Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13.

Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ∼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection. PAPERCLIP.

Regioselective 1,4-conjugate addition of Grignard reagents to nitrodienes in the presence of catalytic amounts of Zn(II) salts.

Grignard reagents undergo facile regioselective 1,4-conjugate addition to nitrodienes in the presence of catalytic amounts of Zn(II) salts with excellent yields. A wide range of ligands such as alkyl, aryl, heteroaryl, allyl, vinyl, 1-alkynyl, and alkoxy ligands were transferred, while a thiolate ligand afforded 1,6-regioselectivity. The reactions were successfully carried out on δ-alkyl- or aryl-substituted α,ß,γ,δ-diunsaturated nitrodiene substrates. Regioselectivity is minimally influenced by temperature or choice of solvent.

Regio- and stereocontrol in the Michael-initiated ring-closure reactions of γ,δ-epoxy-α,ß-unsaturated esters, ketones, sulfones, and amides.

Organozincates or Grignard reagents in the presence of zinc catalysts undergo Michael initiated ring closure (MIRC) reactions with γ,δ-epoxy-α,ß-enoates, enones, enesulfones, and enamides to afford 1,2,3-trisubstituted cyclopropanes. The direction of diastereoselectivity is solvent dependent for alkyl Grignard reagents reacting with epoxy enoates, ensulfones, and enamides but solvent independent for the enones. Excellent diastereoselectivity can be achieved for the epoxy enoates, enones, and ensulfones, while the enamides afford modest diastereoselectivity under optimal conditions. The MIRC reaction can be achieved with phenylmagnesium chloride and these substrates under reaction conditions designed to minimize biphenyl formation.

Conjugate addition reactions of N-carbamoyl-4-pyridones and 2,3-dihydropyridones with Grignard reagents in the absence of Cu(I) salts.

N-Boc- and N-ethoxycarbonyl-4-pyridones and the resulting 2,3-dihydropyridones undergo 1,4-addition reactions with Grignard reagents in the presence of chlorotrimethylsilane (TMSCl) or BF3·Et2O in excellent yields. Copper catalysis is not required, and mechanistic considerations suggest that the reaction is proceeding by a conjugate addition pathway rather than by a pathway involving 1,2-addition to an intermediate pyridinium ion. TMSCl-mediated conjugate addition of Grignard reagents to 2-substituted-2,3-dihydropyridones gives the trans-2,6-disubstitued piperidinones stereoselectively, while cuprate reagents give either the trans or cis diastereomers or mixtures.