Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1

• DOI: 10.1002/cmdc.201000450
• Publication Date: 2010-12-29T16:24:26Z
• Authors: Daniel Spinks; Han B. Ong; Chidochangu P. Mp...; Emma J. Shanks; David A. Robinson; Iain T. Collie; Kevin D. Read; Julie A. Frearson; Paul G. Wyatt; Ruth Brenk; Alan H. Fairlamb; Ian H. Gilbert
• Keywords: Pteridine; Dihydrofolate reductase

Abstract Genetic studies indicate that the enzyme pteridine reductase 1 (PTR1) is essential for survival of protozoan parasite Trypanosoma brucei . Herein, we describe development and optimisation a novel series PTR1 inhibitors, based on benzo[ d ]imidazol‐2‐amine derivatives. Data are reported 33 compounds. This was initially discovered by virtual screening campaign ( J. Med. Chem ., 2009 , 52 4454). The inhibitors adopted an alternative binding mode to those natural ligands, biopterin dihydrobiopterin, classical such as methotrexate. Using both rational medicinal chemistry structure‐based approaches, were able derive compounds with potent activity against T. ${K{{{\rm app}\hfill \atop {\rm i}\hfill}}}$ =7 n M ), which had high selectivity over human dihydrofolate reductase. Unfortunately, these displayed weak parasites. Kinetic analysis main reason lack cell potency due having insufficient enzyme, can be seen from low K m i ratio =25 =2.3 respectively).