2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis:Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization

<i>Mycobacterium tuberculosis</i> (<i>MTb</i>) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose <i>MTb</i> whole-cell structure–activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the <i>ndh</i> encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in <i>MTb</i> was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by <i>ndhA</i> in <i>MTb</i>. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial <i>MTb</i> SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors

The synthesis and decomposition behaviour of methylpalladium (II) N-heterocyclic carbene complexes

This thesis describes the synthesis of methylpalladium(II) complexes bearing various N-heterocyclic carbene (NHC) ligands. The decomposition behaviour of a subset of these complexes is also studied. The catalytic performance of methylpalladium(II) complexes bearing NHC ligands of similar steric bulk but varying basicities was assessed. Palladium(II) complexes bearing two large NHCs were found to be inactive in the Heck reaction of 4-bromoacetophenone and n-butyl acrylate, while methylpalladium(II) carbene dimers bearing bridging halide groups were found to be active pre-catalysts. Ligand basicity was shown, in some cases, to dramatically influence catalytic activity. In addition, the catalytic activity of [Pd(NHC)Me(PP)J13F4-type complexes was assessed. Such complexes were also found to be inactive