Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Cysteine proteases cruzain and rhodesain are key targets for treating Chagas disease and Human African Trypanosomiasis.
• Previous work identified N4-benzyl-N2-phenylquinazoline-2,4-diamine (1a) as a competitive cruzain inhibitor.

Purpose of the Study:

• To synthesize and evaluate analogs of compound 1a for improved antiparasitic activity.
• To optimize lead compounds for potency and reduced undesirable physicochemical properties.

Main Methods:

• Synthesis of 22 quinazoline-2,4-diamine analogs with modifications to the core and substituents.
• Biological evaluation including enzyme inhibition assays, antiparasitic activity testing against Trypanosoma cruzi and Trypanosoma brucei, and counterscreening with myoblasts.
• Structure-based design and physicochemical property prediction were utilized.

Main Results:

• Analogs displayed low micromolar inhibition of target proteases and cidal activity against Trypanosoma cruzi, with high selectivity indices.
• Fourteen compounds demonstrated activity against Trypanosoma brucei at low to mid micromolar concentrations.
• Optimization efforts successfully removed colloidal aggregator characteristics while maintaining enzyme potency.

Conclusions:

• The developed quinazoline-2,4-diamine analogs represent promising leads for the development of new therapeutics against neglected tropical diseases.
• Structure-activity relationship studies and property optimization are crucial for advancing drug candidates.