Withanolides of Athenaea velutina with potential inhibitory properties against SARS coronavirus main protease (mpro): molecular modeling studies.

Since the global COVID-19 pandemic began, the scientific community has dedicated efforts to finding effective antiviral drugs to treat or minimize the effects caused by the SARS-CoV-2 coronavirus. Some targets can act as inhibitor substrates, highlighting the Main Protease (Mpro), which plays an essential role in the translation and transcription of the virus cycle. Withanolides, a class of natural C28 steroidal lactones, are compounds of interest as possible inhibitors of Mpro and other critical targets of the virus, such as papain-like protease. In this study, the isolation of a new withanolide (1), along with the known 27-deoxywithaferin A (2) and 27-deoxy-2,3-dihydrowithaferin A (3), from the leaves of Athenaea velutina (Solanaceae) is described. Their structures were determined using spectroscopic and spectrometric methods (NMR, IR, HRESIMS). Moreover, the interaction and the stability of withanolides 1-3 and withanolide D (4), previously isolated of Acnistus arborescens, against the Mpro target through molecular docking, molecular dynamics, and binding free energy simulations were analyzed. The molecular dynamics results indicated that the complexes formed by the molecular docking simulations between the Mpro target with each of the withanolides 1-4 exhibited good stability during the simulations due to a slight change in the structure of complexes. The binding free energy results suggested that withanolide (1) can be a natural candidate against COVID-19 disease.Communicated by Ramaswamy H. Sarma.

Anti-inflammatory withajardins from the leaves of Athenaea velutina.

Withajardins, uncommon modified withanolide-type steroids, have been isolated exclusively from plants of the Solanaceae family so far. Two undescribed withajardins and the known tuboanosigenin were isolated from the hexane/EtOAc 1:1 extract from Athenaea velutina leaves. Their structures were established by an extensive analysis of 1D and 2D-NMR and HRMS data. The absolute configuration was determined by X-ray diffraction (withajardin L and tuboanosigenin) and circular dichroism (CD) analyses (withajardin M). The anti-inflammatory activity of compounds was evaluated through the inhibition of the lipopolysaccharide (LPS)-induced nitric oxide (NO), TNF-α, and IL-6 release in RAW264.7 cells. The cell viability effects to RAW 264.7 cells showed IC50 values of 74.4-354.4 µM. The compounds attenuated LPS-induced release of NO and decreased pro-inflammatory cytokines TNF-α and IL-6 in RAW264.7 cells.