First-Principles Prediction of the pkas of Anti-inflammatory Oxicams

The gas- and aqueous-phase acidities or a series of oxicams have been computed by combining M05-2X/6-311+G(3df.2p) gas-phase free energies with solvation free energies from the CPCM-UAKS, COSMO-RS, and SMD solvent models. To facilitate accurate gas-phase calculations, a benchmarking study was further earned out to assess the performance of various density functional theory methods against the high-level composite method G3MP2(+). Oxicams are typically diprotic acids, and several tautomcis ale possible in each protonation state The direct thermodynamic cycle and the proton exchange scheme have been employed to compute the microscopic pk(a)s on both solution- and gas-phase equilibrium conformers, and these were combined to yield the macroscopic pK(a) values. Using the direct cycle of pK(a) calculation. the CPCM-UAKS model delivered. reasonably accurate results with MAD similar to I, whereas the SMD and COSMO-RS models performance was less satisfactory with MAD similar to 3. Comparison with experiment also indicates dial direct cycle calculations based on solution conformers generally deliver better accuracy The pinion exchange cycle al fouls further improvement for all solvent models through systematic calor cancellation and therefore provides better reliability lot the pK(a) prediction of compounds of these types The latter approach has been applied to pi edict the pK(a)s of several recently synthesized OX cam derivatives