Expedient on-resin synthesis of peptidic benzimidazoles

Abstract

The benzimidazole moiety is a ubiquitous pharmacophore present in numerous anthelmintic, antibacterial, antiviral, antineoplastic, and antifungal drugs. While the polypharmacology of this heterocycle has spurred the development of numerous solution-phase syntheses, only a handful of disparate and inefficient methods detailing its synthesis on-resin have been reported. Here we report the concise and expedient syntheses of internal and C-terminal peptidic benzimidazoles - an emerging class of peptide deformylase (PDF)-inhibiting antimicrobials. This method benefits from being performed wholly on solid-phase at room temperature resulting in minimal purification and tolerance of temperature-sensitive functionality.

Straightforward Synthesis of Various Chiral Pyrimidines Bearing Stereogenic Center at the C2 position, Including C-Terminal Peptide Isosters

“…This is also particularly desirable as N-heterocycles are considered as highly valuable C-terminal peptides isosteres but their access is still challenging. [9][10][11][12][13][14][15][16][17][18][19][20][21] We present herein our results in this field.…”

“…Scope and limitation for the use of various -chiral carboxamides.As previously stated, peptides with N-heterocyles C-terminal ends are highly desirable compounds. Indeed, C-terminal modified peptidomimetics have been used to limit the enzymatic degradation and to enhance the bioavaibility [9][10][11][12][13][14][15][16][17][18][19][20][21]. To this endeavour, pyrimidines 3ab' and 3ae' derived from Phenylalanine and Valine were deprotected in acidic conditions and then coupled to Cbz-Ala-OH in the presence of PyBOP to give the corresponding C-terminal modified pseudo-peptides 19 and 20 in 65 and 55% yields respectively (Scheme 5).…”

Synthesis of C‐terminal glycine‐rich o‐aminoanilide peptides without overacylation for use in benzotriazole‐mediated native chemical ligation

“…In fact, peptidic benzimidazoles have been previously synthesized based on this observation. [33] The effect of adding an EWG (PheDA-COOMe) at the ophenylenediamine gave us an indication that we could find the right combination of EDG and EWG in the resin and linker to obtain only the C-terminal peptide o-aminoanilide, which could then serve as a precursor for the C-terminal-Bt peptide.…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–4

“…Based on that scaffold and because benzimidazoles are antibacterial agents capable of chelating Fe 2+ ions, benzimidazole conjugates containing amino acids could emerge as alternative inhibitors. Consequently, the elegant solid phase synthesis of such conjugates, as described by Bird et al [5], appears as an essential tool for the design of novel innovative antibiotics.…”