Lead Optimization and Avoidance of Metabolic-perturbing Motif Developing Novel Diarylpyrimidines as Potent HIV-1 NNRTIs
- J Med Chem. 2022 Dec 8;65(23):15608-15626. doi: 10.1021/acs.jmedchem.2c00576.
- 1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, P.R. China.
- 2. Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium.
- 3. China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 250012 Jinan, P.R. China.
Non-nucleoside Reverse Transcriptase inhibitors (NNRTIs) represent an indispensable part of anti-HIV-1 therapy. To discover novel HIV-1 NNRTIs with increased drug resistance profiles and improved pharmacokinetic (PK) properties, a series of novel diarylpyrimidine derivatives were generated via the cocrystal structure-based drug design strategy. Among them, 36a exhibited outstanding Antiviral activity against HIV-1 IIIB and a panel of mutant strains (L100I, K103N, Y181C, Y188L, E138K, F227L + V106A, and RES056), with EC50 ranging from 2.22 to 53.3 nM. Besides, 36a was identified with higher binding affinity (KD = 2.50 μM) and inhibitory activity (IC50 = 0.03 μM) to HIV-1 RT. Molecular docking and molecular dynamics simulation were performed to rationalize the design and the improved drug resistance of these novel inhibitors. Additionally, 36a·HCl exhibited favorable PK (T1/2 = 5.12 h, F = 12.1%) and safety properties (LD50 > 2000 mg/kg). All these suggested that 36a·HCl may serve as a novel drug candidate anti-HIV-1 therapy.