Síntese de novos derivados Ácido (Z)-2-benzamido-3-fenilacrílicos planejados como Inibidores da Fosfodiesterase 4 para o tratamento da asma e COPD

Abstract

Asthma and Chronic Obstructive Pulmonary Disease (COPD) are chronic inflammatory diseases with varying levels of airflow obstruction. Recognition of the critical role of inflammation in the process has been directed the treatment axis for the prevention or blockage of inflammatory changes. For this purpose new drugs have been studied and among them the specific inhibitors of phosphodiesterase 4 (PDE4) have presented promising results due to the control of cAMP levels, which are implicated in smooth, inflammatory and immune muscle cells. This work aimed to synthesize new (Z)- 2-benzamide-3-phenylacrylic acids designed as PDE4 inhibitors (iPDE4), based on pharmacophores present in cilomilast and roflumilast, and to evaluate the inhibitory activity of the synthesized compounds in a theoretical enzymatic model of PDE4 molecular docking. The synthesis for obtaining the new acids goes through four steps. First, a series of succinimide derivatives, which are obtained from the reaction of a substituted benzoic acid with an N-hydroxysuccinimide, DCC in THF at room temperature for 20 h (93-79%). Second, hippuric acid derivatives were produced from the the reaction of succinimide intermediates of the previous step with glycine in basics environment (76-66%). Third, preparation of azalactones following an Erlemmeyer Ploch methodology where the derivatives of hippuric acid, substituted benzaldehydes, sodium acetate are reacted at 120 °C in acetic anhydride (59-49%). Finally, the hydrolysis of azalactones with sodium hydroxide in acetonitrile at room temperature led to the desired acids (96-92%). Molecular docking studies were performed in the GOLD program with the catalytic site of PDE4D (PDB 1XOR) defined around 10.0 Å from tyrosine 159. Redocking was done in order to chose the best base and to validate the model. The best results were obtained with the PLP basis. The acid compounds (1-7) were minimized using Spartan Pro 14.0 software (PM6) and the docking studies were done providing the scores (72,45 - 78,06). Despite the high score values it was make a visual analysis of the interaction poses between ligand and bioreceptor. The main conformers showed the main expected interactions of PDE4 inhibitors: hydrogen bonds of the dimethoxyphenyl groups with Gln369, π-stacking with Phe372 and hydrophilic interactions with the metal site. The synthetic route for obtaining (Z)-2-benzamido-3- phenylacrylic acid was viable and presented good yields, through stable reaction intermediates. Molecular docking studies with the final products presented a theoretical inhibition profile for PDE4 very similar to the inhibitors already described in the literature. The compounds are now under evaluation of theirs PDE4 inhibitory profiles