Fragment Merging, Growing, and Linking Identify New Trypanothione Reductase Inhibitors for Leishmaniasis.

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Parasitology

Background:

• Trypanothione reductase (TR) is a validated drug target for leishmaniasis.
• Developing potent TR inhibitors remains a significant challenge in drug discovery.

Purpose of the Study:

• To apply a fragment-based drug discovery (FBDD) strategy to identify novel inhibitors of trypanothione reductase.
• To guide medicinal chemistry efforts through structure- and ligand-based approaches.

Main Methods:

• Fragment screening and crystallographic analysis identified initial lead fragments.
• Structure-activity relationship (SAR) studies were performed using in silico and in vitro assays.
• Crystallography confirmed the binding of optimized compounds to TR.

Main Results:

• FBDD yielded a series of novel TR inhibitors (compounds 4-14).
• Compound 10 exhibited the most potent TR inhibition (Ki = 0.2 μM).
• Compound 9 demonstrated superior in vitro and ex vivo activity.

Conclusions:

• FBDD is a viable strategy for targeting challenging parasitic enzymes like TR.
• The identified compounds show potential for leishmaniasis drug development, though further optimization for selectivity is required.