{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:52:08Z","timestamp":1787161928515,"version":"build-2736575974"},"reference-count":73,"publisher":"American Chemical Society (ACS)","issue":"5","license":[{"start":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T00:00:00Z","timestamp":1570665600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T00:00:00Z","timestamp":1570665600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T00:00:00Z","timestamp":1570665600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai","doi-asserted-by":"publisher","award":["13ZR1402200"],"award-info":[{"award-number":["13ZR1402200"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010097","name":"China Association for Science and Technology","doi-asserted-by":"publisher","award":["2017QNRC061"],"award-info":[{"award-number":["2017QNRC061"]}],"id":[{"id":"10.13039\/100010097","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["21372050"],"award-info":[{"award-number":["21372050"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Molecular hybridization is a powerful strategy in drug discovery. A series of novel diarylbenzopyrimidine (DABP) analogues were developed by the hybridization of FDA-approved drugs etravirine (ETR) and efavirenz (EFV) as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Substituent modifications resulted in the identification of new DABPs with the combination of the strengths of the two drugs, especially compound 12d, which showed promising activity toward the EFV-resistant K103N mutant. 12d also had a favorable pharmacokinetic (PK) profile with liver microsome clearances of 14.4 \u03bcL\/min\/mg (human) and 33.2 \u03bcL\/min\/mg (rat) and an oral bioavailability of 15.5% in rat. However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment. Further optimizations resulted in a highly potent compound (12z) with no substituents on the phenyl ring and a 2-methyl-6-nitro substitution pattern on the 4-cyanovinyl-2,6-disubstitued phenyl motif. The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased. In particular, this compound exhibited acceptable intrinsic liver microsome stability (human, 34.5 \u03bcL\/min\/mg; rat, 33.2 \u03bcL\/min\/mg) and maintained the good PK profile of its parent compound EFV and showed an oral bioavailability of 16.5% in rat. Molecular docking and structure\u2013activity relationship (SAR) analysis provided further insights into the binding of the DABPs with HIV-1 reverse transcriptase and provided a deeper understanding of the key structural features responsible for their interactions.<\/jats:p>","DOI":"10.1021\/acsinfecdis.9b00229","type":"journal-article","created":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T14:38:16Z","timestamp":1570718296000},"page":"787-801","source":"Crossref","is-referenced-by-count":35,"title":["Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines\nas HIV\u20111 Nonnucleoside Reverse Transcriptase Inhibitors with\nImproved Activity against K103N and E138K Mutants and Pharmacokinetic\nProfiles"],"prefix":"10.1021","volume":"6","author":[{"given":"Sheng","family":"Han","sequence":"first","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]},{"name":"Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Sang","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]},{"name":"Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wu","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]},{"name":"Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Tao","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]},{"name":"Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Pannecouque","sequence":"additional","affiliation":[{"name":"KU Leuven , , Herestraat 49 , ,","place":["Leuven, Belgium, B-3000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"De Clercq","sequence":"additional","affiliation":[{"name":"KU Leuven , , Herestraat 49 , ,","place":["Leuven, Belgium, B-3000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0569-5708","authenticated-orcid":true,"given":"Chunlin","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]},{"name":"Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6734-3388","authenticated-orcid":true,"given":"Fen-Er","family":"Chen","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]},{"name":"Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs , ,","place":["Shanghai, People\u2019s Republic of China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2019,10,10]]},"reference":[{"key":"2026081806123859500_cit1","unstructured":"WHO\n          . (last accessed July 19, 2018) HIV\/AIDS\nfact sheet, http:\/\/www.who.int\/en\/news-room\/fact-sheets\/detail\/hiv-aids."},{"key":"2026081806123859500_cit2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S1075-8593(03)04001-2","article-title":"New Anti-HIV Agents in Preclinical or Clinical Development","volume":"4","author":"De\nClercq","year":"2003","journal-title":"Adv. Antiviral Drug Des."},{"key":"2026081806123859500_cit3","doi-asserted-by":"publisher","first-page":"7991","DOI":"10.1021\/acs.jmedchem.6b00738","article-title":"Design, Synthesis,\nand Evaluation of Thiophene\u00ad[3,2-d]\u00adpyrimidine Derivatives as HIV-1\nNon-nucleoside Reverse Transcriptase Inhibitors with Significantly\nImproved Drug Resistance Profiles","volume":"59","author":"Kang","year":"2016","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit4","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1126\/science.1206399","article-title":"Turning the tide\nagainst HIV","volume":"333","author":"Shattock","year":"2011","journal-title":"Science"},{"key":"2026081806123859500_cit5","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.antiviral.2009.10.007","article-title":"Current status and\nchallenges of antiretroviral research\nand therapy","volume":"85","author":"Este","year":"2010","journal-title":"Antiviral Res."},{"key":"2026081806123859500_cit6","doi-asserted-by":"publisher","first-page":"2849","DOI":"10.1021\/acs.jmedchem.5b00497","article-title":"Anti-HIV Drug Discovery\nand Development: Current Innovations and Future Trends","volume":"59","author":"Zhan","year":"2016","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit7","doi-asserted-by":"publisher","first-page":"4851","DOI":"10.1021\/acs.jmedchem.8b00843","article-title":"The journey\nof HIV-1 non-nucleoside\nreverse transcriptase inhibitors (NNRTIs) from lab to clinic","volume":"62","author":"Namasivayam","year":"2019","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit8","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1345\/aph.1M359","article-title":"Nonnucleoside\nreverse transcriptase inhibitor resistance and the role of the second-generation\nagents","volume":"44","author":"Adams","year":"2010","journal-title":"Ann. Pharmacother."},{"issue":"2","key":"2026081806123859500_cit9","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1021\/acs.jmedchem.8b01238","article-title":"Effect of \u03b1-Methoxy\nSubstitution on the anti-HIV Activity of Dihydropyrimidin-4\u00ad(3H)-ones","volume":"62","author":"Nawrozkij","year":"2019","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit10","doi-asserted-by":"publisher","first-page":"263","DOI":"10.3390\/v8100263","article-title":"Mechanistic Study\nof Common Non-Nucleoside Reverse Transcriptase Inhibitor-Resistant\nMutations with K103N and Y181C Substitutions","volume":"8","author":"Lai","year":"2016","journal-title":"Viruses"},{"key":"2026081806123859500_cit11","doi-asserted-by":"publisher","first-page":"6016","DOI":"10.1021\/ja034308c","article-title":"Validation of a model for the complex\nof HIV-1 reverse transcriptase with nonnucleoside inhibitor TMC125","volume":"125","author":"Udier-Blagovic","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"2026081806123859500_cit12","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/S0140-6736(11)60983-5","article-title":"Rilpivirine versus\nefavirenz with two background nucleoside or nucleotide reverse transcriptase\ninhibitors in treatment-naive adults infected with HIV-1 (THRIVE):\na phase 3, randomised, non-inferiority trial","volume":"378","author":"Cohen","year":"2011","journal-title":"Lancet"},{"key":"2026081806123859500_cit13","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1046\/j.1432-1327.2002.02811.x","article-title":"Structural basis for the inhibitory efficacy of efavirenz (DMP-266),\nMSC194 and PNU142721 towards the HIV-1 RT K103N mutant","volume":"269","author":"Lindberg","year":"2002","journal-title":"Eur. J. Biochem."},{"key":"2026081806123859500_cit14","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1016\/S0969-2126(00)00513-X","article-title":"Structural basis\nfor the resilience of efavirenz (DMP-266)\nto drug resistance mutations in HIV-1 reverse transcriptase","volume":"8","author":"Ren","year":"2000","journal-title":"Structure"},{"key":"2026081806123859500_cit15","doi-asserted-by":"publisher","first-page":"4295","DOI":"10.1021\/jm1002233","article-title":"Crystal structures\nof HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine\n(TMC278): implications for drug design","volume":"53","author":"Lansdon","year":"2010","journal-title":"J. Med.\nChem."},{"key":"2026081806123859500_cit16","doi-asserted-by":"publisher","first-page":"2550","DOI":"10.1021\/jm030558s","article-title":"Roles of conformational and positional adaptability\nin structure-based design of TMC125-R165335 (etravirine) and related\nnon-nucleoside reverse transcriptase inhibitors that are highly potent\nand effective against wild-type and drug-resistant HIV-1 variants","volume":"47","author":"Das","year":"2004","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit17","doi-asserted-by":"publisher","first-page":"2235","DOI":"10.1016\/S0960-894X(01)00412-7","article-title":"Evolution of anti-HIV drug candidates.\nPart 3: Diarylpyrimidine (DAPY) analogues","volume":"11","author":"Ludovici","year":"2001","journal-title":"Bioorg.\nMed. Chem. Lett."},{"key":"2026081806123859500_cit18","doi-asserted-by":"publisher","first-page":"174","DOI":"10.2174\/157340909789054685","article-title":"Recent Advances in NNRTI Design:\nComputer-Aided Molecular\nDesign Approaches","volume":"5","author":"Pungpo","year":"2009","journal-title":"Curr. Comput.-Aided Drug\nDes."},{"key":"2026081806123859500_cit19","doi-asserted-by":"publisher","first-page":"3091","DOI":"10.1021\/jm101626c","article-title":"Diarylpyrimidine-dihydrobenzyloxopyrimidine\nhybrids: new, wide-spectrum anti-HIV-1 agents active at (sub)-nanomolar\nlevel","volume":"54","author":"Rotili","year":"2011","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit20","doi-asserted-by":"publisher","first-page":"3100","DOI":"10.1128\/AAC.00348-13","article-title":"Effect of mutations\nat position E138 in HIV-1 reverse\ntranscriptase and their interactions with the M184I mutation on defining\npatterns of resistance to nonnucleoside reverse transcriptase inhibitors\nrilpivirine and etravirine","volume":"57","author":"Xu","year":"2013","journal-title":"Antimicrob. Agents\nChemother."},{"key":"2026081806123859500_cit21","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1128\/AAC.01192-10","article-title":"Characterization of the E138K resistance\nmutation in HIV-1 reverse transcriptase conferring susceptibility\nto etravirine in B and non-B HIV-1 subtypes","volume":"55","author":"Asahchop","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081806123859500_cit22","doi-asserted-by":"publisher","first-page":"3689","DOI":"10.1021\/acs.jmedchem.5b01827","article-title":"Novel HIV-1 Non-nucleoside Reverse\nTranscriptase Inhibitor Agents: Optimization of Diarylanilines with\nHigh Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant\nVirus","volume":"59","author":"Liu","year":"2016","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit23","doi-asserted-by":"publisher","first-page":"4681","DOI":"10.1128\/AAC.01029-13","article-title":"Basis for early\nand preferential selection of the E138K\nmutation in HIV-1 reverse transcriptase","volume":"57","author":"McCallum","year":"2013","journal-title":"Antimicrob.\nAgents Chemother."},{"key":"2026081806123859500_cit24","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/j.ejmech.2018.03.059","article-title":"Targeting\nthe entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted\n1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type\nand E138K mutant virus","volume":"151","author":"Tian","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"2026081806123859500_cit25","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1021\/acs.jmedchem.8b01656","article-title":"Identification of Dihydrofuro\u00ad[3,4-\nd]\u00adpyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase\nInhibitors with Promising Antiviral Activities and Desirable Physicochemical\nProperties","volume":"62","author":"Kang","year":"2019","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit26","doi-asserted-by":"publisher","first-page":"E36340","DOI":"10.7554\/eLife.36340","article-title":"Structural\nbasis for potent and broad inhibition of HIV-1 RT by thiophene\u00ad[3,2-d]\u00adpyrimidine\nnon-nucleoside inhibitors","volume":"7","author":"Yang","year":"2018","journal-title":"eLife"},{"key":"2026081806123859500_cit27","doi-asserted-by":"publisher","first-page":"1974","DOI":"10.1021\/jm049439i","article-title":"Concentration and pH\ndependent aggregation of hydrophobic drug molecules and relevance\nto oral bioavailability","volume":"48","author":"Frenkel","year":"2005","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit28","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1002\/jcph.107","article-title":"Impact\nof food and different meal types on the pharmacokinetics\nof rilpivirine","volume":"53","author":"Crauwels","year":"2013","journal-title":"J. Clin. Pharmacol."},{"key":"2026081806123859500_cit29","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1177\/135965350801300505","article-title":"Single- and multiple-dose pharmacokinetics\nof etravirine administered as two different formulations in HIV-1-infected\npatients","volume":"13","author":"Kakuda","year":"2008","journal-title":"Antivir Ther"},{"key":"2026081806123859500_cit30","unstructured":"European Medicines\nAgency\n          . (Last updated August 18, 2017) Intelence: European public assessment report - Product\nInformation, https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/intelence."},{"key":"2026081806123859500_cit31","doi-asserted-by":"publisher","first-page":"2083","DOI":"10.1021\/acs.jmedchem.8b01729","article-title":"Exploiting\nthe Tolerant Region I of the Non-Nucleoside Reverse Transcriptase\nInhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed\nHIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly\nImproved Water Solubility and Favorable Safety Profiles","volume":"62","author":"Huang","year":"2019","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit32","doi-asserted-by":"publisher","first-page":"46","DOI":"10.4172\/jbb.1000179","article-title":"Oral Liquid\nFormulation of Etravirine for Enhanced Bioavailability","volume":"06","author":"Liang","year":"2014","journal-title":"J. Bioequivalence Bioavailability"},{"key":"2026081806123859500_cit33","doi-asserted-by":"publisher","first-page":"5039","DOI":"10.1016\/j.bmc.2010.05.081","article-title":"Hybrid diarylbenzopyrimidine\nnon-nucleoside reverse transcriptase inhibitors as promising new leads\nfor improved anti-HIV-1 chemotherapy","volume":"18","author":"Zeng","year":"2010","journal-title":"Bioorg.\nMed. Chem."},{"key":"2026081806123859500_cit34","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.1021\/ja310965h","article-title":"Stabilization\nof ruthenium sensitizers to TiO2 surfaces through cooperative anchoring\ngroups","volume":"135","author":"Brown","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"2026081806123859500_cit35","doi-asserted-by":"publisher","first-page":"4858","DOI":"10.1021\/jm800546t","article-title":"Discovery\nof (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3\u00ad(4H)-yl)-N-(3-(7-methyl-1H-indazol-5\n-yl)-1-oxo-1-(4-(piperidin-1-yl)\u00adpiperidin-1-yl)\u00adpropan-2-yl)\u00adpiperidine-1-carboxami\nde (BMS-694153): a potent antagonist of the human calcitonin gene-related\npeptide receptor for migraine with rapid and efficient intranasal\nexposure","volume":"51","author":"Degnan","year":"2008","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit36","doi-asserted-by":"publisher","first-page":"2936","DOI":"10.1021\/ol2009939","article-title":"Iron-catalyzed\ncycloaddition of alkynenitriles\nand alkynes","volume":"13","author":"D\u2019Souza","year":"2011","journal-title":"Org. Lett."},{"key":"2026081806123859500_cit37","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1021\/op8000383","article-title":"Ligandless\nHeck Coupling between a Halogenated Aniline and Acrylonitrile Catalyzed\nby Pd\/C: Development and Optimization of an Industrial-Scale Heck\nProcess for the Production of a Pharmaceutical Intermediate","volume":"12","author":"Schils","year":"2008","journal-title":"Org. Process Res. Dev."},{"key":"2026081806123859500_cit38","doi-asserted-by":"publisher","first-page":"1854","DOI":"10.1021\/acs.jmedchem.5b01336","article-title":"2,6-Di\u00ad(arylamino)-3-fluoropyridine\nDerivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors","volume":"59","author":"Sergeyev","year":"2016","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit39","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1002\/cctc.201301037","article-title":"Palladium Nanoparticles Supported\non Nitrogen-Functionalized Active\nCarbon: A Stable and Highly Efficient Catalyst for the Selective Hydrogenation\nof Nitroarenes","volume":"6","author":"Li","year":"2014","journal-title":"ChemCatChem"},{"key":"2026081806123859500_cit40","doi-asserted-by":"publisher","first-page":"4149","DOI":"10.1021\/jo2003715","article-title":"Solvent-free\nor low-solvent large-scale preparation of chloropyrimidine and analogues","volume":"76","author":"Sun","year":"2011","journal-title":"J. Org. Chem."},{"key":"2026081806123859500_cit41","doi-asserted-by":"publisher","first-page":"12240","DOI":"10.1021\/ja902679b","article-title":"Influence of biaryl phosphine structure on C-N and\nC-C bond formation","volume":"131","author":"Pratap","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"2026081806123859500_cit42","doi-asserted-by":"publisher","first-page":"6372","DOI":"10.1002\/anie.200460782","article-title":"Pd-catalyzed\namination of nucleoside\narylsulfonates to yield N6-aryl-2,6-diaminopurine nucleosides","volume":"43","author":"Gunda","year":"2004","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026081806123859500_cit43","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1002\/cmdc.201200520","article-title":"Structure-activity\nrelationship study reveals ML240 and ML241 as potent and selective\ninhibitors of p97 ATPase","volume":"8","author":"Chou","year":"2013","journal-title":"ChemMedChem"},{"key":"2026081806123859500_cit44","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1016\/j.ejmech.2012.05.039","article-title":"Synthesis and biological\nevaluation of novel 2-(2-arylmethylene)\u00adhydrazinyl-4-aminoquinazoline\nderivatives as potent antitumor agents","volume":"54","author":"Jiang","year":"2012","journal-title":"Eur.\nJ. Med. Chem."},{"key":"2026081806123859500_cit45","doi-asserted-by":"publisher","first-page":"7855","DOI":"10.1021\/jm800876b","article-title":"Discovery of quinazolines as histamine H4 receptor inverse agonists\nusing a scaffold hopping approach","volume":"51","author":"Smits","year":"2008","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit46","doi-asserted-by":"publisher","first-page":"7955","DOI":"10.1021\/jm500744f","article-title":"Determinants of activity at human\nToll-like receptors\n7 and 8: quantitative structure-activity relationship (QSAR) of diverse\nheterocyclic scaffolds","volume":"57","author":"Yoo","year":"2014","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit47","doi-asserted-by":"publisher","first-page":"2763","DOI":"10.1021\/jm00014a027","article-title":"Reversible inhibitors\nof the gastric (H+\/K+)-ATPase. 5. Substituted 2,4-diaminoquinazolines\nand thienopyrimidines","volume":"38","author":"Ife","year":"1995","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit48","doi-asserted-by":"publisher","first-page":"3860","DOI":"10.1021\/jm9805900","article-title":"Substituted\nisoquinolines and quinazolines\nas potential antiinflammatory agents. Synthesis and biological evaluation\nof inhibitors of tumor necrosis factor alpha","volume":"42","author":"Chao","year":"1999","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit49","doi-asserted-by":"publisher","first-page":"8315","DOI":"10.1021\/acs.jmedchem.5b00258","article-title":"Applications\nof Fluorine in Medicinal Chemistry","volume":"58","author":"Gillis","year":"2015","journal-title":"J. Med.\nChem."},{"issue":"6","key":"2026081806123859500_cit50","doi-asserted-by":"publisher","first-page":"2851","DOI":"10.1021\/acs.jmedchem.8b00147","article-title":"Nitro-Group-Containing Drugs","volume":"62","author":"Nepali","year":"2019","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit51","doi-asserted-by":"publisher","first-page":"7952","DOI":"10.1021\/acs.jmedchem.8b01011","article-title":"2,4,6-Substituted Quinazolines\nwith Extraordinary Inhibitory Potency toward ABCG2","volume":"61","author":"Krapf","year":"2018","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit52","doi-asserted-by":"publisher","first-page":"5449","DOI":"10.1021\/acs.jmedchem.6b00330","article-title":"Synthesis and Biological Evaluation\nof 4-Anilino-quinazolines and\n-quinolines as Inhibitors of Breast Cancer Resistance Protein (ABCG2)","volume":"59","author":"Krapf","year":"2016","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit53","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1039\/C7OB02828H","article-title":"Discovery\nof novel diarylpyrimidines as potent HIV-1 NNRTIs by investigating\nthe chemical space of a less explored \u201chydrophobic channel","volume":"16","author":"Zhou","year":"2018","journal-title":"Org. Biomol. Chem."},{"key":"2026081806123859500_cit54","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1016\/0006-2952(94)90520-7","article-title":"Utility\nof in vitro drug metabolism data in predicting in vivo metabolic clearance","volume":"47","author":"Houston","year":"1994","journal-title":"Biochem. Pharmacol."},{"key":"2026081806123859500_cit55","doi-asserted-by":"publisher","first-page":"2602","DOI":"10.1128\/AAC.39.12.2602","article-title":"L-743, 726 (DMP-266):\na novel, highly potent\nnonnucleoside inhibitor of the human immunodeficiency virus type 1\nreverse transcriptase","volume":"39","author":"Young","year":"1995","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081806123859500_cit56","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1038\/nprot.2011.330","article-title":"A time-of-drug\naddition approach to target identification of antiviral compounds","volume":"6","author":"Daelemans","year":"2011","journal-title":"Nat. Protoc."},{"key":"2026081806123859500_cit57","doi-asserted-by":"publisher","first-page":"4642","DOI":"10.1021\/jm0703690","article-title":"Use of\ndensity functional calculations to predict the regioselectivity of\ndrugs and molecules metabolized by aldehyde oxidase","volume":"50","author":"Torres","year":"2007","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit58","doi-asserted-by":"publisher","first-page":"1466","DOI":"10.1073\/pnas.0711209105","article-title":"High-resolution\nstructures of HIV-1 reverse transcriptase\/TMC278 complexes: strategic\nflexibility explains potency against resistance mutations","volume":"105","author":"Das","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081806123859500_cit59","doi-asserted-by":"publisher","first-page":"213","DOI":"10.3851\/IMP1607","article-title":"Looking for\nan active conformation of the future HIV type-1 non-nucleoside reverse\ntranscriptase inhibitors","volume":"20","author":"La\nRegina","year":"2010","journal-title":"Antivir Chem. Chemother"},{"key":"2026081806123859500_cit60","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.molliq.2017.09.050","article-title":"Structural\nanalysis, solvent effects and intramolecular\ninteractions in rilpivirine: A new non-nucleoside reverse transcriptase\ninhibitor for HIV treatment","volume":"246","author":"Mirhaji","year":"2017","journal-title":"J. Mol. Liq."},{"key":"2026081806123859500_cit61","doi-asserted-by":"publisher","first-page":"7547","DOI":"10.1021\/jm2008453","article-title":"Introduction\nof an electron withdrawing group on the\nhydroxyphenylnaphthol scaffold improves the potency of 17beta-hydroxysteroid\ndehydrogenase type 2 (17beta-HSD2) inhibitors","volume":"54","author":"Wetzel","year":"2011","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit62","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/nprot.2007.517","article-title":"Tetrazolium-based colorimetric assay\nfor the detection of HIV replication inhibitors: revisited 20 years\nlater","volume":"3","author":"Pannecouque","year":"2008","journal-title":"Nat. Protoc."},{"key":"2026081806123859500_cit63","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/0166-0934(88)90134-6","article-title":"Rapid and\nautomated tetrazolium-based colorimetric assay for the detection of\nanti-HIV compounds","volume":"20","author":"Pauwels","year":"1988","journal-title":"J. Virol. Methods"},{"key":"2026081806123859500_cit64","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1006\/viro.1993.1027","article-title":"HIV-1-specific\nreverse transcriptase inhibitors show\ndifferential activity against HIV-1 mutant strains containing different\namino acid substitutions in the reverse transcriptase","volume":"192","author":"Balzarini","year":"1993","journal-title":"Virology"},{"key":"2026081806123859500_cit65","doi-asserted-by":"crossref","first-page":"5353","DOI":"10.1128\/jvi.67.9.5353-5359.1993","article-title":"Treatment of human immunodeficiency virus type 1 (HIV-1)-infected\ncells with combinations of HIV-1-specific inhibitors results in a\ndifferent resistance pattern than does treatment with single-drug\ntherapy","volume":"67","author":"Balzarini","year":"1993","journal-title":"J. Virol"},{"key":"2026081806123859500_cit66","doi-asserted-by":"publisher","first-page":"6952","DOI":"10.1073\/pnas.90.15.6952","article-title":"Human immunodeficiency\nvirus type 1 (HIV-1) strains selected for resistance against the HIV-1-specific\n[2\u2032,5\u2032-bis-O-(tert-butyldimethylsilyl)-3\u2032-spiro-\n5\u2032\u2019-(4\u2032\u2019-amino-1\u2032\u2019,2\u2032\u2019-oxathiole-2\u2032\u2019,2\u2032\u2019-dioxide)]-beta-D-pentofurano\nsyl (TSAO) nucleoside analogues retain sensitivity to HIV-1-specific\nnonnucleoside inhibitors","volume":"90","author":"Balzarini","year":"1993","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"key":"2026081806123859500_cit67","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1124\/mol.61.2.400","article-title":"Chimeric human immunodeficiency virus type 1 and feline\nimmunodeficiency virus reverse transcriptases: role of the subunits\nin resistance\/sensitivity to non-nucleoside reverse transcriptase\ninhibitors","volume":"61","author":"Auwerx","year":"2002","journal-title":"Mol. Pharmacol."},{"key":"2026081806123859500_cit68","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1006\/abio.1997.2177","article-title":"Characterization\nof PicoGreen reagent and development of a fluorescence-based solution\nassay for double-stranded DNA quantitation","volume":"249","author":"Singer","year":"1997","journal-title":"Anal. Biochem."},{"issue":"5","key":"2026081806123859500_cit69","doi-asserted-by":"publisher","first-page":"2276","DOI":"10.1021\/acschemneuro.8b00605","article-title":"Neuroprotective Effect\nof Swertiamain on Cerebral Ischemia\/Reperfusion Injury by Inducing\nthe Nrf2 Protective Pathway","volume":"10","author":"Wang","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"2026081806123859500_cit70","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1021\/jm4017174","article-title":"Rapid identification\nof Keap1-Nrf2 small-molecule inhibitors through structure-based virtual\nscreening and hit-based substructure search","volume":"57","author":"Zhuang","year":"2014","journal-title":"J. Med. Chem."},{"key":"2026081806123859500_cit71","unstructured":"Schro\u0308dinger\n           (2017) Desmond Molecular\nDynamics System for Academic, Schro\u0308dinger, New York, NY."},{"key":"2026081806123859500_cit72","doi-asserted-by":"publisher","first-page":"111603","DOI":"10.1016\/j.ejmech.2019.111603","article-title":"Conformational\nrestriction design of thiophene-biphenyl-DAPY HIV-1 non-nucleoside\nreverse transcriptase inhibitors","volume":"182","author":"Sang","year":"2019","journal-title":"Eur. J. Med.\nChem."},{"key":"2026081806123859500_cit73","doi-asserted-by":"publisher","first-page":"10830","DOI":"10.18632\/oncotarget.2521","article-title":"A novel drug discovery\nstrategy: mechanistic investigation of an\nenantiomeric antitumor agent targeting dual p53 and NF-kappaB pathways","volume":"5","author":"Zhuang","year":"2014","journal-title":"Oncotarget"}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.9b00229","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/5\/787\/12729151\/id9b00229.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/5\/787\/12729151\/id9b00229.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T10:54:42Z","timestamp":1787050482000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/6\/5\/787\/1292930\/Molecular-Hybridization-Inspired-Optimization-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,10]]},"references-count":73,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,10,10]]},"published-print":{"date-parts":[[2020,5,8]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.9b00229","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,10]]}}}