Tuning side arm electronics in unsymmetrical cyclotriazadisulfonamide (CADA) endoplasmic reticulum (ER) translocation inhibitors to improve their human cluster of differentiation 4 (CD4) receptor down-modulating potencies

Cyclotriazadisulfonamide prevents HIV entry into cells by down-modulating surface CD4 receptor expression through binding to the CD4 signal peptide. According to a two-site binding model, 28 new unsymmetrical analogs bearing a benzyl tail group and 9 bearing a cyclohexylmethyl tail have been designed and synthesized. The most potent new CD4 down-modulator (40 (CK147): IC50 63 nM) has a 4-dimethylaminobenzenesulfonyl sidearm. One of the two sidearms was varied with substituents in different positions. This gave a range of CD4 down-modulation potencies that correlated well with anti-HIV-1 activities. The sidearms of 21 of the new benzyl-tailed analogs were modeled by means of quantum mechanical calculations. For CADA analogs with arenesulfonamide sidearms, the pIC50 values for CD4 down-modulation correlated with the component of the electric dipole moment in the aromatic ring, suggesting that an attractive electronic interaction is a major factor determining the stability of the complex between the molecule and its target.status: publishe