Structure guided generation of thieno[3,2-]pyrimidin-4-amine oxidase inhibitors.

Cytochrome oxidase (Cyt-) is an attractive drug target in , especially in the context of developing a drug combination targeting energy metabolism. However, currently few synthetically assessable scaffolds target Cyt-. Herein, we report that thieno[3,2-]pyrimidin-4-amines inhibit Cyt-, and report an initial structure-activity-relationship (SAR) of 13 compounds in three mycobacterial strains: BCG, H37Rv and clinical isolate N0145 in an established ATP depletion assay with or without the cytochrome  :  (QcrB) inhibitor Q203. All compounds displayed activity against BCG and the clinical isolate strain N0145 with ATP IC values from 6 to 54 μM in the presence of Q203 only, as expected from a Cyt- inhibitor. All derivatives were much less potent against H37Rv compared to N0145 (IC's from 24 to >100 μM and 9-52 μM, respectively), an observation that may be attributed to the higher expression of the Cyt--encoding genes in the laboratory-adapted H37Rv strain. -(4-(-butyl)phenethyl)thieno[3,2-]pyrimidin-4-amine () was the most active compound with ATP IC values from 6 to 18 μM against all strains in the presence of Q203, making it a good chemical probe for interrogation the function of the mycobacterial Cyt- under various physiological conditions.