Prostratin and 12‑<i>O</i>‑Tetradecanoylphorbol 13-Acetate Are Potent and Selective Inhibitors of Chikungunya Virus Replication

Abstract

A chemical study of the Vietnamese plant species <i>Trigonostemon howii</i> led to the isolation of a new tigliane-type diterpenoid, trigowiin A (<b>1</b>), along with several known coumarins and phenylpropanoids. The planar structure and the relative configuration of compound <b>1</b> were elucidated based on spectroscopic analysis, including 1D- and 2D-NMR experiments, mass spectrometry, and comparison with literature data. Trigowiin A (<b>1</b>) exhibited moderate antiviral activity in a virus-cell-based assay for Chikungunya virus (CHIKV). Since the structure of compound <b>1</b> is closely related to those of well-known tigliane diterpenoids such as prostratin (<b>2</b>), phorbol (<b>3</b>), 12-<i>O</i>-tetradecanoylphorbol 13-acetate (TPA) (<b>4</b>), and 4α-TPA (<b>5</b>), the antiviral activity of the latter compounds was also evaluated against CHIKV, as well as in virus-cell-based assays of two additional members of the genus <i>Alphavirus</i> (Sindbis virus, SINV, and Semliki forest virus, SFV). Whereas prostratin inhibited CHIKV replication with a moderate EC₅₀ of 2.6 μM and a selectivity index (SI) approximating 30, compound <b>4</b> proved to be an extremely potent inhibitor, with an EC₅₀ of ∼3 nM and a SI near 2000. Interestingly, no or very little activity was observed on the replication of SINV and SFV