A Parallel Synthesis Approach to the Identification of Novel Diheteroarylamide-Based Compounds Blocking HIV Replication: Potential Inhibitors of HIV‑1 Pre-mRNA Alternative Splicing

A 256-compound library was evaluated in an anti-HIV screen to identify structural “mimics” of the fused tetracyclic indole compound <b>1</b> (IDC16) that conserve its anti-HIV activity without associated cytotoxicity. Four diheteroarylamide-type compounds, containing a common 5-nitroisobenzothiazole motif, were identified as active. In subsequent screens, the most potent compound <b>9</b> (1C8) was active against wild-type HIV-1_IIIB (subtype B, X4-tropic) and HIV-1 97USSN54 (subtype A, R5-tropic) with EC₅₀’s of 0.6 and 0.9 μM, respectively. Compound <b>9</b> also inhibited HIV strains resistant to drugs targeting HIV reverse transcriptase, protease, integrase, and coreceptor CCR5 with EC₅₀’s ranging from 0.9 to 1.5 μM. The CC₅₀ value obtained in a cytotoxicity assay for compound <b>9</b> was >100 μM, corresponding to a therapeutic index (CC₅₀/EC₅₀) of approximately 100. Further comparison studies revealed that, whereas the anti-HIV activity for compound <b>9</b> and the parent molecule <b>1</b> are similar, the cytotoxic effect for compound <b>9</b> was, as planned, markedly suppressed