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

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-1 H -imidazol-3-ium-2-yl)amino)benzamido)phenyl)amino)-4,5-dihydro-1 H -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 p K a indicated different ionization states at pH 7.4, which correlated with the DNA binding affinities (Δ T m ) 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.