A 256-compound library was evaluated in an anti-HIV screen to identify structural "mimics" of the fused tetracyclic indole compound 1 (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 9 (1C8) was active against wild-type HIV-1IIIB (subtype B, X4-tropic) and HIV-1 97USSN54 (subtype A, R5-tropic) with EC50's of 0.6 and 0.9 µM, respectively. Compound 9 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 9 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 9 and the parent molecule 1 are similar, the cytotoxic effect for compound 9 was, as planned, markedly suppressed.
Alternative Splicing/drug effects , Anti-HIV Agents/pharmacology , Benzothiazoles/pharmacology , HIV-1/drug effects , HIV-1/growth & development , Pyridones/pharmacology , RNA Precursors/metabolism , RNA, Viral/metabolism , Virus Replication/drug effects , Alternative Splicing/genetics , Anti-HIV Agents/chemistry , Benzothiazoles/chemical synthesis , Benzothiazoles/chemistry , Cell Death/drug effects , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , HIV Reverse Transcriptase/metabolism , HIV-1/genetics , Humans , Integrases/metabolism , Molecular Structure , Peptide Hydrolases/metabolism , Pyridones/chemical synthesis , Pyridones/chemistry , RNA Precursors/genetics , RNA, Viral/genetics , Receptors, CXCR5/antagonists & inhibitors , Structure-Activity Relationship
