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

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-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 pK a indicated different ionization states at pH 7.4, which correlated with the DNA binding affinities (ΔT 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.

A combined approach of structure‐based virtual screening and NMR to interrupt the PD‐1/PD‐L1 axis: Biphenyl‐benzimidazole containing compounds as novel PD‐L1 inhibitors

“…Several literature reports indicate that diversely substituted benzimidazoles feature distinct pharmacological activity and have found applications in diverse therapeutic areas, such as cancer, inflammatory disorders, viral, bacterial, and parasitic infections. [24][25][26][27][28] Thus, starting from 10 we synthesized a small library of derivatives. Among the novel compounds, the homogeneous timeresolved fluorescence (HTRF) binding assay revealed that compound 17 is the most potent one in interrupting the PD-1/PD-L1 complex (IC 50 in the submicromolar range).…”