ThioQ Inhibitors of TB Phosphopanetheinyl Transferase

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<p class="BDAbstract">The essential mycobacterial enzyme phosphopantetheinyl transferase (PptT) is a potential target for anti-tuberculosis drugs. Following the identification of (pyridin-3-ylmethyl)-substituted thioquinazolinones as hits in a screen against PptT, we carried out a structure-activity relationship (SAR) study, focusing on modifications of the 6, 7, and 5&prime;-positions of the thioquinazolinone ring and the <em>N</em>-methylpyridyl group. These studies led to analogs with improved drug-like physicochemical properties and whole-cell activity against <em>Mycobacterium tuberculosis</em> (<em>Mtb)</em>. The resulting thioquinazolinones exert on-target whole-cell activity against <em>Mtb</em> in axenic culture and in macrophages with efficacy comparable to that of clinically used anti-tuberculosis drugs.&nbsp; Increased susceptibility of a <em>pptT</em> hypomorphic strain of <em>Mtb</em>, resistance of PptT Trp170 mutant <em>Mtb</em> strains and identification of relevant mutations in additional resistant mutants corroborated that the thioquinazolinones inhibit <em>Mtb</em> by virtue of their action on PptT. The thioquinazolinones studied did not inhibit growth of other bacteria, were not cytotoxic to mammalian cells, did not bind too most mammalian receptors and ion channels tested, and did not react with glutathione in the presence or absence of liver microsomes. Studies of intra-bacterial compound uptake and metabolism showed that <em>Mtb</em> rapidly took up the thioquinazolinones and rapidly methylated the thione and the 3&prime;-N of the pyridylmethyl group, the products of which were inactive against recombinant PptT.</p>
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