Optimization, and biological evaluation of 3-O-β-chacotriosyl betulinic acid amide derivatives as novel small-molecule Omicron

Abstract

SARS-CoV-2 Omicron viruses possess a high antigenic shift, and the approved anti-SARS-CoV-2 drugs are extremely limited, which makes the development of new antiviral drugs for the clinical treatment and prevention of SARS-CoV-2 outbreaks imperative. We have previously discovered a new series of markedly potent small-molecule inhibitors of SARS-CoV-2 virus entry, exampled by the hit compound 2. Here, we report a further study of bioisosteric replacement of the eater linker at the C-17 position of 2 with a variety of aromatic amine moieties, followed by a focused structure-activity relationship study, leading to the discovery of a series of novel 3-O-β-chacotriosyl BA amide derivatives as small-molecule Omicron fusion inhibitors with improved potency and selectivity index. Particularly, our medicinal chemistry efforts have resulted in a potent, and efficacious lead compound S-10 with appreciable pharmacokinetic properties, which exhibited broad-spectrum potency against Omicron and other variants with EC₅₀ values ranging from 0.82 to 5.45 μM. Mutagenesis studies confirmed that inhibition of Omicron viral entry was mediated by the direct interaction with S in the prefusion state. These results reveal that S-10 is suitable for further optimization as Omicron fusion inhibitors, with the potential to be developed as therapeutic agents for the treatment and control of SARS-CoV-2 ant its variants infections.

Keywords: 3-O-β-chacotriosyl BA; Membrane fusion; Omicron; Structure-activity relationship.