{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:01:18Z","timestamp":1793145678306,"version":"4.5.0"},"reference-count":46,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T00:00:00Z","timestamp":1764979200000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    A novel series of covalent pyrrolo[2,3\u2010\n                    <jats:italic>d<\/jats:italic>\n                    ]pyrimidine cinnamamides was synthesized and evaluated for anticancer activity. The compounds were tested against three cancer cell lines\u2014MDA\u2010MB\u2010231 (triple\u2010negative breast cancer), A549 (non\u2010small cell lung cancer), and U\u201087 MG (glioblastoma), alongside a cytotoxicity assessment on non\u2010tumor NIH\/3\u2009T3 mouse embryonic fibroblast cell line. Compound\n                    <jats:bold>5k<\/jats:bold>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.99\u2009\n                    <jats:bold>\u00b1<\/jats:bold>\n                    \u20090.45\u2009\u03bcM) and\n                    <jats:bold>5i<\/jats:bold>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20091.15\u2009\n                    <jats:bold>\u00b1<\/jats:bold>\n                    \u20090.14\u2009\u03bcM) demonstrated markedly higher potency against MDA\u2010MB\u2010231 cells compared to cisplatin (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200934.36\u2009\u00b1\u20090.16\u2009\u03bcM), whereas\n                    <jats:bold>5e<\/jats:bold>\n                    was found active against A549 cells (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20091.41\u2009\u00b1\u20091.13\u2009\u03bcM). None of the active compounds exhibited significant toxicity against normal NIH\/3\u2009T3 cells. Molecular docking studies involving covalent modification at the ATP\u2010binding sites of EGFR (L858R\/T790M), HER2, and JAK3 via key interactions with Cys797 (EGFR\/HER2) and Cys909 (JAK3) supported their irreversible mechanism of action. Glutathione\u2010binding assay confirmed the covalent adduct formation with a prominent molecular ion peak corresponding to the adduct. Density Functional Theory analyses of the leading compounds revealed low HOMO\u2010LUMO energy gaps, which correlated with elevated electronic reactivity and biological capability. Electrostatic surface potential maps further highlighted distinct electrophilic character around the acrylamide warhead, facilitating potential covalent bond formation with nucleophilic Cys residues in the target proteins. In silico ADMET profiling confirmed favorable drug\u2010likeness and safety attributes. Together, these findings support the discovery of this novel class of covalent pyrrolo[2,3\u2010\n                    <jats:italic>d<\/jats:italic>\n                    ] pyrimidine cinnamamides as promising and safer lead candidates for anticancer therapy, particularly against triple\u2010negative breast cancer.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70211","type":"journal-article","created":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T08:40:04Z","timestamp":1765010404000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Design, Synthesis, Computational Modeling and Biological Evaluation of Novel N\u2010(\n                    <scp>7<\/scp>\n                    <i>H<\/i>\n                    \u2010Pyrrolo[2,3\u2010\n                    <i>d<\/i>\n                    ]pyrimidin\u20104\u2010yl)cinnamamides as Potential Covalent Inhibitors for Oncology"],"prefix":"10.1111","volume":"106","author":[{"given":"Rameshwar S.","family":"Cheke","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences and Technology Institute of Chemical Technology  Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1955-7223","authenticated-orcid":false,"given":"Prashant S.","family":"Kharkar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Technology Institute of Chemical Technology  Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,6]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100044\u2010101256"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2023.106729"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001705\u2010z"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2025.2494857"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40273\u2010018\u20100708\u20104"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ddr.22132"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2023.2204351"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku401"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114643"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2017.07.015"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00044\u2010023\u201003065\u20103"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/17460441.2024.2387122"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2020.152719"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498254.2018.1504256"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/jvp.12101"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.3c01055"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmcr.2024.100217"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c01825"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2024.176484"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24043643"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21812"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b00788"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.compbiomed.2024.108969"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265\u2010017\u20100723\u20103"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201011\u20103145"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867331666230815115111"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867323666160316123609"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10822\u2010012\u20109547\u20100"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15071796"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1177\/0897190020953019"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5NJ03125G"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00104"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2024.107867"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.4103\/ijmr.ijmr_1821_22"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.09.016"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e38105"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3OB00209H"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12032\u2010023\u201002111\u20109"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1134\/S1070363223100195"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13065\u2010018\u20100492\u20104"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12071985"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molstruc.2024.139213"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1515\/med\u20102016\u20100014"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2021.105420"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/mog2.56"}],"container-title":["Chemical 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