Design, synthesis, and biological evaluation of novel ruxolitinib and baricitinib analogues for potential use against COVID-19.
Chem Biol Drug Des
; 2022 Nov 11.
Article
in English
| MEDLINE | ID: covidwho-2242737
ABSTRACT
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Type of study:
Experimental Studies
Topics:
Vaccines
Language:
English
Journal subject:
Biochemistry
/
Pharmacy
/
Pharmacology
Year:
2022
Document Type:
Article
Affiliation country:
Cbdd.14179
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