We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs. Among these, IAS 12 exhibited a remarkable antiviral activity against single and double mutants (K103N EC50 = <0.7 nM; Y181C EC50 = <0.7 nM; Y188L EC50 = 21.3 nM; K103N–Y181C EC50 = 6.2 nM), resulting equally or more active than previuosly reported IAS 6 and some approved anti-HIV-1 drugs. Docking and molecular dynamics simulations of compound 12 in complex with WT, Y181C, Y188L, K103N and K103N–Y181C RTs clarified a general binding mode that was consistent with biological results. Kinetic experiments disclosed that derivative 12 preferentially binds WT and K103N–Y181C RTs to binary and ternary complexes, respectively. Display omitted •We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs.•IAS 12 exhibited a remarkable antiviral activity against K103N–Y181C mutant strain.•Binding mode of IAS 12 was consistent with biological data.•IAS 12 was able to bind K103N–Y181C RT to ternary complex.