Theoretical evaluation of ADMET properties for coumarin derivatives as compounds with therapeutic potential

Coumarins have received a considerable attention in the last three decades as the lead structures for the discovery of orally administrated chemotherapeutics. Despite of the large amounts of in vitro activity information, relatively a little is known about their bioavailability in vivo. This paper presents an evaluation of drug-likeness of 31 coumarin derivatives on the basis of Lipinski's rule of five, and computed ADMET parameters (adsorption, distribution, metabolism, elimination and toxicity). Nine compounds which were predicted as showing the cardiotoxicity, were examined as hERG K⁺ channel blockers using in silico approach. Additionally, an impact of the acetyl group at benzene ring on pharmacokinetic profile was scrutinized for the tested coumarin derivatives. None of the analyzed coumarins violated the Lipinski's rule of five for orally administered drugs, and all tested compounds will remain in the qualitative likelihood of crossing the blood-brain barrier. 7-O-Alkilaminocoumarins showed no hepatotoxicity, but introduction of the nitrile or the amidine groups increased the levels of the hepatoxicity markers. Computed parameters of toxicity revealed cardiotoxic potency of twenty-five tested compounds. The proposed hERG K⁺ channel binding simulations helped in the understanding the molecular basis of coumarins cardiotoxicity. The presented theoretical studies explained some aspects of coumarin pharmacokinetics and identified the positive effect of the acetoxy substituent on the tested parameters.