Exploring the dual effect of novel 1,4-diarylpyranopyrazoles as antiviral and anti-inflammatory for the management of SARS-CoV-2 and associated inflammatory symptoms

COVID-19 and associated substantial inflammations continue to threaten humankind triggering death worldwide. So, the development of new effective antiviral and anti-inflammatory medications is a major scientific goal. Pyranopyrazoles have occupied a crucial position in medicinal chemistry because of their biological importance. Here, we report the design and synthesis of a series of sixteen pyranopyrazole derivatives substituted with two aryl groups at N-1 and C-4. The designed compounds are suggested to show dual activity to combat the emerging Coronaviruses and associated substantial inflammations. All compounds were evaluated for their in vitro antiviral activity and cytotoxicity against SARS-CoV infected Vero cells. As well, the in vitro assay of all derivatives against the SARS-CoV M(pro) target was performed. Results revealed the potential of three pyranopyrazoles (22, 27, and 31) to potently inhibit the viral main protease with IC(50) values of 2.01, 1.83, and 4.60 μM respectively compared with 12.85 and 82.17 μM for GC-376 and lopinavir. Additionally, in vivo anti-inflammatory testing for the most active compound 27 proved its ability to reduce levels of two cytokines (TNF-α and IL-6). Molecular docking and dynamics simulation revealed consistent results with the in vitro enzymatic assay and indicated the stability of the putative complex of 27 with SARS-CoV-2 M(pro). The assessment of metabolic stability and physicochemical properties of 27 have also been conducted. This investigation identified a set of metabolically stable pyranopyrazoles as effective anti-SARS-CoV-2 M(pro) and suppressors of host cell cytokine release. We believe that the new compounds deserve further chemical optimization and evaluation for COVID-19 treatment.