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oai:figshare.com:article/34022552 2026-09-29T10:07:44Z category_4 category_915 category_7 category_19 category_272 category_873 category_106 category_734 category_64 category_132 category_134 portal_63 item_type_6 month_year_09_2026

Novel Synthetic Chalcones Display Potent Anti-Leishmania (Viannia) braziliensis Profile and Inhibit Proteolytic Activities Edgar Schaeffer (6269921) Geovane Dias-Lopes (5814755) Patrícia Queiroz Monteiro (25136513) Julia Maria Borges (25136516) Luzia Monteiro de Castro Côrtes (25136519) Alcides José Monteiro da Silva (25136522) Franklin Souza da Silva (25136525) Carlos Roberto Alves (12440652) Biochemistry Physical Sciences not elsewhere classified Medicine Pharmacology Environmental Sciences not elsewhere classified Chemical Sciences not elsewhere classified Science Policy Biological Sciences not elsewhere classified Cancer Infectious Diseases Virology promising bioactive scaffolds pentavalent antimonials underscore novel synthetic approach multitarget mechanism involving high metabolic stability pronounced inhibitory effect new therapeutic candidates decreased ≥ 34 exhibiting antiparasitic activity inhibit key proteases compounds currently explored chalcones may act chalcone (< b 3j </ b 3i </ b 3d </ b 3b </ b inhibitory activity therapeutic validation 34 %), residual activity antileishmanial activity variable efficacy urgent need si ). showed 47 primarily caused predictive profile murine macrophages macrophage infection likeness properties leishmanicidal effects latin america intracellular amastigotes initially assessed findings suggest essential enzymes effective inhibitors cytotoxicity assays advanced stages acetate buffer 35 %). American Tegumentary Leishmaniasis, primarily caused by Leishmania (Viannia) braziliensis, remains a major public health challenge in Latin America. The variable efficacy and toxicity of pentavalent antimonials underscore the urgent need for new therapeutic candidates. Among the compounds currently explored, chalcones have emerged as promising bioactive scaffolds, exhibiting antiparasitic activity and the potential to inhibit key proteases, which are essential enzymes to virulence and pathogenesis of the parasite. In this study, chalcone derivatives obtained via a novel synthetic approach were evaluated for their antileishmanial activity against L.(V.)braziliensis. Their drug-likeness properties were initially assessed in silico, and the inhibitory activity against proteases was subsequently evaluated using promastigote protein extracts. In Tris–HCl buffer, compound 3j exhibited the most pronounced inhibitory effect, 36% residual activity, followed by compounds 3d and 2′,4′,6′-trimethoxy-chalcone (TMC), which showed 47% residual activity. In acetate buffer, the most effective inhibitors were 3b and 3j (34%), and 3d (35%). Cytotoxicity assays were performed in murine macrophages, and the leishmanicidal effects were evaluated against promastigotes to determine compound selectivity index (SI). TMC, 3b, 3d, 3h, and 3i exhibited SI ≥ 16.74 and were tested against intracellular amastigotes. They decreased ≥34% macrophage infection by intracellular amastigotes, and demonstrated a predictive profile for high metabolic stability with low organ toxicity risk. The findings suggest that these chalcones may act through a multitarget mechanism involving the inhibition of parasite proteases, supporting their progression to advanced stages of therapeutic validation. 2026-09-29T00:00:00Z Text Journal contribution 10.1021/acsomega.6c06140.s001 https://figshare.com/articles/journal_contribution/Novel_Synthetic_Chalcones_Display_Potent_Anti-Leishmania_Viannia_braziliensis_Profile_and_Inhibit_Proteolytic_Activities/34022552 CC BY-NC 4.0