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Although bisindoles represent a promising chemotype, our first-generation 2,2\u2032-di(indol-3-yl)ethanamines, inspired by a natural marine alkaloid, displayed significant cytotoxicity despite potent activity against L. infantum. To address this limitation, we designed and synthesized a second-generation series in which the indole bromine substituents were removed, and N-methylation was prioritized as a strategy to mitigate cytotoxicity. Compounds 1e, 2b, 2f, 3d, and 3e emerged as promising hits, exhibiting potent activity against L. infantum promastigotes (IC50 = 0.6\u20133 \u03bcM) and markedly improved selectivity indices (SI = 11\u201366) in THP-1 cells. These compounds retained efficacy in an in vitro infection model, with 1e, 2b, and 2f displaying IC50 values below 10 \u03bcM against intracellular amastigotes. A pharmacophore model derived from URB1483 and 2f was generated to explore plausible mechanisms of action underlying the antileishmanial activity, with trypanothione reductase (TR) selected as a possible biological target. While compound 2f showed only weak inhibition (IC50 = 71 \u03bcM), this could provide a starting point for the structure-based design of future antileishmanial agents. Preliminary ADME-related evaluations of 1e and 2f revealed improved aqueous solubility, alongside favorable chemical and metabolic stability specifically for 1e. Consequently, while 2f could be a new hit for a still underexploited target, compound 1e emerges as the most balanced lead candidate for future development of antileishmanial derivatives.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00079","type":"journal-article","created":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T22:12:42Z","timestamp":1788127962000},"page":"3028-3042","source":"Crossref","is-referenced-by-count":0,"title":["Second Generation\nof 2,2\u2032-Di(indol-3-yl)ethanamines\nas Antileishmanial Agents: Phenotypic Hit Identification and Pharmacophore\nStudies"],"prefix":"10.1021","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9071-5621","authenticated-orcid":true,"given":"Gian Marco","family":"Elisi","sequence":"first","affiliation":[{"name":"University of Urbino Carlo Bo , , ,","place":["Urbino, Italy, 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06123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Naldi","sequence":"additional","affiliation":[{"name":"Alma Mater Studiorum University of Bologna , ,","place":["Bologna, Italy, 40126"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Peluso","sequence":"additional","affiliation":[{"name":"University of Urbino Carlo Bo , , ,","place":["Urbino, Italy, 61029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0541-2816","authenticated-orcid":true,"given":"Miriam","family":"Go\u0301mez-Benmansour","sequence":"additional","affiliation":[{"name":"University of Urbino Carlo Bo , , ,","place":["Urbino, Italy, 61029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5456-1821","authenticated-orcid":true,"given":"Aurora","family":"Diotallevi","sequence":"additional","affiliation":[{"name":"University of Urbino Carlo Bo , , 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Chem."},{"key":"2026091109074686500_cit4","unstructured":"World Health Organization (WHO) official web page on Leishmaniasis:.\n          \n          https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/leishmaniasis (accessed on 7 January 2026)."},{"key":"2026091109074686500_cit5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0129418","article-title":"Epidemiology\nof imported leishmaniasis in Italy: implications for a European endemic\ncountry","volume":"10","author":"Di Muccio","year":"2015","journal-title":"PLoS One"},{"issue":"4","key":"2026091109074686500_cit6","doi-asserted-by":"publisher","first-page":"2300190","DOI":"10.2807\/1560-7917.ES.2024.29.4.2300190","article-title":"Reemergence of human\nleishmaniasis in northern\nItaly, 2004 to 2022: a retrospective analysis","volume":"29","author":"Todeschini","year":"2023","journal-title":"Euro Surveill"},{"key":"2026091109074686500_cit7","doi-asserted-by":"publisher","first-page":"S10","DOI":"10.1016\/j.jinf.2014.07.016","article-title":"Leishmaniasis","volume":"69","author":"Pace","year":"2014","journal-title":"J. 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