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The effects of the various structural modifications were then correlated with the antiplasmodial activity <jats:italic>in\u2005vitro<\/jats:italic> in phenotypic assays. Among the several derivatives synthetized and compared with the 3D\u2010pharmacophoric map of the original lead, a novel compound, characterized by a western <jats:italic>tert<\/jats:italic>\u2010butyl glycine residue and an eastern 1<jats:italic>S<\/jats:italic>,2<jats:italic>S<\/jats:italic>\u2010aminoacyclohexanol, showed low\u2010nanomolar\u2010range antiplasmodial activity, no signs of cross\u2010resistance and, most importantly, 47\u2010fold improved Phase I metabolic stability when incubated with human liver microsomes. These results highlight the efficacy of <jats:italic>in silico<\/jats:italic>\u2010guided SAR campaigns which will allow us to further optimize the structure of the new lead aiming at testing its efficacy <jats:italic>in\u2005vivo<\/jats:italic> using different routes of administration.<\/jats:p>","DOI":"10.1002\/cmdc.202200355","type":"journal-article","created":{"date-parts":[[2022,9,11]],"date-time":"2022-09-11T22:09:57Z","timestamp":1662934197000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["From DC18 to MR07: A Metabolically Stable 4,4\u2032\u2010Oxybisbenzoyl Amide as a Low\u2010Nanomolar Growth Inhibitor of <i>P. falciparum<\/i>"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9589-3689","authenticated-orcid":false,"given":"Ivan","family":"Bassanini","sequence":"first","affiliation":[{"name":"Istituto di Scienze e Tecnologie Chimiche \u201cGiulio Natta\u201d Consiglio Nazionale delle Ricerche  Via Mario Bianco 9 20131 Milano Italy"},{"name":"Centro Interuniversitario di Ricerca sulla Malaria-Italian Malaria Network  Via Festa del Perdono 7 20122 Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2079-8892","authenticated-orcid":false,"given":"Silvia","family":"Parapini","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche per la Salute Universit\u00e0 degli Studi di Milano  Via Pascal 36 20133 Milano Italy"},{"name":"Centro Interuniversitario di Ricerca sulla Malaria-Italian Malaria Network  Via Festa del Perdono 7 20122 Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9030-1066","authenticated-orcid":false,"given":"Nicoletta","family":"Basilico","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche Universit\u00e0 degli Studi di Milano  Via Pascal 36 20133 Milano Italy"},{"name":"Centro Interuniversitario di Ricerca sulla Malaria-Italian Malaria Network  Via Festa del Perdono 7 20122 Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5108-4492","authenticated-orcid":false,"given":"Donatella","family":"Taramelli","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari Universit\u00e0 degli Studi di Milano  Via Pascal 36 20133 Milano Italy"},{"name":"Centro Interuniversitario di Ricerca sulla Malaria-Italian Malaria Network  Via Festa del Perdono 7 20122 Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4692-7314","authenticated-orcid":false,"given":"Sergio","family":"Romeo","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmaceutiche Universit\u00e0 degli Studi di Milano  Via Mangiagalli 25 20133 Milano Italy"},{"name":"Centro Interuniversitario di Ricerca sulla Malaria-Italian Malaria Network  Via Festa del Perdono 7 20122 Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,9,26]]},"reference":[{"key":"e_1_2_8_1_1","unstructured":"World Health Organization World Malaria Report2021."},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2012.12.007"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3742"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2013.05.005"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2624"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.15-0007"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.2147\/IDR.S279433"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S265602"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/5539544"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201900522"},{"key":"e_1_2_8_11_1","first-page":"56","volume":"11","author":"Bassanini I.","year":"2021","journal-title":"Biomol. 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