Mannosylated N‐Aryl Substituted 3‐Hydroxypyridine‐4‐Ones: Synthesis, Hemagglutination Inhibitory Properties, and Molecular Modeling

Abstract

Structural alterations of the aglycon portions of α-mannosides influence their inhibitory potency toward type 1-fimbriated Escherichia coli. The aim of our work was to prepare and explore inhibitory properties of novel mannosylated N-aryl-substituted 3-hydroxypyridine-4-ones because they possess needed structural characteristics as possible FimH antagonists. Hemagglutination inhibitory tests showed that the examined 3-hydroxypyridine-4-one α-mannosides exhibited better inhibitory activity than methyl α-d-mannopyranoside used as a reference compound. Molecular modeling studies revealed the specific interactions responsible for the observed binding activities toward the mannose-specific FimH lectin. The activity depends on the substituent in p-position on the aglycon aromatic ring.

Comparison of Inhibitory Activities of meta and para Substituted N-aryl 3-Hydroxypyridin-4-one Mannosides Towards Type 1 Fimbriated E. coli

“…Novel compounds 1a-1c were prepared following the previously published procedure for analogous para derivatives. [33] Aryl parts of the pyridinones 1a-1c were Scheme 1. Preparation of pyridinone mannosides 3a-3c: i) autoclave, p-TsOH, H2O, 150 °C, 48 h; ii) AgOTf, collidine, acetobromomannose, dry DCM, -78 °C, 24 h; ii) NaOMe, dry MeOH, 1 h. [2,33] using acetobromomannose as the glycosyl donor and meta substituted N-aryl 3,4-HPs 1a-1c as acceptors in the presence of AgOTf.…”

“…[33] 3,4-HPs possess the needed structural characteristics since they are hydrophobic bicyclic compounds composed of the 3,4-HP core with an aryl extension. The 3,4-HPs, a family of heterocyclic compounds, have been extensively studied due to their broad field of application.…”

“…[33] Of all compounds we have tested so far, they have shown the greatest potential as FimH antagonists. Therefore, we have extended our research on novel N-aryl 3,4-HP derivatives.…”

“…Previously evaluated N-aryl 3-hydroxypyridin-4-one mannosides. [33] was heated in a sealed thick-walled glass tube for 48 h at 150 °C. The crude product, obtained by cooling the reaction mixture to room temperature, was filtered off and recrystallized (from methanol).…”

“…[30][31][32][33] Guinea pig erythrocytes were isolated and used as described. [30,31,33] Mannosides 3a-3c were dissolved in distilled deionized water, and 10 μL of stock sugar solutions (diluted solutions starting from 20 mM concentration) was mixed with 10 μL of bacteria suspension in wells in V-shaped 96-well microtiter plates (Nunc). After 10 min, guinea-pig erythrocytes (10 μL) were added.…”