Figure 1. Synthesis of 2-pyridone based dipeptide mimetics 1,¹ 2,^{2, 3 and 4} and 3¹² have previously been reported and here we present syntheses to 4 from 5.

Figure 2. (a) Crystal structure²⁸ of chaperone PapD and PapG peptide. (b) Bicyclic 2-pyridones 7 were designed to inhibit chaperones as C-terminal mimetics of the pilus adhesin PapG 6. Hydrogen bonds are illustrated as - - - -.

Figure 3. 2-Pyridones 8 and 9 prevent pilus assembly in uropathogenic Escherichia coli and were chosen for further derivatization into extended peptidomimetics.

Figure 4. Retrosynthetic analysis of the four classes of extended peptidomimetics A–D.

Figure 5. The bioactive conformation of the C-terminus of PapG can be adopted by a serine substituted derivative of 2-pyridone 8 in class A (i.e., compound 34, Scheme 2).

Scheme 1. Reagents and conditions: (a) NaNO₂, O₂(g), 4% (v/v) TFA, CH₂Cl₂, rt; (b) Zn dust, AcOH, rt; (c) 0.1 M LiOH, THF/MeOH, rt.

Scheme 2. Reagents and conditions: (a) DIC, HOAt, CH₂Cl₂, rt; (b) For 28 and 29: TFA/CH₂Cl₂, rt, and purification (66–72%), then 0.1 M LiOH, THF/MeOH, rt. For 30–33: 0.1 M LiOH, THF/MeOH, rt.

Scheme 3. Reagents and conditions: (a) formyl acetic anhydride (40 and 41) or acetic anhydride (42 and 43) or isobutyryl chloride (44 and 45), pyridine/CH₂Cl₂, rt; (b) MeSO₂Cl, pyridine, rt; (c) t-BuOK (* gave 49 as racemate) or K⁺i-PrN⁻COOMe (gave 48), i-PrSO₂Cl, THF, −42 °C → rt; (d) for 50–55: 0.1 M LiOH, MeOH/THF, rt. For 56–59: 0.1 M LiOH, MeOH/THF, rt, then Amberlite^® IR120⁺.

Scheme 4. Reagents: (a) Cl⁻Me₂N⁺CHCl, MeCN, reflux; (b) NaClO₂, NaH₂PO₄, DMSO/H₂O, rt; (c) MeNH₂ or i-PrNH₂, DCC, HOAt, CH₂Cl₂, rt; (d) 0.1 M LiOH, THF/MeOH, rt.

Relative affinities for chaperone PapD were determined using relaxation-edited ¹H NMR spectroscopy at a 1:1 ratio of pilicide:chaperone (Relative affinity)

The ability to prevent P pilus assembly in E. coli HB101/pPAP5, cultured with 3.5 mM pilicide in agar, was evaluated with haemagglutination (HA-titre).