{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T14:28:45Z","timestamp":1786804125599,"version":"build-2736575974"},"reference-count":41,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000288","name":"Royal Society","doi-asserted-by":"publisher","award":["IES\/R3\/223055"],"award-info":[{"award-number":["IES\/R3\/223055"]}],"id":[{"id":"10.13039\/501100000288","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2019\/10434-4"],"award-info":[{"award-number":["2019\/10434-4"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Visceral leishmaniasis, caused by the protozoan parasites Leishmania infantum or L. donovani, remains a lethal neglected tropical disease without effective therapy. Current drugs available are toxic, leading to severe side effects, treatment abandonment, and resistance, underscoring the urgent need for new therapeutic options. As Leishmania spp. are auxotrophic for purines, they rely on the purine salvage pathway for their nucleotide biosynthesis. Consequently, nucleoside analogues (NAs) represent a promising class of compounds for the design of antiparasitic agents. This study aimed to investigate the in vitro antileishmanial activity of NA compounds and the cellular alterations induced by treatment. Twelve NA compounds were screened for antileishmanial activity against promastigote and amastigote forms of L. infantum and cytotoxic effects in mammalian cells. Among all compounds evaluated, six of them demonstrated antipromastigote activity, exhibiting 50% effective concentration (EC50) values ranging from 9.29 to 76.74 \u03bcM. As for amastigote activity, two compounds, 5 and 10, were effective, with values of EC50 of 8.02 and 31.95 \u03bcM, respectively. Only compound 1 maintained cellular viability at the maximum concentration tested (&amp;gt;200 \u03bcM). The selective index for the derivatives investigated ranges from 0.5 to 4.2. Compound 5, a tritylated thymidine NA, the most active, was further subjected to analysis of cellular alterations using fluorescent-based approaches. This analogue demonstrated a lack of cytotoxicity against murine peritoneal macrophages up to 50 \u03bcM and nonhemolytic activity up to 100 \u03bcM. When applied at EC50, it did not cause damage to plasma membrane permeability, the integrity of the genetic material, acidocalcisomes, intracellular Ca2+, and ROS levels of treated Leishmania parasites. However, it caused depolarization of the plasma membrane potential, leading to cell death. Further studies are also necessary to understand the enzymatic action of this most active compound, and optimization is required to develop more effective and safer antileishmanial lead compounds. In conclusion, compound 5 might be a suitable candidate for the development of antileishmanial agents.<\/jats:p>","DOI":"10.1021\/acsomega.5c09199","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:51:16Z","timestamp":1772121076000},"page":"14414-14425","source":"Crossref","is-referenced-by-count":1,"title":["Nucleoside Analogue\nwith Thymidine Nucleobase Inhibits\n                    <i>Leishmania infantum<\/i>\n                    and Depolarizes the Plasma Membrane\nPotential In Vitro"],"prefix":"10.1021","volume":"11","author":[{"given":"Clarissa","family":"Menezes","sequence":"first","affiliation":[{"name":"Adolfo Lutz Institute , , ,","place":["Sao Paulo, Brazil, 01246-000"]},{"name":"Secretary of State of Health of Sao Paulo , , ,","place":["Sao Paulo, Brazil, 01246-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid de O.","family":"Dias","sequence":"additional","affiliation":[{"name":"Adolfo Lutz Institute , , ,","place":["Sao Paulo, Brazil, 01246-000"]},{"name":"Secretary of State of Health of Sao Paulo , , ,","place":["Sao Paulo, Brazil, 01246-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Pileggi","sequence":"additional","affiliation":[{"name":"Cardiff University , , , ,","place":["Cardiff, Wales, United Kingdom, CF10 3AT"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2559-7344","authenticated-orcid":true,"given":"Andre G.","family":"Tempone","sequence":"additional","affiliation":[{"name":"Butantan Institute , , ,","place":["Sao Paulo, Brazil, 05503-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4532-9101","authenticated-orcid":true,"given":"Fabrizio","family":"Pertusati","sequence":"additional","affiliation":[{"name":"Cardiff University , , , ,","place":["Cardiff, Wales, United Kingdom, CF10 3AT"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0696-9800","authenticated-orcid":true,"given":"Samanta E. T.","family":"Borborema","sequence":"additional","affiliation":[{"name":"Adolfo Lutz Institute , , ,","place":["Sao Paulo, Brazil, 01246-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"2026081508061521900_cit1","first-page":"471","volume-title":"Global Leishmaniasis, 2022: Assessing Trends over the past\n10 Years","author":"WHO","year":"2023"},{"issue":"10151","key":"2026081508061521900_cit2","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1016\/S0140-6736(18)31204-2","article-title":"Leishmaniasis","volume":"392","author":"Burza","year":"2018","journal-title":"Lancet"},{"issue":"8","key":"2026081508061521900_cit3","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/j.pt.2012.05.005","article-title":"Purine Salvage in\nLeishmania: Complex or Simple by Design ?","volume":"28","author":"Boitz","year":"2012","journal-title":"Trends\nParasitol"},{"issue":"3","key":"2026081508061521900_cit4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/femsre\/fuad020","article-title":"Targeting\nthe Nucleotide Metabolism of Trypanosoma Brucei and Other Trypanosomatids","volume":"47","author":"Hofer","year":"2023","journal-title":"FEMS Microbiol Rev."},{"issue":"2","key":"2026081508061521900_cit5","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.ijpddr.2017.04.003","article-title":"Functional\nand Genetic Evidence That Nucleoside Transport Is Highly Conserved\nin Leishmania Species: Implications for Pyrimidine-Based Chemotherapy","volume":"7","author":"Alzahrani","year":"2017","journal-title":"Int. J. Parasitol Drugs Drug Resist"},{"issue":"3","key":"2026081508061521900_cit6","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1515\/ap-2017-0070","article-title":"In Vitro Effects of\nPurine and Pyrimidine Analogues\non Leishmania Donovani and Leishmania Infantum Promastigotes and Intracellular\nAmastigotes","volume":"62","author":"Azzouz","year":"2017","journal-title":"Acta Parasitol"},{"issue":"22","key":"2026081508061521900_cit7","doi-asserted-by":"publisher","first-page":"5234","DOI":"10.3390\/molecules29225234","article-title":"Nucleoside\nAnalogues for Chagas Disease and Leishmaniasis Therapy: Current Status\nand Future Perspectives","volume":"29","author":"Nwoke","year":"2024","journal-title":"Molecules"},{"key":"2026081508061521900_cit8","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.antiviral.2017.04.013","article-title":"Phosphonoamidate\nProdrugs of C5-Substituted Pyrimidine Acyclic Nucleosides for Antiviral\nTherapy","volume":"143","author":"Pertusati","year":"2017","journal-title":"Antiviral Res."},{"issue":"10","key":"2026081508061521900_cit9","doi-asserted-by":"publisher","first-page":"2864","DOI":"10.1093\/jac\/dkaa268","article-title":"Drug Repurposing:\nPhosphate Prodrugs of Anticancer and Antiviral FDA-Approved Nucleosides\nas Novel Antimicrobials","volume":"75","author":"Pertusati","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"issue":"5","key":"2026081508061521900_cit10","doi-asserted-by":"publisher","first-page":"181","DOI":"10.3851\/IMP2012","article-title":"Medicinal Chemistry of Nucleoside\nPhosphonate Prodrugs for Antiviral Therapy","volume":"22","author":"Pertusati","year":"2012","journal-title":"Antiviral Chem. 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Parasitol."},{"key":"2026081508061521900_cit31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2021.114469","article-title":"Evaluation of Antileishmanial\nPotential of the Antidepressant Escitalopram in Leishmania Infantum","volume":"209","author":"Lima","year":"2022","journal-title":"J. Pharm. Biomed Anal"},{"key":"2026081508061521900_cit32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1590\/0074-02760210379","article-title":"Is the\nMitochondrion a Promising\nDrug Target in Trypanosomatids?","volume":"117","author":"Pedra-Rezende","year":"2022","journal-title":"Mem Inst Oswaldo\nCruz"},{"key":"2026081508061521900_cit33","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.mib.2021.09.002","article-title":"Calcium Signaling in Intracellular Protist Parasites","volume":"64","author":"Docampo","year":"2021","journal-title":"Curr. Opin Microbiol"},{"key":"2026081508061521900_cit34","doi-asserted-by":"publisher","first-page":"46","DOI":"10.3389\/fcimb.2020.00046","article-title":"Disruption\nof Intracellular Calcium Homeostasis as a Therapeutic Target Against\nTrypanosoma Cruzi","volume":"10","author":"Benaim","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"issue":"1","key":"2026081508061521900_cit35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/AAC.01614-17","article-title":"Mechanism of Action of Miltefosine\non Leishmania Donovani Involves the Impairment of Acidocalcisome Function\nand the Activation of the Sphingosine-Dependent Plasma Membrane Ca\n2+ Channel","volume":"62","author":"Pinto-Martinez","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081508061521900_cit36","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1051\/parasite\/2019071","article-title":"Cell Death in Leishmania","volume":"26","author":"Basmaciyan","year":"2019","journal-title":"Parasite"},{"key":"2026081508061521900_cit37","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.actatropica.2019.04.017","article-title":"Antileishmanial\nActivity of H1-Antihistamine Drugs and Cellular Alterations in Leishmania\n(L.) Infantum","volume":"195","author":"de\nMelo Mendes","year":"2019","journal-title":"Acta Trop."},{"issue":"11","key":"2026081508061521900_cit38","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00831-24","article-title":"Synthesis of a Dehydrodieugenol\nB Derivative as a Lead\nCompound for Visceral Leishmaniasis-Mechanism of Action and in Vivo\nPharmacokinetic Studies","volume":"68","author":"Amaral","year":"2024","journal-title":"Antimicrob. Agents\nChemother."},{"issue":"xxxx","key":"2026081508061521900_cit39","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.biochi.2022.12.018","article-title":"Lethal Action of Licarin A Derivatives\nin Leishmania (L.) Infantum: Imbalance of Calcium and Bioenergetic\nMetabolism","volume":"208","author":"de\nCastro Levatti","year":"2023","journal-title":"Biochimie"},{"issue":"6","key":"2026081508061521900_cit40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/AAC.02360-16","article-title":"Meglumine Antimoniate\n(Glucantime) Causes Oxidative Stress-Derived DNA Damage in BALB\/c\nMice Infected by Leishmania (Leishmania) Infantum","volume":"61","author":"Moreira","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"issue":"4","key":"2026081508061521900_cit41","doi-asserted-by":"publisher","first-page":"499","DOI":"10.3390\/ph17040499","article-title":"Saturated Iso-Type\nFatty Acids from the Marine Bacterium Mesoflavibacter Zeaxanthinifaciens\nwith Anti-Trypanosomal Potential","volume":"17","author":"Santos\nFerreira","year":"2024","journal-title":"Pharmaceuticals"}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.5c09199","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/9\/14414\/63268324\/ao5c09199.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/9\/14414\/63268324\/ao5c09199.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T13:52:33Z","timestamp":1786801953000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/9\/14414\/5078878\/Nucleoside-Analogue-with-Thymidine-Nucleobase"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,26]]},"references-count":41,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,2,26]]},"published-print":{"date-parts":[[2026,3,10]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.5c09199","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,26]]}}}