Pyrrolidinobenzoic acid inhibitors of influenza virus neuraminidase: the hydrophobic side chain influences type A subtype selectivity

Abstract

Neuraminidase (NA) plays a critical role in the life cycle of influenza virus and is a target for new therapeutic agents. A series of influenza neuraminidase inhibitors with the pyrrolidinobenzoic acid scaffold containing lipophilic side chains at the C3 position have been synthesized and evaluated for influenza neuraminidase inhibitory activity. The size and geometry of the C3 side chains have been modified in order to investigate structure-activity relationships. The results indicated that size and geometry of the C3-side chain are important for selectivity of inhibition against N1 versus N2 NA, important type A influenza variants that infect man, including the highly lethal avian influenza.

Figure 1

Structures of clinically marketed neuraminidase inhibitors compared to benzoic acid inhibitors.

Scheme 1^a

^aReagents and conditions: (i) MeOH, H₂SO₄, reflux, 15h; (ii) Zn/HCl, EtOAc, 0–20 °C 15h; (iii) diethyl bromomalonate, 120 °C, 22h; (iv) 3-bromopropionic acid, PCl₃, toluene, 100 °C, 22h; (v) NaH, 0–20 °C, 4h; (vi) CCl₄, NBS, AIBN, 80 °C, 3h; (vii) a, BuLi, ROH, −10–20 °C 15h; b, NaBH₄, MeOH, THF, −21h; c, NaOH, MeOH, 20 °C, 1–2h.

Scheme 2^a

^aReagents and conditions: : (i) a, vinyl bromide, dioxane, Et₃N, Pd(PPh₃)₄, pinacolborane, 80 °C, 1h; b, methyl 4-amino-3-iodobenzoate, Ba(OH)₂·8H₂O, water, 90°C, 8h; (ii) a, p-TSA, toluene, diethyl ketomalonate, reflux, 19h; b, NaBH₄, DEC, AcOH, 15h; c, 3-bromopropionic acid, PCl₃, toluene, 100°C, 20h; d, NaH, 0–20 °C, 4h; (iii) Pd/C, H₂, MeOH, 25 °C; (iv) a, NaBH₄, MeOH/THF, 2–5h; b, NaOH, MeOH, 20 °C, 1–2h.