A comparative study of the molecular structure, lipophilicity, solubility, acidity, absorption and polar surface area of coumarinic anticoagulants and direct thrombin inhibitors

Abstract

The methods of computational chemistry have been used to elucidate the molecular properties of coumarinic anticoagulants (acenocoumarol, phenprocoumon, warfarin and tecarfarin) and direct thrombin inhibitors (melagatran, dabigatran and their prodrug forms, ximelagatran and dabigatran etexilate). The geometries and energies of these drugs have been computed at the Becke3LYP/6-311++G(d,p) level of theory. In the case of the vitamin K antagonists (acenocoumarol, phenprocoumon, warfarin and tecarfarin), the most stable tautomer in both the gas-phase and water solution is tautomer A, which contains the 4-hydroxycoumarin moiety. The R(+)-enantiomer of this tautomer is the most stable structure in warfarin and acetocoumarol. For phenprocoumon, the S(−)-enantiomer was the most stable species. The computed dissociation constants show that these drugs are almost completely ionized at physiological pH = 7.4. Tecarfarin is the vitamin K antagonist with the highest lipophilicity. The prodrugs ximelagatran and dabigatran etexilate are described as lipophilic drugs. The prodrugs' metabolites, melagatran and dabigatran, are substantially less lipophilic. The relatively high polar surface area value of acenocoumarol (113.3) results in lessened absorption in comparison with warfarin. Phenprocoumon, with PSA value 50.4, had the highest calculated absorption of all of the anticoagulants in the study. The direct thrombin inhibitors, melagatran and dabigatran, have a high total number of proton donor and proton acceptor groups (15), a high PSA (150) and the lowest absorption of the drugs studied.