Cyclotriazadisulfonamide (CADA, figure) potently inhibits human immunodeficiency virus (HIV) entry and replication by specifically down-modulating the main HIV receptor, CD4. The specific biomolecular target is unknown, but CADA apparently inhibits translocation of nascent CD4 across the membrane of the endoplasmic reticulum. Previous structure-activity relationship (SAR) studies revealed that unsymmetrical CADA analogs bearing one electron-rich substituted benzenesulfonyl side arm are among the most potent (figure). For example, VGD027 (IC50 0.30 �M) and VGD020 (IC50 0.046 �M) with one 4-methoxybenesulfonyl side arm are both more potent than CADA (IC50 0.56 �M) for CD4 receptor down-modulation in CD4-transfected cells (J. Med. Chem. 2011  , 54, 5712). The current study probes the effect of many additional electron-rich arenesulfonyl side arms on CD4 down-modulation and anti-HIV potency. Syntheses and SAR studies are reported for the new compounds, which display a wide range of potency.

Synthesis of electron-rich cyclotriazadisulfonamide (CADA) analogs as anti-HIV and human CD4 receptor down-modulating agents

245th National Meeting (2013)

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