The coronavirus pandemic known as COVID-19 caused by severe acute respiratory syndrome coronavirus 2, threatens public health worldwide. Approval of COVID-19 vaccines and antiviral drugs have greatly reduced the severe cases and mortality rate. However, the continuous mutations of viruses are challenging the efficacies of vaccines and antiviral drugs. A drug repurposing campaign has identified two JAK1/2 inhibitors ruxolitinib and baricitinib as potential antiviral drugs. Ruxolitinib and baricitinib exert dual antiviral effect by modulation of inflammatory response via JAK1/2 and inhibition of viral entry via AAK1 and GAK. Inspired by this, in an effort to diversify chemical space, three analogues ((R)-8, (S)-8, and 9) of ruxolitinib and baricitinb were made using a scaffold hopping strategy. Compound 9 displayed potent and comparable potencies against AAK1, JAK1, and JAK2 compared to baricitinib. Notably, compound 9 showed better selectivity for AAK1, JAK1, and JAK2 over GAK. Besides, compound 9 displayed good druglikeness according to Lipinski''s and Veber''s rule. We thereby identified a potential lead compound 9, which might be used for the further development of anti-coronaviral therapy.
[1]Taizhou Vocat & Tech Coll, Sch Med & Pharmaceut Engn, Taizhou, Zhejiang, Peoples R China.
[2]Fudan Univ, Obstet & Gynecol Hosp, Med Ctr, Shanghai, Peoples R China.
[3]Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Copenhagen, Denmark.
[4]Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2200 Copenhagen, Denmark.
(8.0+极速模式)