Diketoacid HIV-1 integrase inhibitors: an ab initio study

The stable tautomeric forms of two representative arene-substituted diketoacid HIV-1 integrase inhibitors, 5-ClTEP and L-731,988, were investigated by B3LYP with 6-31G*, 6-31G(d,p), and 6-31+G(d,p) basis sets. Optimization with MP2/6-31G* was also performed for 5-ClTEP. The solvation effect was considered using a conductor-like screening model. With the density functional theory method, the trans diketo conformations are more stable than the cis conformers. The difference is 14 kJ mol-1 for 5-ClTEP and 33 kJ mol-1 for L-731,988. Two trans diketo structures were obtained. The difference between these two trans diketo structures is less than 4 kJ mol-1 calculated at the B3LYP/6-311+G(3df,2p) level. Two enol forms prevail over the diketo tautomers and are calculated to have the same free energy. Because there is no barrier observed between these two enol forms, they can interchange easily such that a delocalized transition state is suggested to be the observed form. Contradictory to the results of the MP2 method that predicts a preference for the trans diketo forms, the B3LYP method predicts a preference for the enol tautomers, which is in agreement with the experimental results.