Bruno Freitas Lira

Synthetic approaches and pharmacological activity of 1,3,4-oxadiazoles: a review of the literature from 2000-2012.

This review provides readers with an overview of the main synthetic methodologies for 1,3,4-oxadiazole derivatives, and of their broad spectrum of pharmacological activities as reported over the past twelve years.

Synthesis, Molecular Properties Prediction, and Anti-staphylococcal Activity of N-Acylhydrazones and New 1,3,4-Oxadiazole Derivatives

Five new 1-(2-(5-nitrofuran-2-yl)-5-(aryl)-1,3,4-oxadiazol-3-(2H)-yl) ethanone compounds 5a–e were synthesized by cyclization of N-acylhydrazones 4a–e with acetic anhydride under reflux conditions. Their structures were fully characterized by IR, 1H-NMR, and 13C-NMR. Furthermore, evaluations of the antibacterial activity of the 1,3,4-oxadiazoles 5a–e and N-acylhydrazones 4a–e showed strong activity against several strains of Staphylococcus aureus, with MICs between 4 μg/mL to 32 μg/mL. In silico studies of the parameters of Lipinski’s Rule of Five, as well as the topological polar surface area (TPSA), absorption percentage (% ABS), drug likeness and drug score indicate that these compounds, especially 4a and 5d, have potential to be new drug candidates.

Drug Resistance Modulation in Staphylococcus Aureus, a New Biological Activity for Mesoionic Hydrochloride Compounds

Two salts of the mesoionic compounds 1,4-diphenyl-5-(5-nitro-2-furanyl)-1,3,4-thiadiazolium-2-thiol chloride (MC-1) and 4-phenyl-5-(5-nitro-2-furanyl)-1,3,4-thiadiazolium-2-phenylamine chloride (MC-2) were synthesized utilizing 1,4-diphenyl-thiosemicarbazide and 5-nitro-2-furoyl chloride as starting materials. Their structures were characterized by IR, 1H-NMR, 13C-NMR and elemental analysis. These compounds were analyzed for their influence on the effectiveness of norfloxacin, tetracycline, and erythromycin (standard antibiotics) against resistant strains of Staphylococcus aureus. MC-1 and MC-2, at sub-inhibitory concentrations of 16 μg/mL, favourably modulated the antibiotic activity of tetracycline by 16- and 32-fold, respectively (MIC), and that of erythromycin by 4-fold.

Synthesis and Characterization of some New Mesoionic 1,3-Thiazolium-5-thiolates via Cyclodehydration and in situ 1,3-Dipolar Cycloaddition/Cycloreversion

The title compounds were synthesized from C-aryl-N-methylglycines by N-aroylation followed by a cyclodehydration to form the corresponding 1,3-oxazolium-5-olates. These were not isolated but converted to the title compounds by an in situ 1,3-dipolar cycloaddition/cycloreversion sequence using carbon disulphide. We have studied the cyclodehydration step using acetic anhydride, trifluoroacetic anhydride and 1,3-dicyclohexyl-carbodiimide (DCC) at temperatures not exceding 60oC. Trifluroacetic anhydride proved to be the best reagent, giving a better yield and more easily purified products, although yields were also acceptable with the other two reagents.

Synthesis of new imidazolidin-2,4-dione and 2-thioxoimidazolidin-4-ones via C-phenylglycine derivatives.

Hydantoins and their derivatives constitute a group of pharmaceutical compounds with anticonvulsant and antiarrhythmic properties, and are also used against diabetes. N-3 and C-5 substituted imidazolidines are examples of such products. As such, we have developed a synthesis of 2,4-dione and 2-thioxo-4-one imidazolidinic derivatives by reaction of amino acids with C-phenylglycine, phenyl isocyanate and phenyl isothiocyanate. Four amino-derivatives IG(1-4) and eight imidazolidinic derivatives, IM(1-8), were obtained in yields of 70–74%. The mass, infrared, 1H and 13C-NMR spectra of representative products are discussed.

Antinociceptive Effect of Hydantoin 3-Phenyl-5-(4-ethylphenyl)-imidazolidine-2,4-dione in Mice

Imidazolidine derivatives, or hydantoins, are synthetic compounds with different therapeutic applications. Many imidazolidine derivatives have psychopharmacological properties, such as phenytoin, famous for its anticonvulsant efficacy, but also effective in the treatment of neuropathic pain. The hydantoin, 3-phenyl-5-(4-ethylphenyl)-imidazolidine-2,4-dione (IM-3), synthesized from the amino acid, glycine, was selected for psychopharmacological studies in mice on the basis of its chemical and structural similarity with phenytoin. The first step of this study was to define the LD50, which determined the doses of 50, 100 and 200 mg/kg for subsequent tests. The results obtained from the behavioral screening indicated that IM-3 produces decreased ambulation and analgesia in mice. Motor coordination and anxiety behavior were not affected by treatment with IM-3, as observed in the rotarod and elevated plus-maze tests, respectively. Regarding its antinociceptive properties, IM-3 showed efficacy in the acetic acid-induced writhing test by increasing the latency of the first writhe and reducing the number of writhes, as well as reducing the paw licking time in the second phase of the formalin test. The behavior of treated animals exposed to the hot plate test, however, did not differ from that of the control group. These data suggest that IM-3 has antinociceptive effects in mice, which is probably mediated by anti-inflammatory mechanisms.

Synthesis and Antifungal Activity Against Candida Strains of Mesoionic System Derived From 1,3-Thyazolium-5-thiolate

A series of ten new compounds have been synthetized in satisfactory yields (85-95%) through the treatment of isopropyl mesoionic 1,3-thiazolium-5-thiolate with 2-chloro-N-arylacetamides and characterized by elemental analysis, infrared (IR), 1H and 13C nuclear magnetic resonance (NMR) spectroscopies. The newly synthesized compounds were evaluated as new drug candidates in in silico study and for their antifungal activity against several strains of Candida albicans. In silico study indicates that no compound has potential to be a new drug while four compounds showed medium to strong activity with minimum inhibitory concentration (MIC) range of 256-1024 µg mL-1.

Synthesis, Characterization and Thermal Properties of an Europium (III) Nanocomplex

The coordination of lanthanide íons with organic ligands has provided good luminescent properties and allows its application in molecular light converter devices, which motivates the scientific interest of seeking coordination of these íons with organic ligands that potentiate the luminescence and associate biological properties of the complexes formed. From this perspective the complex was synthesized Eu (III) with mesoionic 2(4-chlorophenyl)-3-methyl (methoxyphenyl)-1,3-thiazole-5-thiolate (MS-1) and bipy, with the aim of its possible application in the areas of photoluminescence and drug. Analyses were performed using TG, DSC, XRD and IR. The complex obtained after reaction of the lanthanide salt and organic ligands showed five stages of decomposition and different fusion of the isolated ligands.

Synthesis, in silico Study and Antimicrobial Evaluation of New Selenoglycolicamides

Nine new compounds derived from selenoglycolic acid were synthesized, and their structures were fully characterized by elemental analysis, infrared (IR), H and C nuclear magnetic resonance (NMR). The compounds were evaluated in an in silico study and showed strong to moderate antibacterial activity against several strains of Staphylococcus aureus. In particular, three compounds exhibited excellent antibacterial activity, with minimum inhibitory concentrations (MICs) between 16 and 64 μg mL. Furthermore, two of the nine compounds showed antifungal activity, with MIC of 1024 and 512 μg mL. In silico studies of the parameters of Lipinski’s rule of five indicate that these compounds have potential to be new drug candidates.

Th1-Biased Immunomodulation and In Vivo Antitumor Effect of a Novel Piperine Analogue

Natural products have an important role as prototypes in the synthesis of new anticancer drugs. Piperine is an alkaloid amide with antitumor activity and significant toxicity. Then, the N-(p-nitrophenyl)acetamide piperinoate (HE-02) was synthesized, and tested for toxicological and antitumor effects. The toxicity was evaluated in vitro (on RAW 264.7 cells and mice erythrocytes) and in vivo (acute toxicity in mice). The Ehrlich ascites carcinoma model was used to evaluate the antitumor activity of HE-02 (6.25, 12.5 or 25 mg/kg, intraperitoneally, i.p.), as well as toxicity. HE-02 induced only 5.01% of hemolysis, and reduced the viability of RAW 264.7 cells by 49.75% at 1000 µg/mL. LD50 (lethal dose 50%) was estimated at around 2000 mg/kg (i.p.). HE-02 reduced Ehrlich tumor cell viability and peritumoral microvessels density. There was an increase of Th1 helper T lymphocytes cytokine profile levels (IL-1β, TNF-α, IL-12) and a decrease of Th2 cytokine profile (IL-4, IL-10). Moreover, an increase was observed on reactive oxygen species and nitric oxide production. Weak in vivo toxicological effects were recorded. Our data provide evidence that the piperine analogue HE-02 present low toxicity, and its antitumor effect involves modulation of immune system to a cytotoxic Th1 profile.