Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors.

A series of compounds based on the dipeptidyl nitrile scaffold were synthesized and assayed for their inhibitory activity against the T. cruzi cysteine protease cruzain. Structure activity relationships (SARs) were established using three, eleven and twelve variations respectively at the P1, P2 and P3 positions.

Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay.

A multi-step cascade strategy using integrated ligand- and target-based virtual screening methods was developed to select a small number of compounds from the ZINC database to be evaluated for trypanocidal activity. Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inhibitors with affinity values (K i) in the low micromolar range (3-60 µM) acting through a competitive inhibition mechanism were identified. This mechanism has been confirmed by determining the binding mode of the cruzain inhibitor Nequimed176 through X-ray crystallographic studies.

The discrete role of chlorine substitutions in the conformation and supramolecular architecture of arylsulfonamides.

Two arylsulfonamide derivatives, N-(4-acetylphenyl)benzenesulfonamide, C(14)H(13)NO(3)S, and N-(4-acetylphenyl)-2,5-dichlorobenzenesulfonamide, C(14)H(11)Cl(2)NO(3)S, differing by the absence or presence of two chloro substituents on one of the phenyl rings, were synthesized and characterized in order to establish structural relationships and the role of chloro substitution on the molecular conformation and crystal assembly. Both arylsulfonamides form inversion-related dimers through C-H···π and π-π interactions. These dimers pack in a similar way in the two structures.