2 research outputs found
Cycloadditions of Noncomplementary Substituted 1,2,3-Triazines
The scope of the [4 + 2] cycloaddition
reactions of substituted
1,2,3-triazines, bearing noncomplementary substitution with electron-withdrawing
groups at C4 and/or C6, is described. The studies define key electronic
and steric effects of substituents impacting the reactivity, mode
(C4/N1 vs C5/N2), and regioselectivity of the cycloaddition reactions
of 1,2,3-triazines with amidines, enamines, and ynamines, providing
access to highly functionalized heterocycles
Target-Based Screen Against a Periplasmic Serine Protease That Regulates Intrabacterial pH Homeostasis in <i>Mycobacterium tuberculosis</i>
<i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) maintains its intrabacterial pH (pH<sub>IB</sub>) near neutrality in the acidic environment of phagosomes within
activated macrophages. A previously reported genetic screen revealed
that <i>Mtb</i> loses this ability when the mycobacterial
acid resistance protease (<i>marP</i>) gene is disrupted.
In the present study, a high throughput screen (HTS) of compounds
against the protease domain of MarP identified benzoxazinones as inhibitors
of MarP. A potent benzoxazinone, BO43 (6-chloro-2-(2ā²-methylphenyl)-4H-1,3-benzoxazin-4-one),
acylated MarP and lowered <i>Mtb</i>ās pH<sub>IB</sub> and survival during incubation at pH 4.5. BO43 had similar effects
on MarP-deficient <i>Mtb</i>, suggesting the existence of
additional target(s). Reaction of an alkynyl-benzoxazinone, BO43T,
with <i>Mycobacterium bovis</i> variant <i>bacille
Calmette-GueĢrin</i> (<i>BCG</i>) followed by
click chemistry with azido-biotin identified both the MarP homologue
and the high temperature requirement A1 (HtrA1) homologue, an essential
protein. Thus, the chemical probe identified through a target-based
screen not only reacted with its intended target in the intact cells
but also implicated an additional enzyme that had eluded a genetic
screen biased against essential genes