Fragment‐Based Design of Pseudo‐Natural Products, Synthesis, and Evaluation of Their <scp>HIV</scp> ‐1 Latency‐Reversing Properties

The goal of this project is to design, synthesize, and test compounds that combine fragments derived from natural products (NPs) for their HIV-1 latency-reversal properties, particularly those that act by histone deacetylase inhibition. A fragment library was created by implementing the Retrosynthetic Combinatorial Analysis Procedure (RECAP) on a collection of NPs isolated from different regions in Africa. The top-scoring docked fragments within the histone deacetylase (HDAC1) binding site were reconstructed to design and synthesize chemical scaffolds that have not been previously described as HDAC inhibitors. Synthesized compounds were then tested for the ability to reverse HIV latency in J-Lat 10.6 cells and/or inhibit cellular histone deacetylases. The synthesized scaffolds include indole-chalcones and aminobenzamides. Of fifty-one synthesized compounds, compound S2-13 was the most active with HIV latency reversal 20.2% ± 6.2% of J-Lat 10.6 cells at 10 μg/mL (25.1 μM), which was comparable to the HIV latency-reversing agent Prostratin. S2-13 also inhibited HDAC activity with a half-maximal inhibitory concentration (IC₅₀) of 17.0 μM. We demonstrate that the use of pseudo-NPs can identify novel chemical scaffolds that can reverse HIV latency and inhibit HDACs in vitro.