Effects of Oxygen Atom Position in Linear Side Chains of Ansellone Analogues on HIV Latency-Reversing Activity

Antiretroviral therapy can manage HIV infections, but a cure remains elusive owing to viral latency. The "shock and kill" strategy uses latency-reversing agents (LRAs) to reactivate viral production toward eliminating latent HIV. However, developing novel LRA scaffolds remains a critical challenge. This study focused on a structurally simplified hydrobenzopyran analogue of ansellone A, a natural product with latency-reversing activity. To investigate the influence of incorporating ether oxygen into the alkyl chain, thought to anchor to the biological membrane, on the biological activity, we designed and synthesized a series of hydrobenzopyran analogs with varying oxygen positions in their lipophilic side chains. Biological evaluation in J-Lat 10.6 and TZM-bl cells revealed that the oxygen atom position did not considerably influence the HIV latency-reversing activity. Furthermore, none of the compounds affected cell viability. These findings suggest that ether-containing hydrobenzopyran derivatives represent a viable and synthetically flexible scaffold for the development of novel LRAs.