Cyclotriazadisulfonamide (CADA) compounds prevent HIV entry and replication in cell culture by inhibiting co-translational translocation of human CD4. A series of unsymmetrical CADA analogs have been synthesized and evaluated for CD4 down-modulation. CK147, having a cyclohexylmethyl tail group and one 4-N,N-dimethylaminobenzenesulfonamide side arm, was found to have highest potency towards CD4 down-modulation in CHO cells transfected with a fluorescent CD4 fusion protein (IC50= 60 nM) and in the T-lymphoid cell line MT-4 expressing human CD4 naturally (IC50= 140 nM). In addition, the CK147-induced reduction in CD4 correlated with enhanced anti-HIV-1 NL4.3 activity (IC50= 180 nM). In this study, we investigated the relationship between calculated dipole moment of one arylsulfonamide side arm of the CADA analog and CD4 down-modulation potency. Generally, it was found that CADA compounds having a larger dipole moment in one side arm and no hydrogen bond donor group exhibit higher potencies for inhibition of CD4 translocation and expression on the cell surface.

Effects of sidearm electron density in unsymmetrical cyclotriazadisulfonamide (CADA) analogs on anti-HIV and human CD4 down-modulating abilities

248th National Meeting (2014)

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