Evaluation of phenylethylamine type entactogens and their metabolites relevant to ecotoxicology – a QSAR study

The impact of the selected entactogens and their o-quinone metabolites on the environment was explored in QSAR studies by the use of predicted molecular descriptors, ADMET properties and environmental toxicity parameters, i.e., acute toxicity in Tetrahymena pyriformis (TOX_ATTP) expressed as Th_pyr_pIGC₅₀/mmol L⁻¹, acute toxicity in Pimephales promelas, the fathead minnow (TOX_FHM) expressed as Minnow LC₅₀/mg L⁻¹, the acute toxicity in Daphnia magna (TOX_DM) expressed as Daphnia LC₅₀/mg L⁻¹ and bioconcentration factor (BCF).

The formation of corresponding o-quinones via benzo-dioxo-lone ring, O-demethylenation was predicted as the main metabolic pathway for all entactogens except for 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propan-2-amine (DiFMDA). The least favourable ADMET profile was revealed for N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-O-methylhydroxylamine (MDMEO).

QSAR studies revealed significant linear correlations between MlogP of entactogens and MlogP of o-quinone metabolites (R = 0.99), and Th_pyr_pIGC₅₀/mmol L⁻¹ (R = 0.94), also their MlogPs with Minnow_LC₅₀/mg L⁻¹ (R = 0.80 and R = 0.78), BCF (R = 0.86 and R = 0.82) and percentage of o-quinones’ yields (R = 0.73 and R = 0.80). Entactogens were predicted as non-biodegradable molecules, whereas the majority of their o-quinones were biodegradable.