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

J Med Chem. 2016 Mar 10;59(5):1869-79. doi: 10.1021/acs.jmedchem.5b01357. Epub 2016 Feb 29.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / drug effects*
  • Alternative Splicing / genetics
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Benzothiazoles / chemical synthesis
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacology*
  • Cell Death / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • HIV-1 / growth & development*
  • Humans
  • Integrases / metabolism
  • Molecular Structure
  • Peptide Hydrolases / metabolism
  • Pyridones / chemical synthesis
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • RNA Precursors / genetics
  • RNA Precursors / metabolism*
  • RNA, Viral / genetics
  • RNA, Viral / metabolism*
  • Receptors, CXCR5 / antagonists & inhibitors
  • Structure-Activity Relationship
  • Virus Replication / drug effects*

Substances

  • 1-methyl-N-(5-nitrobenzo(d)isothiazol-3-yl)-4-oxo-1,4-dihydropyridine-3-carboxamide
  • Anti-HIV Agents
  • Benzothiazoles
  • Pyridones
  • RNA Precursors
  • RNA, Viral
  • Receptors, CXCR5
  • Integrases
  • HIV Reverse Transcriptase
  • Peptide Hydrolases