Synthesis and Structure-Activity Relationship Studies of Cyclotriaza Compounds as CD4 Down-Modulators and Anti-HIV Agents

Cyclotriazadisulfonamide (CADA) inhibits human immunodeficiency virus (HIV) by down-modulating cell surface CD4 receptor expression. More specifically, CADA inhibits co-translational translocation of nascent human CD4 across the endoplasmic reticulum (ER) membrane. The goal of the studies described here is to optimize the effect of electron density of the second side arm on CD4 down-modulation and HIV inhibition. A total of 35 new unsymmetrical CADA compounds were synthesized keeping one sidearm fixed as p-toluenesulfonamide and merely varying the second sidearm. Thirty new CADA analogs having two different arylsulfonamide sidearms were synthesized including 26 analogs with benzyl tail group and 6 analogs with cyclohexylmethyl tail group. Five CADA analogs having one benzamide sidearms while keeping the other sidearm fixed as p-toluenesulfonamide were also synthesized. The new compounds showed a wide range of activity toward CD4 down-modulation. Results showed that CK147 (IC50 53 nM), bearing a 4-dimethylamino sidearm and a cyclohexylmethyl tail group is the most potent CADA analog synthesized to date. Benzamide analogs were found to be less active compared to their corresponding disulfonamide analogs. The general conclusion is that high election density in the second benzenesulfonyl side with electron donating group present at the para position of the second arenesulfonyl side arm, without hydrogen bond donating ability, produces the highest CD4 down-modulating potency. Dipole moments calculated for the model molecule of the second side arm of CADA analogs showed that there is a correlation between the magnitude of the dipole moment and the observed activities. A pyridine tailed CADA analog, SH28, was found to be ten times less active than CADA. To improve the potency, an attempt was made to synthesize more pyridine tailed CADA analogs. Ongoing research on the synthesis of pyridine tailed CADA analogs is believed to help improve drug like properties of CADA compounds.