2. Academic Validation
  3. Synthesis and Biophysical and Biological Studies of N-Phenylbenzamide Derivatives Targeting Kinetoplastid Parasites

Synthesis and Biophysical and Biological Studies of N-Phenylbenzamide Derivatives Targeting Kinetoplastid Parasites

  • J Med Chem. 2023 Oct 12;66(19):13452-13480. doi: 10.1021/acs.jmedchem.3c00697.
J Jonathan Nué-Martinez 1 2,  David Cisneros 1 2,  María Del Valle Moreno-Blázquez 1,  Cristina Fonseca-Berzal 3,  José Ignacio Manzano 4,  Damien Kraeutler 1,  Marzuq A Ungogo 5,  Maha A Aloraini 5,  Hamza A A Elati 5,  Alexandra Ibáñez-Escribano 3,  Laura Lagartera 1,  Tomás Herraiz 6,  Francisco Gamarro 4,  Harry P de Koning 5,  Alicia Gómez-Barrio 3,  Christophe Dardonville 1
Affiliations

Affiliations

  • 1 Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
  • 2 PhD Programme in Medicinal Chemistry, Doctoral School, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain.
  • 3 Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain.
  • 4 Instituto de Parasitología y Biomedicina "Löpez Neyra", IPBLN-CSIC, Parque Tecnolögico de Ciencias de la Salud, 18016 Granada, Spain.
  • 5 Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8TA Glasgow, U.K.
  • 6 Instituto de Ciencia y Tecnología de Alimentos y Nutrición, ICTAN-CSIC, José Antonio Novais 10, Ciudad Universitaria, 28040 Madrid, Spain.
PMID: 37729094 DOI: 10.1021/acs.jmedchem.3c00697
Abstract

The AT-rich mitochondrial DNA (kDNA) of trypanosomatid parasites is a target of DNA minor groove binders. We report the synthesis, antiprotozoal screening, and SAR studies of three series of analogues of the known antiprotozoal kDNA binder 2-((4-(4-((4,5-dihydro-1H-imidazol-3-ium-2-yl)amino)benzamido)phenyl)amino)-4,5-dihydro-1H-imidazol-3-ium (1a). Bis(2-aminoimidazolines) (1) and bis(2-aminobenzimidazoles) (2) showed micromolar range activity against Trypanosoma brucei, whereas bisarylimidamides (3) were submicromolar inhibitors of T. brucei, Trypanosoma cruzi, and Leishmania donovani. None of the compounds showed relevant activity against the urogenital, nonkinetoplastid Parasite Trichomonas vaginalis. We show that series 1 and 3 bind strongly and selectively to the minor groove of AT DNA, whereas series 2 also binds by intercalation. The measured pKa indicated different ionization states at pH 7.4, which correlated with the DNA binding affinities (ΔTm) for series 2 and 3. Compound 3a, which was active and selective against the three parasites and displayed adequate metabolic stability, is a fine candidate for in vivo studies.

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