Targeting the aryl hydrocarbon receptor with a novel set of triarylmethanes

Abstract

The aryl hydrocarbon receptor (AhR) is a chemical sensor upregulating the transcription of responsive genes associated with endocrine homeostasis, oxidative balance and diverse metabolic, immunological and inflammatory processes, which have raised the pharmacological interest on its modulation. Herein, a novel set of 32 unsymmetrical triarylmethane (TAM) class of structures has been synthesized, characterized and their AhR transcriptional activity evaluated using a cell-based assay. Eight of the assayed TAM compounds (14, 15, 18, 19, 21, 22, 25, 28) exhibited AhR agonism but none of them showed antagonist effects. TAMs bearing benzotrifluoride, naphthol or heteroaromatic (indole, quinoline or thiophene) rings seem to be prone to AhR activation unlike phenyl substituted or benzotriazole derivatives. A molecular docking analysis with the AhR ligand binding domain (LBD) showed similarities in the binding mode and in the interactions of the most potent TAM identified 4-(pyridin-2-yl (thiophen-2-yl)methyl)phenol (22) compared to the endogenous AhR agonist 5,11-dihydroindolo[3,2-b]carbazole-12-carbaldehyde (FICZ). Finally, in silico predictions of physicochemical and biopharmaceutical properties for the most potent agonistic compounds were performed and these exhibited acceptable druglikeness and good ADME profiles. To our knowledge, this is the first study assessing the AhR modulatory effects of unsymmetrical TAM class of compounds.