The total synthesis of [Ψ[C(=S)NH]Tpg4]vancomycin aglycon (8) and its unique AgOAc-promoted single-step conversion to [Ψ[C(=NH)NH]Tpg4]vancomycin aglycon (7), conducted on a fully deprotected substrate, are disclosed. The synthetic approach not only permits access to 7, but it also allows late stage access to related residue 4 derivatives, alternative access to [Ψ[CH2NH]Tpg4]vancomycin aglycon (6) from a common late stage intermediate, and provides authentic residue 4 thioamide and amidine derivatives of the vancomycin aglycon that will facilitate ongoing efforts on their semisynthetic preparation. In addition to early stage residue 4 thioamide introduction, allowing differentiation of one of seven amide bonds central to the vancomycin core structure, the approach relied on two aromatic nucleophilic substitution reactions for formation of the 16-membered diaryl ethers in the CD/DE ring systems, an effective macrolactamization for closure of the 12-membered biaryl AB ring system, and the defined order of CD, AB, and DE ring closures. This order of ring closures follows their increasing ease of thermal atropisomer equilibration, permitting the recycling of any newly generated unnatural atropisomer under progressively milder thermal conditions where the atropoisomer stereochemistry already set is not impacted. Full details of the evaluation of 7 and 8 along with several related key synthetic compounds containing the core residue 4 amidine and thioamide modifications are reported. The binding affinity of compounds containing the residue 4 amidine with the model d-Ala-d-Ala ligand 2 was found to be only 2–3 times less than the vancomycin aglycon (5) and this binding affinity is maintained with the model d-Ala-d-Lac ligand 4, representing a nearly 600-fold increase in affinity relative to the vancomycin aglycon. Importantly, the amidines display effective dual, balanced binding affinity for both ligands (Ka 2/4 = 0.9–1.05) and they exhibit potent antimicrobial activity against VanA resistant bacteria (E. faecalis, VanA VRE) at a level accurately reflecting these binding characteristics (MIC = 0.3–0.6 µg/mL), charting a rational approach forward in the development of antibiotics for the treatment of vancomycin-resistant bacterial infections. In sharp contrast, 8 and related residue 4 thioamides failed to bind either 2 or 4 to any appreciable extent, do not exhibit antimicrobial activity, and serve to further underscore the remarkable behavior of the residue 4 amidines.

Designed inhibitors (like 1) of IspF, a key enzyme in the non‐mevalonate pathway for terpene biosynthesis and a potential antimalarial target, were synthesized and evaluated. Since fluorescent probes were introduced in these ligands, their affinity towards IspF from E. coli could be determined by fluorescence titrations. The binding modes of two ligands in ternary complexes with IspF and a ZnII ion were clarified by X‐ray analysis.

The enzymes of the non-mevalonate pathway for isoprenoid biosynthesis are attractive targets for the development of novel drugs against malaria and tuberculosis. This pathway is used exclusively by the corresponding pathogens, but not by humans. A series of water-soluble, cytidine-based inhibitors that were originally designed for the fourth enzyme in the pathway, IspD, were shown to inhibit the subsequent enzyme, the kinase IspE (from Escherichia coli). The binding mode of the inhibitors was verified by co-crystal structure analysis, using Aquifex aeolicus IspE. The crystal structures represent the first reported example of a co-crystal structure of IspE with a synthetic ligand and confirmed that ligand binding affinity originates mainly from the interactions of the nucleobase moiety in the cytidine binding pocket of the enzyme. In contrast, the appended benzimidazole moieties of the ligands adopt various orientations in the active site and establish only poor intermolecular contacts with the protein. Defined binding sites for sulfate ions and glycerol molecules, components in the crystallization buffer, near the well-conserved ATP-binding Gly-rich loop of IspE were observed. The crystal structures of A. aeolicus IspE nicely complement the one from E. coli IspE for use in structure-based design, namely by providing invaluable structural information for the design of inhibitors targeting IspE from Mycobacterium tuberculosis and Plasmodium falciparum. Similar to the enzymes from these pathogens, A. aeolicus IspE directs the OH group of a tyrosine residue into a pocket in the active site. In the E. coli enzyme, on the other hand, this pocket is lined by phenylalanine and has a more pronounced hydrophobic character.

Microwave irradiation promotes the conversion of enaminoketones formed in situ into a variety of heterocycles by reaction with the appropriate bidentate nucleophile. The advantages of the method over previous approaches are short reaction times and facile purification by precipitation of the products in aqueous media. Moreover the convenient one-pot procedure makes these syntheses particularly suitable for library production. Organic reactions in aqueous media have become of great interest as water is not only more environmentally friendly, but also because organic reactions in water often display unique reactivity and selectivity.

The synthesiys and biological evaluation of a series of vancomycin aglycon analogues bearing alternate residue 1 N-methyl-D-amino acids are described. The analogues were prepared to define whether H-bonding D-amino acids could improve the affinity for the model ligands N,N′-Ac 2 -L-Lys-D-Ala-D-Ala (2) and N,N′-Ac 2 -L-Lys-D-Ala-D-Lac (3), and improve antimicrobial activity against vancomycin-sensitive or vancomycin-resistant bacteria. Additionally, a series of analogues with appended nucleophiles (hydrazines and amines) on the residue 1 D-amino acids are described that were examined for their ability to react with the C-terminal ester of 3, forming a covalent attachment of L-Lys-D-Ala to the natural product analogues.