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  3. Fluorescent Marinoquinoline Derivative as Inhibitors of Plasmodium falciparum: SAR Analysis, Mode of Action and In Vivo Studies

Fluorescent Marinoquinoline Derivative as Inhibitors of Plasmodium falciparum: SAR Analysis, Mode of Action and In Vivo Studies

  • J Med Chem. 2025 Oct 23;68(20):21120-21143. doi: 10.1021/acs.jmedchem.5c00138.
Patricia Santos Barbosa 1,  Guilherme Eduardo Souza 2,  Sarah El Chamy Maluf 2,  Vinícius Bonatto 2,  Caio Silva Moura 3,  Giovana Rossi Mendes 2,  Talita Alvarenga Valdes 2,  Yasmin Annunciato 3,  Barbara Dos Santos Rossetto 3,  Priscilla Dantas de Souza Ventura 3,  Gilberto Gaspar Duarte Ortin 1,  Wellington da Silva 1,  Marcelo Yudi Icimoto 4,  Amália Dos Santos Ferreira 5,  Fabio C Cruz 6,  Carolina B G Teles 5,  Dhelio B Pereira 7,  Gustavo Capatti Cassiano 8,  Sofia Santana 9,  Miguel Prudêncio 9 10,  Camila S Barbosa 11,  Igor M R Moura 2,  Renan Marcel Giampauli 12,  Irene Layane De Sousa 12,  Silvana Aparecida Rocco 12,  Marcos L Gazarini 3,  Carlos Roque Duarte Correia 1,  Anna Caroline Campos Aguiar 3 11,  Rafael Victorio Carvalho Guido 2
Affiliations

Affiliations

  • 1 Chemistry Institute, University of Campinas (UNICAMP), Campinas, São Paulo 13083-970, Brazil.
  • 2 São Carlos of Physics Institute, University of São Paulo (USP), São Carlos, São Paulo 13566-590, Brazil.
  • 3 Department of Biosciences, Federal University of São Paulo (UNIFESP), Santos, São Paulo 11015-020, Brazil.
  • 4 Department of Biophysics, Federal University of Sao Paulo, (UNIFESP), Escola Paulista de Medicina, São Paulo, São Paulo CEP 04023-062, Brazil.
  • 5 Leishmaniasis and Malaria Bioassay Platform, Oswaldo Cruz Foundation, Porto Velho, Rondônia 76812-245, Brazil.
  • 6 Department of Pharmacology, Federal University of São Paulo (UNIFESP), Escola Paulista de Medicina, São Paulo, São Paulo 04023-062, Brazil.
  • 7 Research Center in Tropical Medicine of Rondônia, Porto Velho, Rondônia 76812-245, Brazil.
  • 8 Global Health and Tropical Medicine (GHTM), Associate Laboratory in Translation and Innovation Towards Global Health (LA-REAL), Instituto de Higiene e Medicina Tropical, (IHMT), Universidade NOVA de Lisboa (UNL), Lisbon 1099-085, Portugal.
  • 9 Gulbenkian Institute for Molecular Medicine, Lisboa 1649-035, Portugal.
  • 10 Faculdade de Medicina da Universidade de Lisboa, Lisboa 1649-028, Portugal.
  • 11 Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), Escola Paulista de Medicina, São Paulo, São Paulo 04023-062, Brazil.
  • 12 Brazilian Biosciences National Laboratory and Brazilian Center for Research in Energy and Materials (LNBio-CNPEM), Campinas, São Paulo 13083-100, Brazil.
PMID: 41026123 DOI: 10.1021/acs.jmedchem.5c00138
Abstract

We 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 × 10-6 cm/s, human Clinthep,mic = 0.61-0.68 μL min-1 mg-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.

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