Activation of 2,4-diaminoquinazoline in Mycobacterium tuberculosis by Rv3161c, a putative dioxygenase

Abstract

16The diaminoquinazoline series has good potency against Mycobacterium tuberculosis. 17Resistant isolates have mutations in Rv3161c, a putative dioxygenase. We carried out 18 metabolite analysis on wild-type and an Rv3161c mutant strain after exposure to a 19 diaminoquinazoline. The parental compound was found in intracellular extracts from the 20 mutant, but not the wild-type. A metabolite consistent with a mono-hydroxylated form 21 was identified in the wild-type. These data support the hypothesis that Rv3161c 22 metabolizes diaminoquinazolines in M. tuberculosis. 23 24 25 Keywords 26 Diaminoquinazoline, Mycobacterium tuberculosis, anti-tubercular, prodrug, activation, 27 monooxygenases, dioxygenases 28 29 125 129 J, Zhao D, Li F, Cheng M. 2017. Development of 2, 4-diaminoquinazoline derivatives as 130 potent PAK4 inhibitors by the core refinement strategy. European Journal of Medicinal 131 Chemistry 131:1-13. 132 3.