Discovery of novel sulfonamide substituted indolylarylsulfones as potent HIV-1 inhibitors with better safety profiles.
- Author:
Shenghua GAO
1
;
Letian SONG
1
;
Yusen CHENG
1
;
Fabao ZHAO
1
;
Dongwei KANG
1
;
Shu SONG
1
;
Mianling YANG
1
;
Bing YE
1
;
Wei ZHAO
2
;
Yajie TANG
2
;
Erik DE CLERCQ
3
;
Christophe PANNECOUQUE
3
;
Peng ZHAN
1
;
Xinyong LIU
1
Author Information
- Publication Type:Journal Article
- Keywords: Cytotoxicity; HIV-1; Indolylarylsulfone; NNRTIs; Sulfonamide
- From: Acta Pharmaceutica Sinica B 2023;13(6):2747-2764
- CountryChina
- Language:English
- Abstract: 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 activities. Especially, compound R10L4 was endowed with significant inhibitory activity towards wild-type HIV-1 (EC50(WT) = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC50 = 0.017 μmol/L, SI = 13,055), E138K (EC50 = 0.017 μmol/L, SI = 13,123) and Y181C (EC50 = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R10L4 was characterized with significantly reduced cytotoxicity (CC50 = 216.51 μmol/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 insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.
