Design, synthesis and biological evaluation of 5′-C-piperidinyl-5′-O-aminoribosyluridines as potential antibacterial agents

Abstract

The discovery of new antibiotics is critical because the emergence of drug-resistant bacteria has posed a serious public health problem. Caprazamycins, which are nucleoside antibiotics, are a promising lead with a novel mode of action, and we have designed simplified analogues containing a piperidine as a scaffold linking the crucial structural units of caprazamycins. These analogues were step-economically synthesized via a sequential aza-Prins-Ritter reaction. Among the tested compounds, the analogue 7 exhibited good MraY inhibitory activity, antibacterial activity against Gram-positive bacterial strains including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci, and metabolic stability. The observed cytotoxicity of 7 against HepG2 cells was overcome by modulating the fatty acyl side chain. The knowledge obtained from our structure-activity relationship studies of the caprazamycins will provide further direction toward the design of potent MraY inhibitors.

Caprazamycins: Promising lead structures acting on a novel antibacterial target MraY

“…The fact that anti-MraY activity was reported to tolerate a simpler isoxazolidine scaffold encouraged the design of simpler analogues. In continuation of the efforts to explore simpler yet bioequivalent scaffolds, Ichikawa and co-workers synthesized uridine analogues containing a six membered piperidine scaffold (Figure 9) (SI Table 8) [63]. This piperidine scaffold facilitated investigation into the importance of the caprazamycins stereochemistry at the diazepanone's C-6′′′ and at the uridine's C-5′.…”

The Aza‐Prins Reaction in the Synthesis of Natural Products and Analogues

“…With the aim of synthesizing new antibiotics against drug‐resistant bacteria, Ichikawa's group designed simplified analogues of caprazamycin A ( 32 ), a nucleoside antibiotic (Scheme ) . The N atom in the C‐6′ position is critical for the activity of the natural product, so the authors thought to replace the central diazepanone core with a piperidine ring.…”

Recent Applications of Ritter Reactions in Organic Syntheses

“…[2] Many efforts have been made in the field of catalytic transformations of the Ritter reaction to develop an environmentally friendly synthetic pathway, in which many different catalysts have been reported, such as 2,4-dinitrobenzenesulfonic acid, o-benzenedisulfonimide, FeCl 3 ⋅ 6H 2 O, Bi (OTf) 3 . [3] This reaction was applied in the synthesis of biologically active molecules, such as anti-allergic, [4] antibiotic, antitumor, [5] antibacterial, [6] anti-influenza, [7] antiproliferactive [8] and antimicrobial drugs [9] (Scheme 2).…”

“…This reaction was applied in the synthesis of biologically active molecules, such as anti‐allergic, [4] antibiotic, antitumor, [5] antibacterial, [6] anti‐influenza, [7] antiproliferactive [8] and antimicrobial drugs [9] (Scheme 2).…”