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While these scaffolds have been extensively investigated in medicinal chemistry, their role in multitarget drug design has received comparatively less attention. This review provides a comprehensive overview of purine\u2010 and pyrrolopyrimidine\u2010based compounds reported over the last two decades from a multitarget medicinal chemistry perspective, with particular emphasis on the design principles and SAR underlying simultaneous modulation of multiple biological targets. By systematically comparing compounds across different target classes, we highlight the key structural features responsible for multitarget activity and discuss how specific scaffold modifications influence potency, selectivity, and polypharmacological profiles. Representative examples are presented to illustrate the successful application of these scaffolds in the development of dual\u2010 and multitarget inhibitors with promising anticancer, anti\u2010inflammatory, and drug resistance\u2010overcoming activities. Particular attention is devoted to compounds capable of overcoming drug resistance through the simultaneous modulation of complementary biological pathways. Overall, this review provides an integrated medicinal chemistry framework for understanding multitarget purine\u2010 and pyrrolopyrimidine\u2010based ligands and identifies emerging opportunities and challenges for the development of next\u2010generation polypharmacological agents.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70296","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T19:31:15Z","timestamp":1783625475000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Purine and Pyrrolopyrimidine\u2010Based Small Molecules as Multitarget Therapeutics"],"prefix":"10.1002","volume":"359","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0534-3020","authenticated-orcid":false,"given":"Federica","family":"Borghi","sequence":"first","affiliation":[{"name":"Department of Life Science (DSV) University of Modena and Reggio Emilia Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Laus","sequence":"additional","affiliation":[{"name":"Department of Life Science (DSV) University of Modena and Reggio Emilia Modena Italy"},{"name":"Center for Advanced Studies Research and Development in Sardinia (CRS4) Pula Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Sorbi","sequence":"additional","affiliation":[{"name":"Department of Life Science (DSV) University of Modena and Reggio Emilia Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Rastelli","sequence":"additional","affiliation":[{"name":"Department of Life Science (DSV) University of Modena and Reggio Emilia Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molstruc.2022.134308"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.08.023"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.115.099325"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112571"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1462399409000969"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0083-6729(03)01012-4"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-007-9046-2"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.202300208"},{"issue":"5","key":"e_1_2_8_10_1","first-page":"659","article-title":"The Role of Human Bromodomains in Chromatin Biology and Gene Transcription","volume":"12","author":"Sanchez R.","year":"2009","journal-title":"Current Opinion in Drug Discovery & Development"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2015.01.007"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115730"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12986-020-00478-4"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000256354.95791.f1"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00268-4"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.812774"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm5006463"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2015.00157"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867328666210902145102"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jscs.2023.101712"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/9780470524961.ch1"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2010.03.052"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2003.08.034"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.5b00483"},{"key":"e_1_2_8_25_1","first-page":"2099","article-title":"PD153035, a Tyrosine Kinase Inhibitor, Prevents Epidermal Growth Factor Receptor Activation and Inhibits Growth of Cancer Cells in a Receptor Number\u2010Dependent Manner","volume":"3","author":"Bos M.","year":"1997","journal-title":"Clinical Cancer Research"},{"key":"e_1_2_8_26_1","article-title":"SU5416 Is a Potent and Selective Inhibitor of the Vascular Endothelial Growth Factor Receptor (Flk\u20101\/KDR) That Inhibits Tyrosine Kinase Catalysis, Tumor Vascularization, and Growth of Multiple Tumor Types","author":"Fong T. 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