Hit-to-lead optimization of a 2-aminobenzimidazole series as new candidates for chagas disease.

Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. Because current treatments present several limitations, including long duration, variable efficacy and serious side effects, there is an urgent need to explore new antitrypanosomal drugs. The present study describes the hit-to-lead optimization of a 2-aminobenzimidazole hit 1 identified through in vitro phenotypic screening of a chemical library against intracellular Trypanosoma cruzi amastigotes, which focused on optimizing potency, selectivity, microsomal stability and lipophilicity. Multiparametric Structure-Activity Relationships were investigated using a set of 277 derivatives. Although the physicochemical and biological properties of the initial hits were improved, a combination of low kinetic solubility and in vitro cytotoxicity against mammalian cells prevented progression of the best compounds to an efficacy study using a mouse model of Chagas disease.

Multilamellar-to-Unilamellar Transition Induced by Diphenylalanine in Lipid Vesicles.

In the present work, we investigate the effect of two short phenylalanine-based peptides on lipid membranes. A simplified model membrane composed of lecithin vesicles was used to incorporate different amounts of the two amino acid sequences, the dimmer l,l-diphenylallanine (FF) and the trimmer cysteine-diphenylallanine (CFF). Spectroscopic and scattering techniques were applied to probe in detail the structural behavior of lipid membranes in the presence of the peptides. The experimental results demonstrate that both peptides are located mainly at the interface of the membrane interacting with phosphate groups modifying membrane thickness and flexibility. The multilamellar structure of the vesicles is preserved with inclusion of small amounts of FF, accompanied by changes in membrane thickness and elasticity. Finally, a multi- to unilamellar transition is observed as a result of peptide self-association into a crystalline structure onto the membrane interface.