Structure-based optimization of 2,3-dioxopyrrolidines as potential inhibitors of flaviviral methyltransferases

Molecular Simulations Group, Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina,
Santacruz East, Mumbai-400 098, India
Aix-Marseille Univ, CNRS, AFMB UMR 7257, Marseille, France
Ambernath Organics Pvt. Ltd., 222, The Summit Business Bay, Andheri (E), Mumbai-400 093, India
E-mail: evans.coutinho@bcp.edu.in, santosh.nandan@ambernathorganic.com
Manuscript received online 30 June 2020, accepted 20 July 2020

Various studies have shown that NS5 RNA methyltransferase (MTase) is a key enzyme involved in mRNA capping, a step crucial for flaviviral replication. Therefore, it has been identified as a potential target for therapeutic intervention in infections arising due to flaviviruses. In this paper, we report computer-assisted design of 2,3-dioxopyrrolidines, which were synthesised as guided by molecular docking studies on DENV and ZIKA MTase. Their chemical structures and geometric configuration were characterized by FT-IR, NMR (¹³C and ¹H), MS and small molecule X-ray crystallography. Subsequently, their inhibitory potential was evaluated using an enzyme-based assay in DENV MTase (N7 and 2'O-MTase) and Zika virus MTase (N7 and 2'O-MTase). Furthermore, these molecules were also screened against RNMT (human N7 MTase). The most potent lead (compound W07) is seen to inhibit MTase from DENV with IC₅₀ = 24.6±3.8 µM and ZIKA with IC₅₀ = 9.0±1.7 µM. However, it also inhibits human N7 MTase, indicating plausible toxicity in humans. There is scope to further optimize these molecules to achieve selectivity towards flaviviral MTases.