Design, Synthesis, and Biological Evaluation of Novel 2-Heteroaryl-oxazolidine-4-one Derivatives as Novel HBV Capsid Assembly Modulators

Using 2-pyrazole oxazolidine-4-one derivative 1 as the lead compound, a series of novel 2-heteroaryl-oxazolidine-4-one derivatives were designed and synthesized by replacing pyrazole moiety with other heterocycles, including methyl pyrazole, oxazole, thiazole, triazole, and reverse pyrazoles, based on the principle of bioisosterism. The structures of target compounds were established by ¹H-NMR, ¹³C-NMR, and electrospray ionization (ESI)-MS. Majority of these compounds showed moderate to good inhibitory activities against hepatitis B virus (HBV) DNA proliferation with low cytotoxicities. Especially, compound 7g showed the most potent anti-HBV activity with EC₅₀ value of 0.059 µM, accompanied with better selectivity index (SI) value than that of lead compound. Our research revealed the structure-activity relationship (SAR) of these newly designed compounds and compound 7g was identified as the potential HBV capsid assembly modulator.