RT Journal Article
T1 Synthesis and Biophysical and Biological Studies of N-Phenylbenzamide Derivatives Targeting Kinetoplastid Parasites
A1 Nué-Martinez, J.J.
A1 Cisneros, David
A1 Moreno-Blázquez, María del Valle
A1 Fonseca-Berzal, Cristina
A1 Manzano, J.I
A1 Kraeutler, D
A1 Ungogo, M.A
A1 Aloraini, M.A
A1 Elati, H.A.A
A1 Ibáñez Escribano, Alexandra
A1 Lagartera, L
A1 Herraiz, Tomás
A1 Gamarro, Francisco
A1 de Koning, Harry P
A1 Gómez-Barrio, Alicia
A1 Dardonville, Christophe
AB 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.
PB ACS Publications
YR 2023
FD 2023-09-20
LK https://hdl.handle.net/20.500.14352/104177
UL https://hdl.handle.net/20.500.14352/104177
LA eng
NO Agencia Estatal de Investigación
NO European Regional Development Fund
NO Recovery and Resilience Facility, RRF, NextGenerationEU
NO Petroleum Technology Development Fund
DS Docta Complutense
RD 12 abr 2025