Raquel de Oliveira Lopes

Synthesis and pharmacological evaluation of N-phenyl-acetamide sulfonamides designed as novel non-hepatotoxic analgesic candidates.

In this paper we report the design, synthesis and pharmacological evaluation of a series of N-phenyl-acetamide sulfonamide derivatives (5a-g), planned by structural modification on the prototype paracetamol (1). In this series (5a-g), compound LASSBio-1300 (5e; ID(50)=5.81 micromol/kg) stands out as a new non-hepatotoxic analgesic drug candidate. The increase of area, volume and electrostatic potential of paracetamols analogues seems to be beneficial to the analgesic activity. Unlike paracetamol (1) and the other analogues (5a, 5d-g), compounds 5b and 5c presented an important anti-hypernociceptive activity associated to inflammatory pain.

Docking, synthesis and pharmacological activity of novel urea-derivatives designed as p38 MAPK inhibitors.

p38 mitogen-activated protein kinase (p38 MAPK) is an important signal transducing enzyme involved in many cellular regulations, including signaling pathways, pain and inflammation. Several p38 MAPK inhibitors have been developed as drug candidates to treatment of autoimmune disorders, such as rheumatoid arthritis. In this paper we reported the docking, synthesis and pharmacological activity of novel urea-derivatives (4a-e) designed as p38 MAPK inhibitors. These derivatives presented good theoretical affinity to the target p38 MAPK, standing out compound 4e (LASSBio-998), which showed a better score value compared to the prototype GK-00687. This compound was able to reduce in vitro TNF-α production and was orally active in a hypernociceptive murine model sensible to p38 MAPK inhibitors. Otherwise, compound 4e presented a dose-dependent analgesic effect in a model of antigen (mBSA)-induced arthritis and anti-inflammatory profile in carrageenan induced paw edema, indicating its potential as a new antiarthritis prototype.

Improving the Toolbox of Bioreductions by the Use of Continuous Flow Systems

Packed bed reactors can be used as an interesting alternative on the bioreduction of β-ketoesteres mediated by immobilized microorganisms. Here in, we report our results on the bioreduction of ethyl 3-oxohexanoate by immobilized Kluyveromyces marxianus cells and tert-butyl 3-oxobutanoate by immobilized Rhodotorula rubra cells under continuous flow conditions leading the desired β-hydroxy esters corresponding in high yields and enantiomeric excess.

Whole Cells in Enantioselective Reduction of tert-Butyl Acetoacetate

Abstract The β-ketoester tert-butyl acetoacetate was enantioselectively reduced to tert-butyl (S)-3-hydroxybutanoate by seven microorganism strains. The best result using free cells was obtained with the yeast R. rubra, which furnished 97.6% ee and higher than 99% of conversion within 24 h. After immobilization in calcium alginate spheres, R. rubra furnished 96% ee and higher than 99% ee within 24 h, even if substrate concentration was 58 mM. Immobilized cells were reused three times without loss of enantioselectivity. GRAPHICAL ABSTRACT

Studies on the continuous-flow synthesis of nonpeptidal bis-tetrahydrofuran moiety of Darunavir

The use of continuous-flow chemistry has shown to be an important tool in improving API manufacture. In the present paper, we report the use of continuous-flow reactors in the synthesis of the bicyclic side chain of antiretroviral Darunavir.

Whole cells in enantioselective reduction of benzyl acetoacetate.

The β-ketoester benzyl acetoacetate was enantioselectively reduced to benzyl (S)-3-hydroxybutanoate by seven microorganism species. The best result using free cells was obtained with the yeast Hansenula sp., which furnished 97% ee and 85% of conversion within 24 h. After immobilization in calcium alginate spheres, K.marxianus showed to be more stable after 2 cycles of reaction.

Synthesis of oxazolones under Dakin-West conditions

We proceeded the reaction using phenylalanine (520 mg; 3 mmol), chloroacetic anhydride (1,5 g; 9 mmol; 3 eq), methylimidazole (0,105 ml, 1,2 mmol; 0,5 eq) as the catalyst and dioxane as the solvent (5 ml). 2 The reaction was kept under reflux during 2 hours. Afterwards, water was added to hydrolyze the remaining anhydride. The organic layer was washed with saturated solution of potassium bicarbonate and water and then dried with anhydrous Na2SO4. After evaporation of the solvent, the product was recrystalized in a mixture of ethyl acetate and hexane (468 mg; 84% yield). Surprisingly, the espectroscopical data for the isolated product indicated the absence of methylene as well as the chlorine atom. A methyl group was observed in these analysis. These data correspond with the data reported for oxazolone 2 as the sole product of the reaction.