Structure-activity relationship study of the pyridine moiety of isothiazolo[4, 3-b]pyridines as antiviral agents targeting cyclin G-associated kinase. Issue 1 (1st January 2020)

• Record Type: Journal Article
• Authors: Martinez-Gualda, Belén; Pu, Szu-Yuan; Froeyen, Mathy; Herdewijn, Piet; Einav, Shirit; De Jonghe, Steven
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 1(2020)
• Publication Date: 2020-01-01
• Subjects: Cyclin G-associated kinase -- Isothiazolo[4, 3-b]pyridine -- Dengue virus -- Kinase inhibitor -- Antiviral drugs; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.115188
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Novel 3, 5- and 3, 6-disubstituted isothiazolo[4, 3- b ]pyridines were synthesized. Compounds were evaluated for GAK binding affinity. The most potent isothiazolo[4, 3- b ]pyridine analogue was endowed with a GAK IC50 value of 0.024 µM. This compound also exhibited antiviral activity against dengue virus. Abstract: Previously, we reported the discovery of 3, 6-disubstituted isothiazolo[4, 3- b ]pyridines as potent and selective cyclin G-associated kinase (GAK) inhibitors with promising antiviral activity. In this manuscript, the structure-activity relationship study was expanded to synthesis of isothiazolo[4, 3- b ]pyridines with modifications of the pyridine moiety. This effort led to the discovery of an isothiazolo[4, 3- b ]pyridine derivative with a 3, 4-dimethoxyphenyl residue at position 5 that displayed low nanomolar GAK binding affinity and antiviral activity against dengue virus.