{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T01:14:59Z","timestamp":1788052499296,"version":"build-2784847793"},"reference-count":36,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/100009108","name":"Shandong University","doi-asserted-by":"publisher","award":["SDZZ-ZR-202501359"],"award-info":[{"award-number":["SDZZ-ZR-202501359"]}],"id":[{"id":"10.13039\/100009108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009108","name":"Shandong University","doi-asserted-by":"publisher","award":["2023YFE0206500"],"award-info":[{"award-number":["2023YFE0206500"]}],"id":[{"id":"10.13039\/100009108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009108","name":"Shandong University","doi-asserted-by":"publisher","award":["82373727"],"award-info":[{"award-number":["82373727"]}],"id":[{"id":"10.13039\/100009108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009108","name":"Shandong University","doi-asserted-by":"publisher","award":["82273773"],"award-info":[{"award-number":["82273773"]}],"id":[{"id":"10.13039\/100009108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People's Republic of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Medicinal Chemistry"],"published-print":{"date-parts":[[2026,11]]},"DOI":"10.1016\/j.ejmech.2026.119193","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T15:06:27Z","timestamp":1785510387000},"page":"119193","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"special_numbering":"C","title":["Rational design of dual-site NNRTIs based on 2,4,5-trisubstituted pyrimidine scaffold for potent inhibition of resistant HIV-1"],"prefix":"10.1016","volume":"318","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5580-4722","authenticated-orcid":false,"given":"Xiangkai","family":"Ji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyi","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2985-8890","authenticated-orcid":false,"given":"Erik","family":"De Clercq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Pannecouque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongwei","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ejmech.2026.119193_bib1","article-title":"Twice-yearly lenacapavir demonstrated exceptional efficacy for HIV prevention","volume":"5","author":"Xu","year":"2024","journal-title":"Innovation"},{"key":"10.1016\/j.ejmech.2026.119193_bib2","article-title":"Stem cell research finds possible HIV cure with cord blood transplant","volume":"3","author":"Marley","year":"2022","journal-title":"Innovation"},{"key":"10.1016\/j.ejmech.2026.119193_bib3","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0140-6736(18)31311-4","article-title":"HIV","volume":"392","author":"Ghosn","year":"2018","journal-title":"Lancet"},{"key":"10.1016\/j.ejmech.2026.119193_bib4","doi-asserted-by":"crossref","DOI":"10.1016\/j.cclet.2022.07.006","article-title":"Linker optimization of HEPT derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors: from S=O to CHOR","volume":"34","author":"Hao","year":"2023","journal-title":"Chin. Chem. Lett."},{"key":"10.1016\/j.ejmech.2026.119193_bib5","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1126\/science.1206399","article-title":"AIDS. Turning the tide against HIV","volume":"333","author":"Shattock","year":"2011","journal-title":"Science"},{"key":"10.1016\/j.ejmech.2026.119193_bib6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1056\/NEJMp1916753","article-title":"Four decades of HIV\/AIDS - much accomplished, much to Do","volume":"383","author":"Fauci","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.ejmech.2026.119193_bib7","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/med.22080","article-title":"Deciphering the enigmas of non-nucleoside reverse transcriptase inhibitors (NNRTIs): a medicinal chemistry expedition towards combating HIV drug resistance","volume":"45","author":"Zhang","year":"2025","journal-title":"Med. Res. Rev."},{"key":"10.1016\/j.ejmech.2026.119193_bib8","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.cclet.2019.11.020","article-title":"Fragment-based discovery of sulfur-containing diarylbenzopyrimidines as novel nonnucleoside reverse transcriptase inhibitors","volume":"31","author":"Han","year":"2020","journal-title":"Chin. Chem. Lett."},{"key":"10.1016\/j.ejmech.2026.119193_bib9","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.apsb.2019.09.007","article-title":"Improving the positional adaptability: structure-based design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors","volume":"10","author":"Jin","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"10.1016\/j.ejmech.2026.119193_bib10","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2023.115114","article-title":"Hybrids of delavirdine and piperdin-4-yl-aminopyrimidines (DPAPYs) as potent HIV-1 NNRTIs: design, synthesis and biological activities","volume":"248","author":"Ming","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib11","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1021\/acs.jmedchem.1c01676","article-title":"Discovery of novel Pyridine-Dimethyl-Phenyl-DAPY hybrids by molecular fusing of Methyl-Pyrimidine-DAPYs and Difluoro-Pyridinyl-DAPYs: improving the druggability toward high inhibitory activity, solubility, safety, and PK","volume":"65","author":"Ding","year":"2022","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib12","doi-asserted-by":"crossref","first-page":"8564","DOI":"10.1021\/acs.jmedchem.5c00202","article-title":"Deuteration strategy-inspired design of novel diarylpyrimidine derivatives as potent non-nucleoside reverse transcriptase inhibitors featuring improved efficacy, selectivity, and druggability","volume":"68","author":"Zhang","year":"2025","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib13","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1016\/j.apsb.2021.11.009","article-title":"Approved HIV reverse transcriptase inhibitors in the past decade","volume":"12","author":"Li","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"10.1016\/j.ejmech.2026.119193_bib14","doi-asserted-by":"crossref","DOI":"10.1016\/j.pscia.2025.100079","article-title":"Artificial neural network guided optimization of tenofovir and Cyanovirin-N multipurpose preventive hydrogel formulation developed using the box behnken design model","volume":"3","author":"Oyediran","year":"2025","journal-title":"Pharmaceutical Science Advances"},{"key":"10.1016\/j.ejmech.2026.119193_bib15","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1016\/j.apsb.2022.08.017","article-title":"Development of fluorine-substituted NH(2)-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors: boosting the safety and metabolic stability","volume":"13","author":"Jin","year":"2023","journal-title":"Acta Pharm. Sin. B"},{"key":"10.1016\/j.ejmech.2026.119193_bib16","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2025.117271","article-title":"Structure-based discovery of novel diarylpyrimidines as potent and selective non-nucleoside reverse transcriptase inhibitors: from CH(CN)-Biphenyl-Diarylpyrimidines to CNNH(2)-Biphenyl-Diarylpyrimidines","volume":"285","author":"Chen","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib17","doi-asserted-by":"crossref","first-page":"19889","DOI":"10.1021\/acs.jmedchem.4c02413","article-title":"Expanding the solvent\/protein region occupation of the non-nucleoside reverse transcriptase inhibitor binding pocket for improved broad-spectrum Anti-HIV-1 efficacy: from rigid phenyl-diarylpyrimidines to flexible hydrophilic piperidine-diarylpyrimidines","volume":"67","author":"Huang","year":"2024","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib18","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2021.113450","article-title":"Design and evaluation of novel piperidine HIV-1 protease inhibitors with potency against DRV-resistant variants","volume":"220","author":"Zhu","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib19","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1016\/j.cclet.2020.09.035","article-title":"Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors","volume":"32","author":"Li","year":"2021","journal-title":"Chin. Chem. Lett."},{"key":"10.1016\/j.ejmech.2026.119193_bib20","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2020.113051","article-title":"Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp(3) values and favorable drug-like properties","volume":"213","author":"Jiang","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib21","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2023.115605","article-title":"Discovery of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles as potent HIV-1 NNRTIs with improved anti-resistance and drug-like profiles","volume":"258","author":"Jiang","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib22","doi-asserted-by":"crossref","DOI":"10.1016\/j.pscia.2025.100094","article-title":"Conquering viral drug resistance: structural and mechanistic paradigms for antiresistance drug design","volume":"3","author":"Wang","year":"2025","journal-title":"Pharmaceutical Science Advances"},{"key":"10.1016\/j.ejmech.2026.119193_bib23","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1021\/acs.jmedchem.5b00497","article-title":"Anti-HIV drug discovery and development: current innovations and future trends","volume":"59","author":"Zhan","year":"2016","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib24","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.apsb.2019.11.010","article-title":"Development of non-nucleoside reverse transcriptase inhibitors (NNRTIs): our past twenty years","volume":"10","author":"Zhuang","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"10.1016\/j.ejmech.2026.119193_bib25","doi-asserted-by":"crossref","first-page":"2738","DOI":"10.1021\/jm301271j","article-title":"Detecting allosteric sites of HIV-1 reverse transcriptase by X-ray crystallographic fragment screening","volume":"56","author":"Bauman","year":"2013","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib26","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2020.113063","article-title":"Design, synthesis, and evaluation of \"dual-site\"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase","volume":"211","author":"Feng","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib27","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/(SICI)1098-1128(200003)20:2<129::AID-MED2>3.0.CO;2-A","article-title":"The HIV-1 reverse transcription (RT) process as target for RT inhibitors","volume":"20","author":"Jonckheere","year":"2000","journal-title":"Med. Res. Rev."},{"key":"10.1016\/j.ejmech.2026.119193_bib28","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.1021\/acs.jmedchem.1c00268","article-title":"2,4,5-Trisubstituted pyrimidines as potent HIV-1 NNRTIs: rational design, synthesis, activity evaluation, and crystallographic studies","volume":"64","author":"Kang","year":"2021","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib29","doi-asserted-by":"crossref","DOI":"10.1016\/j.cclet.2023.108827","article-title":"Design, synthesis, and biological evaluation of benzo[4,5]thieno[2,3-d]pyrimidine derivatives as novel HIV-1 NNRTIs","volume":"35","author":"Meng","year":"2024","journal-title":"Chin. Chem. Lett."},{"key":"10.1016\/j.ejmech.2026.119193_bib30","doi-asserted-by":"crossref","first-page":"11430","DOI":"10.1021\/acs.jmedchem.9b01446","article-title":"Ligand-based design of Nondimethylphenyl-Diarylpyrimidines with improved metabolic stability, safety, and oral pharmacokinetic profiles","volume":"62","author":"Sang","year":"2019","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib31","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2022.115045","article-title":"Identification of \"dual-site\"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase","volume":"247","author":"Feng","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119193_bib32","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/nprot.2007.517","article-title":"Tetrazolium-based colorimetric assay for the detection of HIV replication inhibitors: revisited 20 years later","volume":"3","author":"Pannecouque","year":"2008","journal-title":"Nat. Protoc."},{"key":"10.1016\/j.ejmech.2026.119193_bib33","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/S0026-895X(24)12873-8","article-title":"Chimeric human immunodeficiency virus type 1 and feline immunodeficiency virus reverse transcriptases: role of the subunits in resistance\/sensitivity to non-nucleoside reverse transcriptase inhibitors","volume":"61","author":"Auwerx","year":"2002","journal-title":"Mol. Pharmacol."},{"key":"10.1016\/j.ejmech.2026.119193_bib34","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1006\/abio.1997.2177","article-title":"Characterization of PicoGreen reagent and development of a fluorescence-based solution assay for double-stranded DNA quantitation","volume":"249","author":"Singer","year":"1997","journal-title":"Anal. Biochem."},{"key":"10.1016\/j.ejmech.2026.119193_bib35","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.36340","article-title":"Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors","volume":"7","author":"Yang","year":"2018","journal-title":"eLife"},{"key":"10.1016\/j.ejmech.2026.119193_bib36","doi-asserted-by":"crossref","first-page":"4295","DOI":"10.1021\/jm1002233","article-title":"Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278): implications for drug design","volume":"53","author":"Lansdon","year":"2010","journal-title":"J. Med. Chem."}],"container-title":["European Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523426006380?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523426006380?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:23:49Z","timestamp":1788049429000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0223523426006380"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,11]]},"references-count":36,"alternative-id":["S0223523426006380"],"URL":"https:\/\/doi.org\/10.1016\/j.ejmech.2026.119193","relation":{},"ISSN":["0223-5234"],"issn-type":[{"value":"0223-5234","type":"print"}],"subject":[],"published":{"date-parts":[[2026,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Rational design of dual-site NNRTIs based on 2,4,5-trisubstituted pyrimidine scaffold for potent inhibition of resistant HIV-1","name":"articletitle","label":"Article Title"},{"value":"European Journal of Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejmech.2026.119193","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"119193"}}