{"doi":"10.1002/cmdc.202200058","title":"Design, Synthesis and X‐Ray Structural Studies of Potent HIV‐1 Protease Inhibitors Containing C‐4 Substituted Tricyclic Hexahydro‐Furofuran Derivatives as P2 Ligands","abstract":"The design, synthesis, X-ray structural, and biological evaluation of a series of highly potent HIV-1 protease inhibitors are reported herein. These inhibitors incorporate novel cyclohexane-fused tricyclic bis-tetrahydrofuran as P2 ligands in combination with a variety of P1 and P2' ligands. The inhibitor with a difluoromethylphenyl P1 ligand and a cyclopropylaminobenzothiazole P2' ligand exhibited the most potent antiviral activity. Also, it maintained potent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The corresponding inhibitor with an enantiomeric ligand was significantly less potent in these antiviral assays. The new P2 ligands were synthesized in optically active form using enzymatic desymmetrization of meso-diols as the key step. To obtain molecular insight, two high-resolution X-ray structures of inhibitor-bound HIV-1 protease were determined and structural analyses have been highlighted.","journal":"ChemMedChem","year":2022,"id":278496,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":755218,"name":"Satish Kovela","orcid":null,"position":2,"is_corresponding":false},{"id":951059,"name":"Ashish Sharma","orcid":"0000-0003-1428-3542","position":3,"is_corresponding":false},{"id":234710,"name":"Dana Shahabi","orcid":null,"position":4,"is_corresponding":false},{"id":951549,"name":"Ajay K. Ghosh","orcid":null,"position":5,"is_corresponding":false},{"id":951550,"name":"Denver R. Hopkins","orcid":null,"position":7,"is_corresponding":false},{"id":728878,"name":"Monika Yadav","orcid":"0000-0003-3772-2317","position":8,"is_corresponding":false},{"id":951060,"name":"Megan Johnson","orcid":"0000-0002-5968-9469","position":9,"is_corresponding":false},{"id":951061,"name":"Johnson Agniswamy","orcid":"0000-0002-3053-5677","position":10,"is_corresponding":false},{"id":639356,"name":"Yuan‐Fang Wang","orcid":null,"position":11,"is_corresponding":false},{"id":137994,"name":"Shin-ichiro Hattori","orcid":null,"position":12,"is_corresponding":false},{"id":495658,"name":"Nobuyo Higashi‐Kuwata","orcid":"0000-0002-9404-3532","position":13,"is_corresponding":false},{"id":295830,"name":"Manabu Aoki","orcid":"0000-0001-7089-831X","position":14,"is_corresponding":false},{"id":651046,"name":"Masayuki Amano","orcid":"0000-0003-0516-9502","position":15,"is_corresponding":false},{"id":484834,"name":"Irene T. Weber","orcid":"0000-0003-4876-7393","position":16,"is_corresponding":false},{"id":295833,"name":"Hiroaki Mitsuya","orcid":"0000-0001-9274-3853","position":17,"is_corresponding":false},{"id":233704,"name":"Arun K. Ghosh","orcid":"0000-0003-2472-1841","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T00:28:47.357993Z","pmid":"35170223","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}