Discovery of novel sulfonamide substituted indolylarylsulfones as potent HIV-1 inhibitors with better safety profiles

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activ-ities. Especially, compound R10L4 was endowed with significant inhibitory activity towards wild-type HIV-1 (EC50(WT) = 0.007 & mu;mol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC50 = 0.017 & mu;mol/L, SI = 13,055), E138K (EC50 = 0.017 & mu;mol/L, SI = 13,123) and Y181C (EC50 = 0.045 & mu;mol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R10L4 was characterized with significantly reduced cytotoxicity (CC50 = 216.51 & mu;mol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R10L4 and HIV-1 RT. Additionally, R10L4 presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious in-sights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.& COPY; 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

The study found that Indolylarylsulfones (IASs) have potent antiviral activity against HIV-1 but high cytotoxicity. To address this issue, researchers synthesized a compound called R10L4 with reduced cytotoxicity and significant inhibitory activity against wild-type and mutant strains of HIV-1. The results suggest that R10L4 may be a promising non-nucleoside reverse transcriptase inhibitor.