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-<i>d</i>]pyrimidine derivatives were designed and synthesized. Compound <b>9a</b> yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than <b>ETR</b> against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of <b>9a</b> 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 <b>9a</b>^res strain. Furthermore, <b>9a</b> was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, <b>9a</b> exhibited optimal pharmacokinetic properties in rats (<i>F</i> = 37.06%) and safety in mice (LD₅₀ > 2000 mg/kg), which highlights <b>9a</b> as a promising anti-HIV-1 drug candidate.