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Keywords:

  • Chemoavailability;
  • Computational chemistry;
  • Bioorganic chemistry;
  • Michael acceptor;
  • Carbonyl ester;
  • Michael addition;
  • Transition state;
  • Reaction barrier;
  • Aquatic toxicity

Abstract

For a Michael-acceptor set of 45 α,β-unsaturated esters, the 2nd-order rate constant of reaction with glutathione, log kGSH, was modeled through the quantum chemical reaction barrier (ΔE) employing methane thiol as model nucleophile. Regression of their 48-h toxicity toward the ciliates Tetrahymena pyriformis (log EC50, 50 % growth inhibition) on log Kow (octanol/water partition coefficient) and log kGSH revealed a variation in the relative weights of hydrophobicity and electrophilic reactivity as determinants of the aquatic toxicity. The difference DKk=log Kow−log kGSH turned out as a suitable means for predictively discriminating between narcosis-level (DKk>3.0) and excess-toxic (DKk<2.0) compounds. In the intermediate DKk range (2.0≤DKk≤3.0), both narcosis-level and reactive-toxicity models are applicable for predicting aquatic toxicity. As such, DKk represents the chemoavailability of Michael-acceptor esters, characterizing their likelihood for undertaking covalent reactions with thiol sites of endogenous peptides and proteins. At the same time, DKk introduces a straightforward way for characterizing the applicability domain of QSAR (quantitative structure-activity relationship) models for predicting the toxicity of Michael-acceptor esters. The resultant model suite comprising QSARs for reactive toxicity and baseline narcosis is triggered by the compounds’ chemoavailability, and yields predictions superior to existing approaches.