Discovery of novel indolylarylsulfones as potent HIV-1 NNRTIs via structure-guided scaffold morphing.

Abstract

For more in-depth exploration of the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing different chiral N-substituted pyrrolidine, azetidine or substituted sulfonamide groups at indole-2-carboxamide were designed and synthesized as potent HIV NNRTIs by structure-guided scaffold morphing approach. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC50 values ranging from 0.0043\u202fμM to 4.42\u202fμM. Notably, compound 27 (EC50\u202f=\u202f4.7\u202fnM, SI\u202f=\u202f5183) and 33 (EC50\u202f=\u202f4.3\u202fnM, SI\u202f=\u202f7083) were identified as the most potent compounds, which were more active than nevirapine, lamivudine and efavirenz, and also reached the same order of etravirine. Furthermore, some compounds maintained excellent activity against various single HIV-1 mutants (L100I, K103\u202fN, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC50 values in low-micromolar concentration ranges. Notably, 34 displayed outstanding potency against F227L/V106A (EC50\u202f=\u202f0.094\u202fμM), and also showed exceptional activity against E138K (EC50\u202f=\u202f0.014\u202fμM), L100I (EC50\u202f=\u202f0.011\u202fμM) and K103\u202fN (EC50\u202f=\u202f0.025\u202fμM). Additionally, most compounds showed markedly reduced cytotoxicity (CC50) compared to lead compounds, especially 36 (CC50\u202f>\u202f234.91\u202fμM, SI\u202f>\u202f18727) and 37 (CC50\u202f>\u202f252.49\u202fμM, SI\u202f>\u202f15152). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization.