Síntese, atividades biológicas e estudo in silico frente ao COVID-19 dos ácidos deoxicólico, quenodeoxicólico e seus derivados

Abstract

Bile acids (ABs) are amphipathic molecules with 24 carbon atoms that consist of a rigid hydrophobic steroid core with a hydroxyl group at the C-3 carbon and an attached flexible aliphatic acid side chain. In the present work, deoxycholic and chenodeoxycholic bile acids are highlighted, which have additional hydroxyl groups at carbons C-12 and C-7, respectively. Chemical modifications carried out in the hydroxyl groups at carbons C-3, C-7, C-12 and in the carboxyl group (C-24) of the respective bile acids allowed the production of twenty-nine semi-synthetic derivatives, being twenty derivatives of deoxycholic acid and nine of chenodeoxycholic acid, of which thirteen are unpublished in the literature and for six, 13C NMR data are being described for the first time. All derivatives obtained were characterized by IR spectroscopic methods, 1H NMR, 13C-BB NMR, 13C-DEPT 135° NMR or JMOD and, spectrometrically, UPLC-QTOF-MS. All were submitted to the qualitative assay for inhibition of the enzyme acetylcholinesterase, in which the compounds ADC-16, ADC-17, AQDC, AQDC-1 and AQDC-2 were the ones that obtained the best results with values of inhibition halos close or higher (9-11 mm) to the standard Eserine salt (10 mm). They were also submitted to the cytotoxicity test, and nine showed a satisfactory antiproliferative effect, especially the ADC-5 product with an IC50 value of 19.98 µM. Additionally, a computational study involving molecular docking, physicochemical/ drugability parameters and molecular dynamics was carried out. In this, the AQDC-3 compound showed good bioaffinity (binding affinity) receptor-ligand (S glycoprotein-derived) and good drugability result, showing a promising ligand in the search for bioactive compounds for the treatment of COVID-19.