Bioisosterism-driven design of orally active, safe, and broad-spectrum biphenyl-DAPY derivatives as highly potent HIV-1 non-nucleoside reverse transcriptase inhibitors.
10.1016/j.apsb.2025.06.016
- Author:
Xiao-Mei CHEN
1
;
Qing-Qing HAO
1
;
Christophe PANNECOUQUE
2
;
Erik DE CLERCQ
2
;
Shuai WANG
3
;
Fen-Er CHEN
1
Author Information
1. Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
2. Rega Institute for Medical Research, KU Leuven, Herestraat 49, Leuven B-3000, Belgium.
3. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
- Publication Type:Journal Article
- Keywords:
AIDS;
Anti-resistance potency;
Bioisosterism;
Diarylpyrimidines;
HIV-1;
NNRTIs;
Oral bioavailability;
Safety
- From:
Acta Pharmaceutica Sinica B
2025;15(8):4115-4136
- CountryChina
- Language:English
-
Abstract:
This study aimed to identify ideal pharmaceutical candidates featuring strong anti-HIV-1 activity and desirable drug-like characteristics. Our endeavor involved the implementation of a bioisosterism strategy, leading to the discovery of an assemblage of halogen-containing biphenyl-diarylpyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Notably, compound A12 demonstrated exceptional efficacy against both WT HIV-1 (EC50 = 1.9 nmol/L) and seven mutant strains (EC50 = 1.7-157 nmol/L), surpassing that of the lead compound 6 and comparable to etravirine. Furthermore, this analog exhibited minimal adverse effects with significantly reduced cytotoxicity (CC50 = 195 μmol/L) and a high selectivity index (SI = 102,608), superior to those of etravirine (CC50 > 4.6 μmol/L, SI > 1436) and rilpivirine (CC50 = 3.98 μmol/L, SI = 3989). It displayed low inhibition of CYP (IC50 = 6.99-25 μmol/L) and hERG (IC50 > 40 μmol/L), indicating a safer profile compared to etravirine and rilpivirine. No acute toxicity or organ pathological damage was observed at a single dose of 2 g/kg. Additionally, A12 exhibited favorable oral bioavailability (F = 29.2%) and an extended elimination half-life (T 1/2 = 13.56 h), enabling convenient oral administration at minimal doses. These findings indicated that A12 could serve as a promising drug candidate for HIV treatment.
