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Their application in synthetic organic chemistry and medicinal chemistry, in combination with privileged scaffolds, is gaining momentum in recent years. The Ugi reaction is one of the most widely used MCRs in medicinal chemistry, and it is even used for the synthesis of several active pharmaceutical ingredients. Isatin, known for its biological activities and synthetic versatility, has been vastly used in several MCRs, however it was rarely used in combination with the Ugi reaction. Herein we report the first library of isatin\u2010based Ugi 4 component reaction (U4CR) derivatives. Reaction optimization and scope were thoroughly explored, as well as mechanistic insights were obtained using DFT calculations. The resulting library was evaluated in what concerns its druglike properties, pharmacokinetic profile assessment <jats:italic>in silico<\/jats:italic> and antiproliferative activity <jats:italic>in\u2005vitro<\/jats:italic>, with several compounds bearing interesting druglike properties. Biological screening against six tumor cell lines, showed that the majority of the compounds display antiproliferative activity in the low and sub\u2010micromolar range, with the achievement of nanomolar activity (0.1\u2005nM, 6.5\u2005nM and 5.4\u2005nM against HBL\u2010100, HeLa and WiDr, respectively) for the more active compound.<\/jats:p>","DOI":"10.1002\/ajoc.202100684","type":"journal-article","created":{"date-parts":[[2021,11,2]],"date-time":"2021-11-02T17:40:45Z","timestamp":1635874845000},"page":"3434-3455","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Ugi Adducts of Isatin as Promising Antiproliferative Agents with Druglike Properties"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1455-7470","authenticated-orcid":false,"given":"Pedro","family":"Brand\u00e3o","sequence":"first","affiliation":[{"name":"CQC and Department of Chemistry University of Coimbra  3004-535 Coimbra Portugal"},{"name":"LAQV-REQUIMTE University of \u00c9vora  Rua Rom\u00e3o Ramalho, 59 7000 \u00c9vora Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7975-1960","authenticated-orcid":false,"given":"Adri\u00e1n","family":"Puerta","sequence":"additional","affiliation":[{"name":"BioLab Instituto Universitario de Bio-Org\u00e1nica Antonio Gonz\u00e1lez (IUBO-AG) Universidad de La Laguna  PO Box 456 38200 La Laguna Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6268-6552","authenticated-orcid":false,"given":"Jos\u00e9 M.","family":"Padr\u00f3n","sequence":"additional","affiliation":[{"name":"BioLab Instituto Universitario de Bio-Org\u00e1nica Antonio Gonz\u00e1lez (IUBO-AG) Universidad de La Laguna  PO Box 456 38200 La Laguna Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5729-6189","authenticated-orcid":false,"given":"Maxim L.","family":"Kuznetsov","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural Instituto Superior T\u00e9cnico Universidade de Lisboa  Avenida Rovisco Pais 1049-001 Lisbon Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8248-1116","authenticated-orcid":false,"given":"Anthony J.","family":"Burke","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE University of \u00c9vora  Rua Rom\u00e3o Ramalho, 59 7000 \u00c9vora Portugal"},{"name":"Department of Chemistry University of Evora  Rua Rom\u00e3o Ramalho, 59 7000 \u00c9vora Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7460-3758","authenticated-orcid":false,"given":"Marta","family":"Pineiro","sequence":"additional","affiliation":[{"name":"CQC and Department of Chemistry University of Coimbra  3004-535 Coimbra Portugal"}]}],"member":"311","published-online":{"date-parts":[[2021,11,12]]},"reference":[{"key":"e_1_2_11_1_1","unstructured":"\u00a0"},{"key":"e_1_2_11_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2010.03.003"},{"key":"e_1_2_11_3_2","doi-asserted-by":"publisher","DOI":"10.1039\/C4QO00088A"},{"key":"e_1_2_11_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/tcr.201500201"},{"key":"e_1_2_11_5_1","unstructured":"\u00a0"},{"key":"e_1_2_11_6_2","doi-asserted-by":"publisher","DOI":"10.2174\/1570179416666190718153703"},{"key":"e_1_2_11_7_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25030505"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4GC00013G"},{"key":"e_1_2_11_9_1","first-page":"386","volume":"71","author":"Ugi I.","year":"1959","journal-title":"Angew. 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