In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas

A newly validated
target for tuberculosis treatment is phosphopantetheinyl
transferase, an essential enzyme that plays a critical role in the
biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis. The structure–activity
relationships of a recently disclosed inhibitor, amidinourea (AU)
8918 (1), were explored, focusing on the biochemical
potency, determination of whole-cell on-target activity for active
compounds, and profiling of selective active congeners. These studies
show that the AU moiety in AU 8918 is largely optimized and that potency
enhancements are obtained in analogues containing a para-substituted
aromatic ring. Preliminary data reveal that while some analogues,
including 1, have demonstrated cardiotoxicity (e.g.,
changes in cardiomyocyte beat rate, amplitude, and peak width) and
inhibit Cav1.2 and Nav1.5 ion channels (although
not hERG channels), inhibition of the ion channels is largely diminished
for some of the para-substituted analogues, such as 5k (p-benzamide) and 5n (p-phenylsulfonamide).