungal growth of five different types of fungi, viz., Fusarium solani, F. oxysporum, F. moniliforme, F. decemcellulare and F. lateritium in a preliminary evaluation. Both of these activities are being disclosed for the first time for 1,2,4-oxadiazole-5-yl ring linked at C-3 of propionic acid.

First ultrasound-mediated one-pot synthesis of N-substituted amides.

Ultrasound irradiation, an efficient and innocuous technique of reagent activation for synthesizing organic compounds, has been applied with success to transform seven carboxylic acids to fourteen secondary amides in good to excellent yields. The reaction has worked well either with aryl or alkyl carboxylic acids as well as with aromatic or aliphatic amines. This methodology is expeditious and reliable for preparing secondary carboxamides which in many cases are embedded in the C-5 side-chain of 1,2,4-oxadiazoles (14, 15, 17-27). The elemental analyses of new compounds (19-27) in conjunction with the spectral data of all synthesized amides gave an idea about their structures, while the crystallographic data of one of the compounds (26) supplied information concerning the configurational behavior of the amidic part and also the conformational aspect of the entire molecule in the crystalline state.

Synthesis and cytotoxic profile of glycosyl-triazole linked to 1,2,4-oxadiazole moiety at C-5 through a straight-chain carbon and oxygen atoms.

The convergent synthesis of an unusual (but simple) class of compounds 5a-g has been achieved by the copper-catalyzed [3+2] cycloaddition reaction of 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl azide 4 with propynyl 3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propionates 3a-g. The formerly known azide 4 has been prepared according to the literature procedure; however, the synthesis of esters 3a-g is being reported for the first time. The infrared as well as (1)H NMR spectra of all new products are in agreement with their proposed structures. By carrying out the nOe experiment of one of the final compounds 5a, we have been able to establish that only the 1,4-regioisomers have been formed in the cycloaddition reaction. All final products presented weak cytotoxic activity, but 5e and 5g had somewhat better behaviour showing 22-25% cell growth inhibition against two cell strains: NCI-H(292) (lung carcinoma) and HEp-2 (larynx carcinoma).

Synthesis and antiinflammatory activity of 4-amino-2-aryl-5-cyano-6-{3- and 4-(N-phthalimidophenyl)} pyrimidines.

Six new 4-amino-5-cyano-2,6-diarylpyrimidines 5a-h has been synthesized in a facile manner by reacting the appropriate arylamidines 4a-d with bisnitriles 3a-e. Reduction of the nitro group of 5a-e using Pd in ethyl acetate furnished 6a-e in good yields. Reaction of 6a-e individually with phthalic anhydride yielded 7a-e in good to excellent yields. The newly synthesized heterocycles were characterized by IR, (1)H-NMR and mass spectral data. Compounds 5f-h and 7a-e were also evaluated against inflammation. Pyrimidines 5g, h exhibited better antiinflammatory activity when compared with acetylsalicylic acid (ASA). Phthalimide derivatives 7a-e also presented antiinflammatory activity, and three of them, viz., 7a-c have been found to be twice more active than aspirin. Cytotoxical evaluations of compounds 7a-e using neoplastic cells (NCI-H(292) and Hep-2) presented 41% of growth inhibition of neoplastic cells NCI-H(292).

A handy and solventless direct route to primary 3-[3-aryl)-1,2,4-oxadiazol-5-yl]propionamides using microwave irradiation.

A one-step, simple and straightforward synthesis of the title amides from the corresponding carboxylic acids, urea and imidazole under microwave irradiation is described.

Genotoxic activity of 3-[3-phenyl-1,2,4-oxadiazol-5-yl] propionic acid and its peptidyl derivatives determined by Ames and SOS response tests.

Compounds derived from 1,2,4-oxadiazole have being reported for their anti-inflammatory activity. However, those compounds should be devoid of any genotoxic side effect. In this work, the genotoxic activity of peptidomimetic moiety-containing 1,2,4-oxadiazoles derivatives was tested based on the Ames and SOS Chromotest. The results showed no mutagenic activity on the Ames test for 3-[3-phenyl-1,2,4-oxadiazol-5-yl] propionic acid (POPA) parental drug, but a weak SOS response induction on Chromotest. The chemical modifications reduced that response to a non-significative level, with l-phenylalanine peptidomimetic derivative being showing the lowest induction response. The results pointed out for the effectiveness of promoting chemical modifications of biological active compounds to increase its mode of action, showed in previous work, without increasing and even decreasing its DNA damage effect.

Synthesis of 3-aryl-5-decapentyl-1,2,4-oxadiazoles possessing antiinflammatory and antitumor properties.

A simple, convenient and straightforward synthesis of 3-aryl-1,2,4-oxadiazoles 4a-f from arylamidoximes 1a-f and palmitic acid 2 is described. Compounds 4a-f are non-lethal in mice at four times the therapeutic dose (i.p., LD50>1 g kg(-1) of the animals' body weight). These heterocycles have been found to possess antiinflammatory property similar to aspirin and ibuprofen. Three compounds, viz., 4a, d, e have also been evaluated for antitumor activity, where 4d exhibited an excellent activity comparable to lapachol.

Total synthesis and identification of two diastereoisomers of 1-methyl-2-[N-(p-tolylsulfonyl)-2-pyrrolidinyl]ethyl beta-L-fucopyranoside.

The reaction of a racemic mixture of (2R,2'S)- and (2S,2'R)-N-(p-tolylsulfonyl)-2-pyrrolidinyl-2-propanol, prepared from (S)-proline, with 2,3,4-tri-O-acetyl-alpha-L-fucopyranosyl trichloroacetimidate led to both diastereoisomers of the title compound after O-deacetylation.

Mass spectrometric analysis of 1,2,4-oxadiazoles and 4,5-dihydro-1,2,4-oxadiazoles.

1,2,4-Oxadiazoles and 4,5-dihydro-1,2,4-oxadiazoles are an interesting class of compounds because of their pharmacological and other properties. Although short descriptions of these compounds under mass spectrometric conditions exist, we thought it worthwhile to write a comprehensive review of this class of compounds. Therefore, this revision deals first with 1,2,4-oxadiazoles and then 4,5-dihydro-1,2,4-oxadiazoles from 1964 until the year 2002. Much work on these compounds has been described under electron impact conditions and only a little under chemical ionization (CI).

Synthesis and hypolipidemic activity of N-substituted phthalimides. Part V.

A series of N-aryl- or N-(1,2,4-triazol-yl)-phthalimides (4a-4i) have been synthesized starting from phthalic anhydride (1) and an appropriate amine (2a-2i). All compounds presented hypolipidemic activity, but compound 4d proved to be the most active and reduced plasma cholesterol and triglyceride levels in Swiss white mice significantly.

Synthesis of new branched-chain amino sugars.

1,3-Dipolar cycloaddition of methylideneaniline N-oxide to sugar enones is described. The addition occurred exclusively from the side opposite to the aglycone affording the corresponding alkyl alpha-D-lyxo-hexopyranosid-(2,3:5',4')-phenylisoxazolidin-4-uloses. Hydrogenation of these compounds readily yielded the corresponding alkyl 3-deoxy-3-N-phenylaminomethyl-alpha-D-talopyranoside, that were readily transformed to the acetates. The structure and conformation of the bicyclic compounds were determined by 1H NMR studies and semi-empirical molecular orbital calculations employing the AM1 method.

Antiinflammatory property of 3-aryl-5-(n-propyl)-1,2,4-oxadiazoles and antimicrobial property of 3-aryl-5-(n-propyl)-4,5-dihydro-1,2,4-oxadiazoles: their syntheses and spectroscopic studies.

The synthesis of six 3-aryl-5-(n-propyl)-4,5dihydro-1,2,4-oxadiazoles 3a-f has been achieved in a facile manner by the reaction of an appropriate arylamidoxime 1a-f with butyraldehyde 2. Oxidation of 3a-f individually using MnO(2) in CH(2)Cl(2) or sodium hypochlorite in THF/H(2)O furnished 1,2,4-oxadiazoles 4a-f in good to excellent yields. Compounds 4a-f were also evaluated against inflammation. Except 4e, all of them reduced inflammation, however, 4c presented better antiinflammatory activity. A preliminary antimicrobial activity tests of 3a-f showed that these compounds possess activity against some microorganisms. In fact, 3c and 3f have been found to be more effective against Staphylococcus aureus, Mycobacterium smegmatis, and Candida albicans.