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We identified compounds\n            <jats:bold>5i3<\/jats:bold>\n            and\n            <jats:bold>5e2<\/jats:bold>\n            , with robust antiviral efficacy against wild-type HIV-1 and rilpivirine-resistant strains. Encouragingly, in vitro selection of mutant strains with\n            <jats:bold>5i3<\/jats:bold>\n            took 39 passages to select resistance, with no phenotypic cross-resistance observed with known RT drugs. Co-crystal structures of wild-type and mutant RT with\n            <jats:bold>5i3<\/jats:bold>\n            and\n            <jats:bold>5e2<\/jats:bold>\n            revealed their resilience toward resistance mutations due to enhanced conformational flexibility and positional adaptability.\n            <jats:bold>5i3<\/jats:bold>\n            exhibited good pharmacokinetic properties and favorable safety profiles, without substantial cytochrome P450 inhibition, and excellent oral bioavailability. 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