Antileishmanial High-Throughput Drug Screening Reveals Drug Candidates with New Scaffolds

Drugs currently available for leishmaniasis treatment often show parasite resistance, highly toxic side effects and prohibitive costs commonly incompatible with patients from the tropical endemic countries. In this sense, there is an urgent need for new drugs as a treatment solution for this neglected disease. Here we show the development and implementation of an automated high-throughput viability screening assay for the discovery of new drugs against Leishmania. Assay validation was done with Leishmania promastigote forms, including the screening of 4,000 compounds with known pharmacological properties. In an attempt to find new compounds with leishmanicidal properties, 26,500 structurally diverse chemical compounds were screened. A cut-off of 70% growth inhibition in the primary screening led to the identification of 567 active compounds. Cellular toxicity and selectivity were responsible for the exclusion of 78% of the pre-selected compounds. The activity of the remaining 124 compounds was confirmed against the intramacrophagic amastigote form of the parasite. In vitro microsomal stability and cytochrome P450 (CYP) inhibition of the two most active compounds from this screening effort were assessed to obtain preliminary information on their metabolism in the host. The HTS approach employed here resulted in the discovery of two new antileishmanial compounds, bringing promising candidates to the leishmaniasis drug discovery pipeline

Optically pure, water-stable metallo-helical ‘flexicate’ assemblies with antibiotic activity

The helicates—chiral assemblies of two or more metal atoms linked by short or relatively rigid multidentate organic ligands—may be regarded as non-peptide mimetics of α-helices because they are of comparable size and have shown some relevant biological activity. Unfortunately, these beautiful helical compounds have remained difficult to use in the medicinal arena because they contain mixtures of isomers, cannot be optimized for specific purposes, are insoluble, or are too difficult to synthesize. Instead, we have now prepared thermodynamically stable single enantiomers of monometallic units connected by organic linkers. Our highly adaptable self-assembly approach enables the rapid preparation of ranges of water-stable, helicate-like compounds with high stereochemical purity. One such iron(II) ‘flexicate’ system exhibits specific interactions with DNA, promising antimicrobial activity against a Gram-positive bacterium (methicillin-resistant Staphylococcus aureus, MRSA252), but also, unusually, a Gram-negative bacterium (Escherichia coli, MC4100), as well as low toxicity towards a non-mammalian model organism (Caenorhabditis elegans)