Santos Barbosa, PatriciaSouza, Guilherme EduardoMaluf, Sarah El ChamyBonatto, ViníciusMoura, Caio SilvaMendes, Giovana RossiValdes, Talita AlvarengaAnnunciato, YasminRossetto, Barbara dos SantosVentura, Priscilla Dantas de SouzaOrtin, Gilberto Gaspar Duarteda Silva, WellingtonIcimoto, Marcelo YudiFerreira, Amália dos SantosCruz, Fabio C.Teles, Carolina B. G.Pereira, Dhelio B.Cassiano, Gustavo CapattiSantana, SofiaPrudêncio, MiguelBarbosa, Camila S.Moura, Igor M. R.Giampauli, Renan MarcelDe Sousa, Irene LayaneRocco, Silvana AparecidaGazarini, Marcos L.Correia, Carlos Roque DuarteAguiar, Anna Caroline CamposGuido, Rafael Victorio Carvalho2026-03-112026-03-112025-10-230022-2623PURE: 152514430PURE UUID: d4cb10d7-e7ab-4737-a188-8183ea22561cScopus: 105019589475WOS: 001584713400001PubMed: 41026123PubMedCentral: PMC12557366http://hdl.handle.net/10362/201282Funding information: We acknowledge financial support from the São Paulo Research Foundation (FAPESP grants 2014/25770-6, 2013/07600-3, and 2023/00383-9 to C.R.D.C.; 2018/03143-0 to P.S.B., 2018/07287-7 to G.E.S.; 2023/09209-1 to V.B.; 2020/14429-2 to S.E.C.M.; 2022/01063-5 to G.R.M.; 2024/04949-0 to T.A.V.; 2022/03731-5, and 2023/03295-3 to W.S.; 2021/03977-1 to I.M.R.M.; 2013/07600-3, 2020/12904-5, and 2024/04805-8 to R.V.C.G.; 2019/19708-0 to A.C.C.A.), the Brazilian National Research Council (CNPq grants 457027/2014-2, and 305387/2013-8 to C.R.D.C.; 133404/2018-8 to G.G.D.O.; 142488/2020-8 to W.S.; 310602/2021-1 and 303062/2025-8 to R.V.C.G.), and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. This study was funded in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior─Brasil (CAPES)─Finance Code 001. We acknowledge Dr. Daniela Trivella, and Dr. Marjorie Bruder, from LNBio/CNPEM, for HRMS analyses during the pandemic of COVID-19 as well as the doctoral student Christian Herrera for the support with the chemistry. The authors also acknowledge Selvita S.A. (Kraków, Poland) for making the predictions. M.P. acknowledges the “la Caixa” Foundation (Spain)’s grant HR21-848 and European Union Horizon Europe programme grant 101080744 for support. We also thank the computational resources provided by “Centro Nacional de Processamento de Alto Desempenho em São Paulo (CENAPAD-SP)”. Publisher Copyright: © 2025 The Authors. Published by American Chemical SocietyWe present insights into the mechanism of action of marinoquinolines (MQ), a novel class of lead candidates. Using a divergent synthetic approach, we developed a series of 20 new analogues with fluorescence properties. Structure–activity relationships analysis identified 19 as an attractive compound showing a combination of favorable in vitro (IC503D7= 0.28 μM; CC50HepG2= 53 μM), ex vivo (EC50Pf= 1.2 μM; EC50Pv= 0.53 μM), in vivo (3 × 50 mg/kg oral dose resulted in a 96% reduction in parasitemia in Plasmodium berghei-infected mice), physicochemical (Sol7.4= 171 μM; LogD7.4= 3.9), and pharmacokinetic (P_app = 9.4 × 10–6cm/s, human Clinthep,mic= 0.61–0.68 μL min–1mg–1) properties. Compound 19 selectively accumulates in infected erythrocytes, enters the digest vacuole and inhibits Plasmodium falciparum proteolytic activity, suggesting that MQs act as protease inhibitors. These findings strengthen the evidence that MQs are promising lead candidates for antimalarial drug discovery.2412828731engMolecular MedicineDrug Discoveryjournal article10.1021/acs.jmedchem.5c00138https://www.scopus.com/pages/publications/105019589475