Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 6, Pages 2633-2647Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01832
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Funding
- KU Leuven (GOA) [10/014, PF/10/018]
- Foundation of Scientific Research (FWO) [G-0485-08, G-0528-12]
- Foundation Dormeur, Vaduz
- CHAARM project of the European Commission [242135]
- National Science Foundation [CHE-0521191]
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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 analogues bearing a benzyl tail group and nine 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 side arm. One of the two side arms 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 side arms of 21 of the new benzyl-tailed analogues were modeled by means of quantum mechanical calculations. For-CADA analogues with arenesulfonamide side arms, the pIC(50) 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.
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