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New drugs and molecular targets are urgently needed to address the emergence and spread of drug-resistant tuberculosis. Mycobacterium tuberculosis ( Mtb) inosine 5'-monophosphate dehydrogenase 2 ( MtbIMPDH2) is a promising yet controversial potential target. The inhibition of MtbIMPDH2 blocks the biosynthesis of guanine nucleotides, but high concentrations of guanine can potentially rescue the bacteria. Herein we describe an expansion of the structure-activity relationship (SAR) for the benzoxazole series of MtbIMPDH2 inhibitors and demonstrate that minimum inhibitory concentrations (MIC) of ≤1 μM can be achieved. The antibacterial activity of the most promising compound, 17b (Q151), is derived from the inhibition of MtbIMPDH2 as demonstrated by conditional knockdown and resistant strains. Importantly, guanine does not change the MIC of 17b, alleviating the concern that guanine salvage can protect Mtb in vivo. These findings suggest that MtbIMPDH2 is a vulnerable target for tuberculosis.

Incorporation of ferrocenyl group to peptides is an efficient method to alter their hydrophobicity. Ferrocenyl group can also act as an electrochemical probe when incorporated onto functional peptides. Most often, ferrocene is incorporated onto peptides post-synthesis via amide, ester or triazole linkages. Stable amino acids containing ferrocene as a C-linked side chain are potentially useful building units for the synthesis of ferrocene-containing peptides. We report here an efficient route to synthesize ferrocene-containing amino acids that are stable and can be used in peptide synthesis. Coupling of 2-ferrocenyl-1,3-dithiane and iodides derived from aspartic acid or glutamic acid using n-butyllithium leads to the incorporation of a ferrocenyl unit to the δ-position or e-position of an α-amino acid. The reduction or hydrolysis of the dithiane group yields an alkyl or an oxo derivative. The usability of the synthesized amino acids is demonstrated by incorporating one of the amino acids in both C-terminus and N-terminus of tripeptides in solution phase.

A very effective one-pot three component reaction of 4-bromobutanal or 5-bromopentanal, acetone, and p -anisidine catalyzed by proline is reported. A three component Mannich reaction followed by cyclization leading to the synthesis of 2-substituted pyrrolidine and piperidine derivatives through simultaneous formation of two C–N and one C–C bond is reported. The usefulness of the reaction is demonstrated by the synthesis of (±)coniine, (±)pelletrine, (±)sedridine, and (±)allosedridine.

The purine nucleotide pathways are tempting targets for antibiotic design. However, the vulnerability of these potential targets is questioned by the potential redundancy of the de novo biosynthesis and salvage pathways questions. Indeed, genetic experiments suggest that the vulnerability of these enzymes varies with pathogen and environmental niche. More target validation in the form of conditional knockouts could provide the confidence needed to launch drug discovery efforts. The purine conversion pathways are required for both de novo synthesis and salvage, suggesting that these four enzymes, adenylosuccinate synthetase, adenylosuccinate lyase, IMP dehydrogenase and GMP synthetase, are the better candidates. Even here the similarity of the active sites in pathogen and host enzymes can be discouraging. To date, only inhibitors of IMP dehydrogenase have been pursued with a significant effort. Mammalian and bacterial IMP dehydrogenases have dramatically different cofactor binding sites that can be exploited to identify selective inhibitors. Antibacterial activity has been reported against Gram positive pathogens and Mycobacterium tuberculosis, but no compound has achieved the critical milestone of activity in an animal model of infection.