{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T22:51:30Z","timestamp":1776293490107,"version":"3.50.1"},"reference-count":31,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T00:00:00Z","timestamp":1718236800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Herein we report the design and the synthesis of a library of new and more hydrophilic bisindole analogues based on our previously identified antileishmanial compound URB1483 that failed the preliminary <jats:italic>in vivo<\/jats:italic> test. The novel bisindoles were phenotypically screened for efficacy against <jats:italic>Leishmania infantum<\/jats:italic> promastigotes and simultaneously for toxicity on human macrophage-like THP-1 cells. Among the less toxic compounds, eight bisindoles showed IC<jats:sub>50<\/jats:sub> below 10 \u03bcM. The most selective compound <jats:bold>1h<\/jats:bold> (selectivity index = 10.1, comparable to miltefosine) and the most potent compound <jats:bold>2c<\/jats:bold> (IC<jats:sub>50<\/jats:sub> = 2.7 \u03bcM) were tested for their efficacy on <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic> intracellular amastigotes. The compounds also demonstrated their efficacy in the <jats:italic>in vitro<\/jats:italic> infection model, showing IC<jats:sub>50<\/jats:sub> of 11.1 and 6.8 \u03bcM for <jats:bold>1h<\/jats:bold> and <jats:bold>2c<\/jats:bold>, respectively. Moreover, <jats:bold>1h<\/jats:bold> showed a better toxicity profile than the commercial drug miltefosine. For all these reasons, <jats:bold>1h<\/jats:bold> could be a possible new starting point for hydrophilic antileishmanial agents with low cytotoxicity on human macrophage-like cells.<\/jats:p>","DOI":"10.1371\/journal.pone.0301901","type":"journal-article","created":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T17:52:50Z","timestamp":1718301170000},"page":"e0301901","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Exploring hydrophilic 2,2-di(indol-3-yl)ethanamine derivatives against Leishmania infantum"],"prefix":"10.1371","volume":"19","author":[{"given":"Alessia","family":"Centanni","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5456-1821","authenticated-orcid":true,"given":"Aurora","family":"Diotallevi","sequence":"additional","affiliation":[]},{"given":"Gloria","family":"Buffi","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9411-4487","authenticated-orcid":true,"given":"Diego","family":"Olivieri","sequence":"additional","affiliation":[]},{"given":"Nuno","family":"Santar\u00e9m","sequence":"additional","affiliation":[]},{"given":"Antti","family":"Lehtinen","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0370-7653","authenticated-orcid":true,"given":"Jari","family":"Yli-Kauhaluoma","sequence":"additional","affiliation":[]},{"given":"Anabela","family":"Cordeiro-da-Silva","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6084-684X","authenticated-orcid":true,"given":"Paula","family":"Kiuru","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3667-1207","authenticated-orcid":true,"given":"Simone","family":"Lucarini","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1747-526X","authenticated-orcid":true,"given":"Luca","family":"Galluzzi","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2024,6,13]]},"reference":[{"key":"pone.0301901.ref001","doi-asserted-by":"crossref","first-page":"11305","DOI":"10.1021\/cr500365f","article-title":"Recent developments in drug discovery for leishmaniasis and human African trypanosomiasis","volume":"114","author":"AS Nagle","year":"2014","journal-title":"Chem Rev"},{"key":"pone.0301901.ref002","unstructured":"World Health Organization (WHO) official web page on Leishmaniasis: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/leishmaniasis (accessed on 11 December 2023)."},{"key":"pone.0301901.ref003","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/d41586-018-05765-y","article-title":"Drug candidate and target for leishmaniasis","volume":"560","author":"CMC Catta-Preta","year":"2018","journal-title":"Nature"},{"issue":"6","key":"pone.0301901.ref004","doi-asserted-by":"crossref","first-page":"e0129418","DOI":"10.1371\/journal.pone.0129418","article-title":"Epidemiology of imported leishmaniasis in Italy: implications for a European endemic country","volume":"10","author":"T Di Muccio","year":"2015","journal-title":"PLoS One"},{"key":"pone.0301901.ref005","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1186\/s13071-016-1553-y","article-title":"Possibilities and challenges for developing a successful vaccine for leishmaniasis.","volume":"9","author":"S Srivastava","year":"2016","journal-title":"Parasites & Vectors"},{"issue":"12","key":"pone.0301901.ref006","doi-asserted-by":"crossref","first-page":"e0006052","DOI":"10.1371\/journal.pntd.0006052","article-title":"Drug resistance and treatment failure in leishmaniasis: A 21st century challenge","volume":"11","author":"A Ponte-Sucre","year":"2017","journal-title":"PLoS Negl Trop Dis"},{"issue":"10","key":"pone.0301901.ref007","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1002\/chir.23494","article-title":"A recent update on new synthetic chiral compounds with antileishmanial activity","volume":"34","author":"M Verboni","year":"2022","journal-title":"Chirality"},{"key":"pone.0301901.ref008","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.ejmech.2018.10.022","article-title":"Bekhit AEDA. 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