Zika Virus Inhibitors Based on a 1,3-Disubstituted 1 H-Pyrazolo[3,4- d]pyrimidine-amine Scaffold

Abstract

To search for Zika virus (ZIKV) antivirals, we have further explored previously reported 7H-pyrrolo[2,3-d]pyrimidines by examining an alternative substitution pattern of their central scaffold, leading to compound 5 with low micromolar antiviral activity. To circumvent the synthetic difficulties associated with compound 5, we have exploited a 1H-pyrazolo[3,4-d]pyrimidine scaffold and performed structure-activity relationship studies on its peripheral rings A and B. While ring B is less sensitive to structural modifications, an electron-withdrawing group at the para position of ring A is preferred for enhanced antiviral activity. Overall, we have not only discovered an alternative substitution pattern centered on a 1H-pyrazolo[3,4-d]pyrimidine scaffold but also generated anti-ZIKV compounds including 6 and 13, which possess low micromolar antiviral activity and relatively low cytotoxicity. These compounds represent new chemotypes that will be further optimized in our continued efforts to discover anti-ZIKV agents.

Keywords: Zika virus; Zika virus inhibitors; antiviral agents; flavivirus.

Figure 1

Selected known ZIKV inhibitors.

Scheme 1

Synthesis of 5,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidin-4-amine analogs. Reagents and conditions: (a) NBS, DMF; (b) ⁿBuLi, –78 °C, THF/hexanes; then DMF, rt; (c) 4-nitrobenzyl bromide, Cs₂CO₃, CH₃CN; (d) NaBH₄, MeOH/THF, 0 °C; (e) aniline, Na(OAc)₃BH, AcOH, dichloroethane; (f) ammonia solution, dioxane, 120 °C; (g) phenol, Ph₃P, DEAD, THF; (h) ammonia solution, dioxane, 120 °C.

Scheme 2

Synthesis of 1,3-disubstituted 1H-pyrazolo[3,4-d]pyrimidin-4-amine analogs. Reagents and conditions: (a) TrCl, Cs₂CO₃, DMF, 50 °C; (b) Bu₃Sn(CH=CH₂), Pd(PPh₃)₄, toluene, 110 °C; (c) OsO₄, NaIO₄, dioxane/H₂O, rt; (d) NaBH₄, MeOH/THF, 0 °C; (e) i. MsCl, Et₃N, DMAP, CH₂Cl₂; ii. varied phenols, Cs₂CO₃, DMF; (f) TFA, Et₃SiH, CH₂Cl₂, 0 °C; (g) Cs₂CO₃, CH₃CN or DMF.