{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T18:50:46Z","timestamp":1781981446053,"version":"3.54.5"},"reference-count":21,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22077018"],"award-info":[{"award-number":["22077018"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Bioorganic Chemistry"],"published-print":{"date-parts":[[2023,11]]},"DOI":"10.1016\/j.bioorg.2023.106783","type":"journal-article","created":{"date-parts":[[2023,8,12]],"date-time":"2023-08-12T16:32:20Z","timestamp":1691857940000},"page":"106783","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":5,"special_numbering":"C","title":["Development of novel HEPT analogs featuring significantly improved anti-resistance potency against HIV-1 through chemical space exploration of the tolerant region I"],"prefix":"10.1016","volume":"140","author":[{"given":"Ruo-Lan","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Pannecouque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"De Clercq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fen-Er","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.bioorg.2023.106783_b0005","unstructured":"https:\/\/www.unaids.org\/sites\/default\/files\/media_asset\/UNAIDS_FactSheet_en.pdf (Global HIV & AIDS statistics-Fact sheet accessed 2022)."},{"issue":"6","key":"10.1016\/j.bioorg.2023.106783_b0010","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.bioorg.2023.106783_b0015","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0140-6736(18)31311-4","volume":"392","author":"Ghosn","year":"2018","journal-title":"Lancet"},{"issue":"2","key":"10.1016\/j.bioorg.2023.106783_b0020","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0753-3322(99)80063-8","article-title":"Highly active antiretroviral therapy (Haart) for the treatment of infection with human immunodeficiency virus type 1","volume":"53","author":"Shafer","year":"1999","journal-title":"Biomed. Pharmacother."},{"key":"10.1016\/j.bioorg.2023.106783_b0025","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0885-3924(00)00245-1","article-title":"The use of highly active antiretroviral therapy (HAART) in patients with advanced HIV infection: impact on medical, palliative care, and quality of life outcomes","volume":"21","author":"Brechtl","year":"2001","journal-title":"J. Pain Symptom Manag."},{"issue":"10","key":"10.1016\/j.bioorg.2023.106783_b0030","doi-asserted-by":"crossref","first-page":"4851","DOI":"10.1021\/acs.jmedchem.8b00843","article-title":"The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic","volume":"62","author":"Namasivayam","year":"2019","journal-title":"J. Med. Chem."},{"issue":"5","key":"10.1016\/j.bioorg.2023.106783_b0035","doi-asserted-by":"crossref","first-page":"3729","DOI":"10.1021\/acs.jmedchem.1c01758","article-title":"Contemporary Medicinal Chemistry Strategies for the Discovery and Development of Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors","volume":"65","author":"Wang","year":"2022","journal-title":"J. Med. Chem."},{"issue":"3","key":"10.1016\/j.bioorg.2023.106783_b0040","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1021\/acs.jmedchem.2c01574","article-title":"Design and Synthesis of Novel HIV-1 NNRTIs with Bicyclic Cores and with Improved Physicochemical Properties","volume":"66","author":"Prener","year":"2023","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.bioorg.2023.106783_b0045","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1021\/acs.jmedchem.5b01827","article-title":"Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus","volume":"59","author":"Liu","year":"2016","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.bioorg.2023.106783_b0050","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1021\/acsmedchemlett.1c00505","article-title":"Lead Optimization: Synthesis and Biological Evaluation of PBT-1 Derivatives as Novel Antitumor Agents","volume":"12","author":"Xie","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"issue":"12","key":"10.1016\/j.bioorg.2023.106783_b0055","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1021\/jm960765a","article-title":"Synthesis and anti-HIV activity of novel N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)","volume":"40","author":"Pontikis","year":"1997","journal-title":"J. Med. Chem."},{"issue":"2","key":"10.1016\/j.bioorg.2023.106783_b0060","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ejmech.2006.09.018","article-title":"Synthesis and anti-HIV activity evaluation of 1-[(alkenyl or alkynyl or alkyloxy)methyl]-5-alkyl-6-(1-naphthoyl)-2,4-pyrimidinediones as novel non-nucleoside HIV-1 reverse transcriptase inhibitors","volume":"42","author":"Ji","year":"2007","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.bioorg.2023.106783_b0065","doi-asserted-by":"crossref","first-page":"114939","DOI":"10.1016\/j.ejmech.2022.114939","article-title":"Structure-guided design of novel HEPT analogs with enhanced potency and safety: From Isopropyl-HEPTs to Cyclopropyl-HEPTs","volume":"246","author":"Zhou","year":"2023","journal-title":"Eur. J. Med. Chem."},{"issue":"26","key":"10.1016\/j.bioorg.2023.106783_b0070","doi-asserted-by":"crossref","first-page":"5721","DOI":"10.1021\/jm020949r","article-title":"Synthesis of novel N-1 (allyloxymethyl) analogues of 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, emivirine) with improved activity against HIV-1 and its mutants","volume":"45","author":"El-Brollosy","year":"2002","journal-title":"J. Med. Chem."},{"issue":"22","key":"10.1016\/j.bioorg.2023.106783_b0075","doi-asserted-by":"crossref","first-page":"4500","DOI":"10.1021\/jm990192c","article-title":"Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants","volume":"42","author":"Hopkins","year":"1999","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.bioorg.2023.106783_b0080","doi-asserted-by":"crossref","first-page":"3545","DOI":"10.2174\/138161205774414510","article-title":"Why drugs fail\u2013a study on side effects in new chemical entities","volume":"11","author":"Schuster","year":"2005","journal-title":"Curr. Pharm. Design"},{"key":"10.1016\/j.bioorg.2023.106783_b0085","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2020.112290","article-title":"hERG toxicity assessment: Useful guidelines for drug design","volume":"195","author":"Garrido","year":"2020","journal-title":"Eur. J. Med. Chem."},{"issue":"7","key":"10.1016\/j.bioorg.2023.106783_b0090","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nrd.2015.34","article-title":"Evolution of strategies to improve preclinical cardiac safety testing","volume":"15","author":"Gintant","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"issue":"11","key":"10.1016\/j.bioorg.2023.106783_b0095","doi-asserted-by":"crossref","first-page":"3931","DOI":"10.1007\/s00204-020-02912-1","article-title":"CYP-associated drug-drug interactions: A mission accomplished?","volume":"94","author":"Pelkonen","year":"2020","journal-title":"Arch. Toxicol."},{"issue":"7","key":"10.1016\/j.bioorg.2023.106783_b0100","doi-asserted-by":"crossref","first-page":"4755","DOI":"10.1021\/acs.jmedchem.2c01900","article-title":"Fragment Hopping-Based Design of Novel Biphenyl-DAPY Derivatives as Potent Non-Nucleoside Reverse Transcriptase Inhibitors Featuring Significantly Improved Anti-Resistance Efficacy","volume":"66","author":"Sang","year":"2023","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.bioorg.2023.106783_b0105","series-title":"A Comprehensive Guide to Toxicology in Preclinical Drug Development","first-page":"87","article-title":"Chapter 5 - Acute, Sub-Acute, Sub-Chronic and Chronic General Toxicity Testing for Preclinical Drug Development","author":"Denny","year":"2013"}],"container-title":["Bioorganic Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0045206823004443?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0045206823004443?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T08:46:29Z","timestamp":1758617189000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0045206823004443"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11]]},"references-count":21,"alternative-id":["S0045206823004443"],"URL":"https:\/\/doi.org\/10.1016\/j.bioorg.2023.106783","relation":{},"ISSN":["0045-2068"],"issn-type":[{"value":"0045-2068","type":"print"}],"subject":[],"published":{"date-parts":[[2023,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Development of novel HEPT analogs featuring significantly improved anti-resistance potency against HIV-1 through chemical space exploration of the tolerant region I","name":"articletitle","label":"Article Title"},{"value":"Bioorganic Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bioorg.2023.106783","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2023 Elsevier Inc. All rights reserved.","name":"copyright","label":"Copyright"}],"article-number":"106783"}}