Diversity-Oriented Synthesis Yields a New Drug Lead for Treatment of Chagas Disease

Abstract

A phenotypic high-throughput screen using ∼100,000 compounds prepared using Diversity-Oriented Synthesis yielded stereoisomeric compounds with nanomolar growth-inhibition activity against the parasite Trypanosoma cruzi, the etiological agent of Chagas disease. After evaluating stereochemical dependence on solubility, plasma protein binding and microsomal stability, the SSS analogue (5) was chosen for structure-activity relationship studies. The p-phenoxy benzyl group appended to the secondary amine could be replaced with halobenzyl groups without loss in potency. The exocyclic primary alcohol is not needed for activity but the isonicotinamide substructure is required for activity. Most importantly, these compounds are trypanocidal and hence are attractive as drug leads for both acute and chronic stages of Chagas disease. Analogue (5) was nominated as the molecular libraries probe ML341 and is available through the Molecular Libraries Probe Production Centers Network.

Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes

“…3), a DOS-derived smallmolecule probe (Carmody et al , 2010; Dandapani et al , 2014). ML341 is potent against several strains of T. cruzi including the clinical cardiotropic isolate CA-1 strain, clone 72 (CA-I/72) (IC 50 = 1 nM).…”

Impact of Stereospecific Intramolecular Hydrogen Bonding on Cell Permeability and Physicochemical Properties

“…31 The key structural features of 1 – 8 include an eight-membered fused ring system, three stereocenters, and physicochemical properties at the border of the RO5 (Table 1). Medicinal chemistry efforts and structure–activity relationships have been described elsewhere.…”

Oxalyl Boronates Enable Modular Synthesis of Bioactive Imidazoles

“…[1] Approaches that utilize readily accessible reagents are deemed particularly useful. [1] Approaches that utilize readily accessible reagents are deemed particularly useful.…”