Total synthesis of grandisine D (5) was achieved by a Brønsted acid mediated Morita-Baylis-Hillman (MBH) ring-closure reaction and stereoselective aldol condensation with (S)-5-methylcyclohexenone (9) as key steps. The MBH approach was also applicable for the construction of the aza-fused bicyclic systems of pyrrolizidine and stemona alkaloids.

Bacterial resistance is rapidly growing, necessitating the need to discover new agents. Novel bacterial topoisomerase inhibitors (NBTIs) are new class of broad-spectrum antibacterial agents targeting bacterial DNA gyrase and topoisomerase IV. This class of inhibitors binds to an alternative binding site relative to fluoroquinolones and shows no cross-resistance to quinolones. NBTIs consist of three structural motifs. A structure activity relationship of the left hand motif 1,5-naphthyridine of oxabicyclooctane-linked NBTIs is described. Fifty five compounds were evaluated against a panel of key Gram-positive and Gram-negative strains of bacteria, as well as for hERG activity and five compounds were tested for in vivo efficacy in murine model of Staphylococcus aureus infection. These studies suggest that only a narrow range (activating and deactivating) of substitutions at C-2 and C-7 are tolerated for optimal antibacterial activity and spectrum. An alkoxy (methoxy) and CN at C-2, and a halogen and hydroxyl at C-7, appeared to be preferred in this series. Substitutions on the other three carbons generally have detrimental effect on the activity. No clear hERG activity SAR emerged from these substitutions.

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Herein we report a scaffold-hopping approach to identify a new scaffold with a zinc binding headgroup. Structural information was used to give novel oxazolidinone-based LpxC inhibitors. In particular, the most potent compound, 23j, showed a low efflux ratio, nanomolar potencies against E. coli LpxC enzyme, and excellent antibacterial activity against E. coli and K. pneumoniae. Computational docking was used to predict the interaction between 23j and E. coli LpxC, suggesting that the interactions with C207 and C63 contribute to the strong activity. These results provide new insights into the design of next-generation LpxC inhibitors.KEYWORDS: Antibacterial, Gram-negative bacteria, LpxC, scaffold hopping, oxazolidinone I n recent years, infections caused by antibiotic-resistant bacteria have emerged as major threats to human communities worldwide. 1 However, the late-stage clinical development pipeline for antibacterials has been unacceptably lean in recent decades. 2 In particular, no drugs have reached advanced stages of development for the treatment of infection due to multidrug-resistant Gram-negative bacteria. Thus, there is a great need to develop new mechanisms by which Gramnegative antibacterial agents can combat bacterial antibiotic resistance. 3,4 One of the emerging targets in Gram-negative bacteria is LpxC, an essential enzyme in the lipid A biosynthetic pathway. Because LpxC does not show homology to any mammalian protein, it is a promising antibiotic target for developing novel therapeutics against multidrug-resistant Gram-negative pathogens. 5 LpxC inhibitors have drawn much attention in new entities for Gram-negative antibacterial agents. 6 To date, extensive investigations have been carried out on the mechanism underlying the LpxC enzyme. 7,8 Those studies have identified a zinc ion to catalyze deacetylation and a hydrophobic tunnel binding a myristate fatty acyl chain of the natural substrate. Merck researchers discovered 1 (L-161,240) containing an oxazoline scaffold in the mid-1990s, 6 and recently several LpxC inhibitors have been reported as antibacterial agents, 9−17 although to our knowledge none have reached the market yet.Among the well-characterized compounds, threonyl-hydroxamate derivatives are representative LpxC inhibitors, such as 2 (CHIR-090) and 3 (LPC-009) (Figure 1a). 18,19 According to a few reports on the binding modes of these compounds, the threonyl-hydroxamate group of 2 and that of 3 occupy the active site, and its diphenyl acetylene or phenyl-diyne group penetrates the hydrophobic passage. 19−21 Herein we report a scaffold hopping approach to identify a new scaffold with a zinc-binding headgroup. Additionally, we describe the synthesis, biological evaluation, and docking analysis of oxazolidinone-based LpxC inhibitors. Among these compounds, 23j showed remarkable antibacterial activity.

This article describes in detail the first total synthesis of grandisine alkaloids, grandisines B, D, and F, which show affinity for the human delta-opioid receptor. The key steps in this synthesis are construction of the isoquinuclidinone moiety of 2 by intramolecular imine formation and the tetracyclic ring system of 4 by stereoselective ring closure of the enolate of amine 8 generated by 1,4-addition of ammonia to 9. Synthesis of key intermediate 9 featured a highly stereoselective Brønsted acid mediated Morita-Baylis-Hillman (MBH) reaction via the N-acyl iminium ion.

Sustainable and efficient manufacturing methods for N-methylated peptides remain underexplored despite growing interest in therapeutic N-methylated peptides within the pharmaceutical industry. A methodology for the coupling of C-terminally unprotected N-methylamino acids mediated by an isostearic acid halide (ISTAX) and silylating reagent has been developed. This approach allows for the coupling of a wide variety of amino acids and peptides in high yields under mild conditions without the need for a C-terminal deprotection step in the process of C-terminal elongation. These advantages make this a useful synthetic method for the production of peptide therapeutics and diagnostics containing N-methylamino acids.

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