{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T18:14:31Z","timestamp":1769537671728,"version":"3.49.0"},"reference-count":44,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":15,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Globally, colorectal cancer (\n                    <jats:styled-content style=\"fixed-case\">CRC<\/jats:styled-content>\n                    ) is the second most common cause of cancer\u2010related deaths and the third most common cancer. Thymidylate synthase (\n                    <jats:styled-content style=\"fixed-case\">TS<\/jats:styled-content>\n                    ), a key enzyme involved in\n                    <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content>\n                    biosynthesis, has emerged as a promising molecular target for anticancer therapy. In the present study, we designed and synthesized a series of 22 benzylated pyrrole\u2010based pyrido[2,3\u2010\n                    <jats:italic>d<\/jats:italic>\n                    ]pyrimidines using Claisen Schmidt and Michael addition reactions, and evaluated their anticancer potential against four human cancer cell lines:\n                    <jats:styled-content style=\"fixed-case\">HCT<\/jats:styled-content>\n                    116 (colorectal),\n                    <jats:styled-content style=\"fixed-case\">A549<\/jats:styled-content>\n                    (lung),\n                    <jats:styled-content style=\"fixed-case\">MCF<\/jats:styled-content>\n                    \u20107 (breast), and\n                    <jats:styled-content style=\"fixed-case\">MDA<\/jats:styled-content>\n                    \u2010\n                    <jats:styled-content style=\"fixed-case\">MB<\/jats:styled-content>\n                    \u2010231 (triple\u2010negative breast cancer) as well as for\n                    <jats:styled-content style=\"fixed-case\">TS<\/jats:styled-content>\n                    inhibitory potential. Compounds 1c and 2i exhibited potent TS inhibition with IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 11.50\u2009\u00b1\u20091.08\u2009nM and 17.12\u2009\u00b1\u20090.91\u2009nM, respectively, comparable to the standard drug raltitrexed (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200912.51\u2009\u00b1\u20090.91\u2009nM). Molecular docking studies revealed stronger binding affinities of these compounds compared to raltitrexed, involving key interactions with the catalytic residue Cys195 of TS. Additionally, compounds 1c and 2i exhibited good stability in 300\u2009ns molecular dynamics simulations along with acceptable drug\u2010like properties and oral bioavailability. These findings suggest that compounds 1c and 2i are promising lead candidates for the development of TS inhibitors.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70240","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T11:57:32Z","timestamp":1768564652000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Anticancer Assessment of Benzylated Pyrrole\u2010Based Pyrido[2,3\u2010\n                    <i>d<\/i>\n                    ]Pyrimidines as Thymidylate Synthase Inhibitors"],"prefix":"10.1111","volume":"107","author":[{"given":"Adarsh","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences and Natural Products Central University of Punjab  Bathinda India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonu","family":"Rajput","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Central University of Punjab  Bathinda India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ankit Kumar","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Natural Products Central University of Punjab  Bathinda India"},{"name":"Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences Sam Higginbottom University of Agriculture, Technology and Sciences  Prayagraj India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vineet","family":"Prajapati","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Natural Products Central University of Punjab  Bathinda India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amita","family":"Verma","sequence":"additional","affiliation":[{"name":"Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences Sam Higginbottom University of Agriculture, Technology and Sciences  Prayagraj India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prateek","family":"Pathak","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, Quality Assurance and Pharmaceutical Chemistry, School of Pharmacy GITAM (Deemed to be University), Hyderabad Campus  Hyderabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7498-5680","authenticated-orcid":false,"given":"Umashanker","family":"Navik","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Central University of Punjab  Bathinda India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jurica","family":"Novak","sequence":"additional","affiliation":[{"name":"Center for Informatics and Computing Ru\u0111er Bo\u0161kovi\u0107 Institute  Zagreb Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4284-2826","authenticated-orcid":false,"given":"Pradeep","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Natural Products Central University of Punjab  Bathinda India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph13110390"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9991(83)90014-1"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-310912"},{"key":"e_1_2_14_5_1","volume-title":"Organic Medicinal Chemicals (Synthetic and Natural)","author":"Barrowcliff M.","year":"1921"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.540110404"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.2174\/2666001602666220722112558"},{"key":"e_1_2_14_8_1","volume-title":"Amber 2023","author":"Case D. 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