{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:47:02Z","timestamp":1792784822531,"version":"4.5.0"},"reference-count":42,"publisher":"American Chemical Society (ACS)","issue":"37","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Science Committee, Ministry of Science and Higher Education of the Republic of Kazakhstan","award":["AP23488790"],"award-info":[{"award-number":["AP23488790"]}],"id":[{"id":"https:\/\/ror.org\/05tyne317","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Integrastatins and their biogenetic counterparts possess a rare heterotetracyclic framework containing an unprecedented [6\/6\/6\/6]-tetracyclic skeleton and a central [3\/3\/1]-bicyclic ketal core with high pharmaceutical potential, particularly due to their potent anti-HIV-1 integrase activity. Despite their promising scaffolds, a systematic consolidation of their chemistry and biology has been entirely lacking, creating a critical gap between the complex architecture of these natural polyketides and the targeted design of drug-like inhibitors. Herein, we present the first comprehensive review of this field, systematically analyzing 42 peer-reviewed publications from 1999 to 2025 retrieved from the Scopus, Web of Science, PubMed, and PubChem databases. Structural analysis confirms that while these rigid, nonplanar V-shaped molecules comply with Lipinski\u2019s Rule of Five as a baseline filter for drug-likeness, deeper ADMET profiling further highlights their high predicted human intestinal absorption (HIA) alongside a low risk of cardiotoxicity. Synthetically, we detail how the field has fundamentally evolved from an arduous 11-step sequence in 2003 to highly streamlined, atom-economical one-step protocols in 2008 and 2021, culminating in the 2025 total syntheses that successfully resolved long-standing structural misinterpretations of epicoccolide A and epicocconigrone A. Furthermore, a comparative assessment across eight critical synthetic parameters highlights the operational trade-offs between step efficiency, scalability, and functional group tolerance in current cascade cyclizations. Biologically, we evaluate the extensive in vitro and in silico profiling of over 30 synthetic derivatives, highlighting their antimicrobial (M. bovis, S. aureus, P. carotovorum, C. albicans), antitubercular, and antiviral (SARS-CoV-2 and HIV-1 integrase inhibition) potencies. Integrating pharmacophore mapping with in silico ADMET profiling demonstrates that despite favorable absorption and cardiac safety, predicted liabilities such as human hepatotoxicity, carcinogenicity, and skin sensitization highlight critical areas for targeted structural modification. Ultimately, by bridging synthetic methodology with in silico and experimental bioactivity evaluation, this review establishes epoxybenzooxocine-based heterocycles as viable early-stage lead platforms and outlines strategic directions to advance these scaffolds in targeted drug discovery.<\/jats:p>","DOI":"10.1021\/acsomega.6c06756","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T01:01:58Z","timestamp":1788915718000},"page":"54847-54869","source":"Crossref","is-referenced-by-count":0,"title":["The Epoxybenzooxocine\nCore of Integrastatins and Analogs:\nA Comprehensive Review of Structure, Synthetic Approaches, and Biological\nApplications"],"prefix":"10.1021","volume":"11","author":[{"given":"Aida S.","family":"Rakhimzhanova","sequence":"first","affiliation":[{"name":"Buketov Karaganda National Research University , , ,","place":["Karaganda, Kazakhstan, 100024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6319-666X","authenticated-orcid":true,"given":"Irina A.","family":"Pustolaikina","sequence":"additional","affiliation":[{"name":"Buketov Karaganda National Research University , , ,","place":["Karaganda, Kazakhstan, 100024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfiya F.","family":"Kurmanova","sequence":"additional","affiliation":[{"name":"Buketov Karaganda National Research University , , ,","place":["Karaganda, Kazakhstan, 100024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruslan A.","family":"Muzaparov","sequence":"additional","affiliation":[{"name":"Buketov Karaganda National Research University , , ,","place":["Karaganda, Kazakhstan, 100024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darya D.","family":"Kapishnikova","sequence":"additional","affiliation":[{"name":"Saint Petersburg State University , , ,","place":["Saint Petersburg, Russia, 198504"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena L.","family":"Stalinskaya","sequence":"additional","affiliation":[{"name":"Tyumen State University , , ,","place":["Tyumen, Russia, 625003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5772-2096","authenticated-orcid":true,"given":"Ivan V.","family":"Kulakov","sequence":"additional","affiliation":[{"name":"Buketov Karaganda National Research University , , ,","place":["Karaganda, Kazakhstan, 100024"]},{"name":"Tyumen State University , , ,","place":["Tyumen, Russia, 625003"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"issue":"2","key":"2026092211033171300_cit1","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.2529","article-title":"Pharmacological\nadvances in anti-retroviral\ntherapy for human immunodeficiency virus-1 infection: A comprehensive\nreview","volume":"34","author":"Azzman","year":"2024","journal-title":"Rev. Med. Virol."},{"issue":"16","key":"2026092211033171300_cit2","doi-asserted-by":"publisher","first-page":"7367","DOI":"10.1080\/07391102.2021.1901144","article-title":"Antiretroviral drug activity and potential for pre-exposure\nprophylaxis against COVID-19 and HIV infection","volume":"40","author":"Copertino","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"issue":"27","key":"2026092211033171300_cit3","doi-asserted-by":"publisher","first-page":"15775","DOI":"10.1039\/D0RA01899F","article-title":"Anti-HIV drug repurposing\nagainst SARS-CoV-2","volume":"10","author":"Sang","year":"2020","journal-title":"RSC Adv."},{"issue":"5","key":"2026092211033171300_cit4","doi-asserted-by":"publisher","first-page":"4963","DOI":"10.1007\/s11030-024-11068-4","article-title":"Structural\naspects of HIV-1 integrase inhibitors: SAR studies and synthetic strategies","volume":"29","author":"Barik","year":"2025","journal-title":"Mol. Diversity"},{"issue":"14","key":"2026092211033171300_cit5","doi-asserted-by":"publisher","first-page":"2491","DOI":"10.1007\/s00018-018-2772-5","article-title":"Cellular and molecular\nmechanisms of HIV-1 integration\ntargeting","volume":"75","author":"Engelman","year":"2018","journal-title":"Cell. Mol. 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Med.\nChem."},{"issue":"6","key":"2026092211033171300_cit9","doi-asserted-by":"publisher","first-page":"774","DOI":"10.3390\/biom15060774","article-title":"Exploring the Therapeutic\nPotential\nof Natural Compounds and Plant Extracts in Human Health","volume":"15","author":"Zeppa","year":"2025","journal-title":"Biomolecules"},{"issue":"1","key":"2026092211033171300_cit10","doi-asserted-by":"publisher","first-page":"327","DOI":"10.3390\/app16010327","article-title":"Plant-Derived Bioactive Compounds\nOne Health Perspective","volume":"16","author":"Gonc\u0327alves","year":"2026","journal-title":"Appl. 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Efficient Isolation, Structure Elucidation,\nand Inhibitory Activities of Isocomplestatin, Chloropeptin I, New\nComplestatins, A and B, and Acid-Hydrolysis Products of Chloropeptin\nI","volume":"64","author":"Singh","year":"2001","journal-title":"J. Nat. Prod."},{"issue":"13","key":"2026092211033171300_cit14","doi-asserted-by":"publisher","first-page":"2351","DOI":"10.1016\/S0040-4039(02)00265-4","article-title":"Integrastatins:\nstructure and HIV-1\nintegrase inhibitory activities of two novel racemic tetracyclic aromatic\nheterocycles produced by two fungal species","volume":"43","author":"Singh","year":"2002","journal-title":"Tetrahedron Lett."},{"issue":"3","key":"2026092211033171300_cit15","doi-asserted-by":"publisher","first-page":"0277","DOI":"10.1358\/dof.2005.030.03.885746","article-title":"Discovery of natural\nproduct inhibitors of HIV-1 integrase at Merck","volume":"30","author":"Singh","year":"2005","journal-title":"Drugs Of The Future"},{"issue":"10","key":"2026092211033171300_cit16","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.2174\/1568026043388394","article-title":"HIV-1 Integrase\nInhibitors: A Decade\nof Research and Two Drugs in Clinical Trial","volume":"4","author":"Johnson","year":"2004","journal-title":"Curr. Top. Med. Chem."},{"issue":"15","key":"2026092211033171300_cit17","doi-asserted-by":"publisher","first-page":"3174","DOI":"10.1002\/ejoc.201300146","article-title":"Epicoccolides:\nAntimicrobial and Antifungal Polyketides from an Endophytic Fungus\nEpicoccum sp. Associated with Theobroma cacao","volume":"2013","author":"Talontsi","year":"2013","journal-title":"Eur. J. Org. Chem."},{"issue":"1","key":"2026092211033171300_cit18","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1021\/np4005745","article-title":"Protein Kinase and HDAC Inhibitors from the Endophytic\nFungus Epicoccum nigrum","volume":"77","author":"El Amrani","year":"2014","journal-title":"J. Nat. Prod."},{"key":"2026092211033171300_cit19","unstructured":"National Center for Biotechnology Information.\n          \n          PubChem.\nCompound Summary for CID 10046792, Integrastatin A. Retrieved March\n23, 2026\n          https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Integrastatin-A."},{"key":"2026092211033171300_cit20","unstructured":"National Center for Biotechnology Information.\n          \n          PubChem.\nCompound Summary for CID 464001, Integrastatin B. Retrieved March\n23, 2026. https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Integrastatin-B."},{"key":"2026092211033171300_cit21","unstructured":"National Center for Biotechnology Information.\n          \n          PubChem.\nCompound Summary for CID 71732639, Epicoccolide A. Retrieved March\n25, 2026\n          https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Epicoccolide-A."},{"key":"2026092211033171300_cit22","unstructured":"National Center for Biotechnology Information.\n          \n          PubChem.\nCompound Summary for CID 73891099, Epicocconigrone A. Retrieved March\n26, 2026\n          https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Epicocconigrone-A."},{"issue":"12","key":"2026092211033171300_cit23","doi-asserted-by":"publisher","first-page":"3599","DOI":"10.1021\/ja00402a071","article-title":"The first\ngeneral index of molecular complexity","volume":"103","author":"Bertz","year":"1981","journal-title":"J. Am.\nChem. Soc."},{"issue":"D1","key":"2026092211033171300_cit24","doi-asserted-by":"publisher","first-page":"D1373","DOI":"10.1093\/nar\/gkac956","article-title":"PubChem 2023 update","volume":"51","author":"Kim","year":"2023","journal-title":"Nucleic Acids Res."},{"issue":"23","key":"2026092211033171300_cit25","doi-asserted-by":"publisher","first-page":"4441","DOI":"10.1021\/ol035786v","article-title":"Synthesis\nof the Integrastatin Nucleus\nUsing the Ramberg\u2013Ba\u0308cklund Reaction","volume":"5","author":"Foot","year":"2003","journal-title":"Org. Lett."},{"issue":"5","key":"2026092211033171300_cit26","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1039\/B418426B","article-title":"Unexpected Z-stereoselectivity\nin the Ramberg\u2013Ba\u0308cklund reaction of diarylsulfones leading\nto cis-stilbenes: the effect of aryl substituents and application\nin the synthesis of the integrastatin nucleus","volume":"3","author":"Foot","year":"2005","journal-title":"Org. Biomol. Chem."},{"key":"2026092211033171300_cit27","doi-asserted-by":"publisher","first-page":"3151","DOI":"10.1039\/b801755g","article-title":"An expeditious one-step entry to\nthe tetracyclic core of integrastatins","volume":"27","author":"Ramana","year":"2008","journal-title":"Chem.\nCommun."},{"issue":"15","key":"2026092211033171300_cit28","doi-asserted-by":"publisher","first-page":"5354","DOI":"10.1039\/c1ob05725a","article-title":"A rapid\nand convergent synthesis\nof the integrastatin core","volume":"9","author":"Tadross","year":"2011","journal-title":"Org. Biomol. Chem."},{"issue":"6","key":"2026092211033171300_cit29","doi-asserted-by":"publisher","first-page":"1458","DOI":"10.1021\/acs.orglett.6b00404","article-title":"Total Synthesis\nof Integrastatin B Enabled by a Benzofuran\nOxidative Dearomatization Cascade","volume":"18","author":"More","year":"2016","journal-title":"Org. Lett."},{"issue":"3","key":"2026092211033171300_cit30","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1021\/acs.orglett.5b03707","article-title":"o-Quinone Methides via Oxone-Mediated Benzofuran Oxidative\nDearomatization and Their Intramolecular Cycloaddition with Carbonyl\nGroups: An Expeditious Construction of the Central Tetracyclic Core\nof Integrastatins, Epicoccolide A, and Epicocconigrone A","volume":"18","author":"More","year":"2016","journal-title":"Org. Lett."},{"issue":"18","key":"2026092211033171300_cit31","doi-asserted-by":"publisher","first-page":"11935","DOI":"10.1021\/acs.joc.9b01796","article-title":"Synthesis of the\nTetracyclic Cores\nof the Integrastatins, Epicoccolide A and Epicocconigrone A","volume":"84","author":"Jeong","year":"2019","journal-title":"J. Org. Chem."},{"issue":"8","key":"2026092211033171300_cit32","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1246\/bcsj.20200070","article-title":"Improved and\nPractical Synthesis of the Integrastatin Core","volume":"93","author":"Yamagiwa","year":"2020","journal-title":"Bull. Chem. Soc. Jpn."},{"issue":"7","key":"2026092211033171300_cit33","doi-asserted-by":"publisher","first-page":"3559","DOI":"10.1039\/D0NJ06117D","article-title":"Synthesis of new\nrepresentatives of 11,12-dihydro-5H-5,11-epoxybenzo[7,8]oxocino[4,3-b]pyridines\n\u2013 structural analogues ofintegrastatins A, B","volume":"45","author":"Kulakov","year":"2021","journal-title":"New J. Chem."},{"issue":"5","key":"2026092211033171300_cit34","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1134\/S107036322205022X","article-title":"Cyclization Reaction\nof 3,5-Diacetyl-2,6-dimethylpyridine with Salicylic Aldehyde and Its\nDerivatives: Quantum-Chemical Study and Molecular Docking","volume":"92","author":"Stalinskaya","year":"2022","journal-title":"Russ. J. Gen. Chem."},{"issue":"4 (116)","key":"2026092211033171300_cit35","doi-asserted-by":"publisher","first-page":"44","DOI":"10.31489\/2959-0663\/4-24-13","article-title":"A Series of Novel\nIntegrastatins Analogues: In silico\nStudy of Physicochemical and Bioactivity Parameters","volume":"29","author":"Rakhimzhanova","year":"2024","journal-title":"Eurasian J. Chem."},{"issue":"2","key":"2026092211033171300_cit36","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1055\/s-0042-1751521","article-title":"Synthesis of New Structural Analogues of Natural Integrastatins\nwith a Basic Epoxybenzo[7,8]oxocine Skeleton: Combined Experimental\nand Computational Study","volume":"56","author":"Kulakov","year":"2024","journal-title":"Synthesis"},{"issue":"15","key":"2026092211033171300_cit37","doi-asserted-by":"publisher","first-page":"1799","DOI":"10.1055\/a-2239-6657","article-title":"Synthesis of a New\nHeterocyclic System: Pyrimidine Structural Analogues of Natural Integrastatins\nA B","volume":"35","author":"Chikunov","year":"2024","journal-title":"Synlett"},{"issue":"24","key":"2026092211033171300_cit38","doi-asserted-by":"publisher","first-page":"6539","DOI":"10.1021\/acs.orglett.5c02032","article-title":"Total Synthesis of Epicoccolides\nA and B by Oxidative Skeleton Rearrangement Leads to a Structural\nRevision and Questions the Proposed Biosynthesis","volume":"27","author":"Treiber","year":"2025","journal-title":"Org. Lett."},{"issue":"12","key":"2026092211033171300_cit39","doi-asserted-by":"publisher","first-page":"3701","DOI":"10.3390\/molecules27123701","article-title":"Synthesis and Antiviral Properties\nagainst SARS-CoV-2\nof Epoxybenzooxocino[4,3-b]Pyridine Derivatives","volume":"27","author":"Stalinskaya","year":"2022","journal-title":"Molecules"},{"key":"2026092211033171300_cit40","doi-asserted-by":"publisher","first-page":"134689","DOI":"10.1016\/j.molstruc.2022.134689","article-title":"Synthesis\nand bacteriostatic properties of epoxybenzooxocino[4,3-b]pyridine\nderivatives","volume":"1275","author":"Stalinskaya","year":"2023","journal-title":"J. Mol. Struct."},{"issue":"1\u20132","key":"2026092211033171300_cit41","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s10593-024-03291-6","article-title":"The synthesis and\nantitubercular activity of 4,5-dihydro-1H-pyrazole derivatives with\na basic epoxybenzo[7,8]oxocine framework","volume":"60","author":"Stalinskaya","year":"2024","journal-title":"Chem.\nHeterocycl. Compd."},{"key":"2026092211033171300_cit42","doi-asserted-by":"publisher","first-page":"143346","DOI":"10.1016\/j.molstruc.2025.143346","article-title":"Synthesis,\ncharacterization, and computational study of s-methylthio- and n-methylamine\nsubstituted epoxybenzo[7,8]oxocyno[4,3-b]pyridine derivatives","volume":"1348","author":"Stalinskaya","year":"2025","journal-title":"J. Mol. Struct."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c06756","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/37\/54847\/68453594\/acsomega.6c06756.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/37\/54847\/68453594\/acsomega.6c06756.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:03:22Z","timestamp":1790093002000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/37\/54847\/5426664\/The-Epoxybenzooxocine-Core-of-Integrastatins-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":42,"journal-issue":{"issue":"37","published-online":{"date-parts":[[2026,9,8]]},"published-print":{"date-parts":[[2026,9,22]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c06756","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]}}}