Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.

The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-]pyrimidine derivatives were designed and synthesized. Compound yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant strain. Furthermore, was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, exhibited optimal pharmacokinetic properties in rats ( = 37.06%) and safety in mice (LD > 2000 mg/kg), which highlights as a promising anti-HIV-1 drug candidate.