Design, synthesis and evaluation of novel HIV-1 NNRTIs with dual structural conformations targeting the entrance channel of the NNRTI binding pocket

• Published in: European journal of medicinal chemistry Vol. 115; pp. 53 - 62
• Main Authors: Meng, Qing, Chen, Xuwang, Kang, Dongwei, Huang, Boshi, Li, Wenxin, Zhan, Peng, Daelemans, Dirk, De Clercq, Erik, Pannecouque, Christophe, Liu, Xinyong
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 10.06.2016; Elsevier
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Binding Sites - drug effects; Chemistry, Medicinal; DAPY derivatives; Dose-Response Relationship, Drug; Drug Design; Dual structural conformations; Entrance channel; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 NNRTIs; Humans; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Molecular Structure; Pharmacology & Pharmacy; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; SARs; Science & Technology; Structure-Activity Relationship; Virus Replication - drug effects; DAPY derivatives; SARs; Entrance channel; HIV-1 NNRTIs; Dual structural conformations; MOLECULAR HYBRIDIZATION; COLORIMETRIC ASSAY; DRUG DESIGN; CRYSTAL-STRUCTURES; BROAD POTENCY; DISCOVERY; REVERSE-TRANSCRIPTASE INHIBITORS; INDOLYL ARYL SULFONES; RESISTANT MUTANT VIRUSES; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.02.068

On the basis of structure-based bioisosteric replacement and molecular hybridization strategy, a series of novel dual structural-conformation inhibitors targeting the “entrance channel” of HIV-1 NNRTIs binding pocket (NNIBP) were designed and synthesized. All of the new compounds were evaluated for their anti-HIV activities in MT-4 cells using the MTT method. Five compounds exhibited moderate to excellent potencies inhibiting wild-type (wt) HIV-1 replication with EC50 values ranging from 31.36 μM to 0.11 μM. Among them, compound 15b was identified as the most potent inhibitor with EC50 values of 0.11 μM and 2.18 μM against wt and K103N/Y181C double mutant HIV-1 strain (RES056), respectively. In addition, preliminary structure–activity relationships (SARs) and molecular simulation studies were discussed, which may provide valuable insights for further optimization. A series of novel DAPY derivatives with dual structural conformations targeting the entrance channel of the NNRTI binding pocket were identified as inhibitors of wild-type and double mutant HIV-1 strains. [Display omitted] •Novel DAPY derivatives were HIV-1 inhibitors with dual structural conformations.•These compounds were designed to target the entrance channel of the NNIBP.•15b was the most promising inhibitor against wt and double mutant HIV-1 strains.•Preliminary SARs and molecular simulation of these new analogs were detailed.