Síntese e avaliação de novos análogos aril-acilidrazônicos do canabidiol

Abstract

This work focused on the synthesis of rationally drug designed, inspired by the structure of canabidiol (CBD), with R and S-carvone as starting materials. Eight substances named PQM-242 to PQM-249, with novel structural pattern, were synthesized, characterized and evaluated by in silico and pharmacological models. The analysis of the scavenging activity of DPPH radicals showed their antioxidant properties similar to quercetin and ascorbic acid, especially for PQM-247 with IC50 of 4.76μM and a good metal chelating activity, especially for Zn2+. The in silico study suggested that PQM-244, PQM-245, PQM-248 and PQM-249 have adequate ability for overcoming the blood brain barrier, leading to better CNS activity, whereas molecular docking studies showed that the target-compounds have good affinities for cannabinoid receptors, especially for CB1, for which PQM-249 exhibited an affinity slightly greater than CBD. In vitro pharmacological evaluation showed that the target-substances are not cytotoxic, except for PQM-244 and PQM-247, which exhibited CC50 values of 2.92 and 7.95 μM, respectively. In the antidepressive-type models (forced swimming test and tail suspension test) and anxiolytic-type models (open field test and light-dark test), the substances did not show an anxiolytic effect. However, they have been shown to act as antidepressants in the dose of 100μM (10mg/kg for CBD), highlighting compound PQM-249 that showed antidepressant effect in both tests.