Synthesis and Structure−Activity Relationship Studies of CD4 Down-Modulating Cyclotriazadisulfonamide (CADA) Analogues

• Published in: Journal of medicinal chemistry Vol. 49; no. 4; pp. 1291 - 1312
• Main Authors: Bell, Thomas W, Anugu, Sreenivasa, Bailey, Patrick, Catalano, Vincent J, Dey, Kaka, Drew, Michael G. B, Duffy, Noah H, Jin, Qi, Samala, Meinrado F, Sodoma, Andrej, Welch, William H, Schols, Dominique, Vermeire, Kurt
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.02.2006; Amer Chemical Soc
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; CD4 Antigens - biosynthesis; Cell Line; Chemistry, Medicinal; Crystallography, X-Ray; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; HIV-1 - drug effects; Humans; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Conformation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Quantitative Structure-Activity Relationship; Science & Technology; REPLICATION; HIV; ANALYSIS COMSIA; MOLECULAR SIMILARITY INDEXES; RECEPTOR; ANTI-CD4 MONOCLONAL-ANTIBODY; HUMAN-IMMUNODEFICIENCY-VIRUS; FIELD ANALYSIS; INHIBITOR; EXPRESSION; Sulfonamide; HIV-1 virus; Prediction; Retroviridae; Lentivirus; In vitro; Modeling; Macrocycle; Virus; Three dimensional model; Structure activity relation; Molecular model; Comparative molecular field analysis method; Antiviral; Human immunodeficiency virus; Chemical synthesis; Conformation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0582524

HIV attachment via the CD4 receptor is an important target for developing novel approaches to HIV chemotherapy. Cyclotriazadisulfonamide (CADA) inhibits HIV at submicromolar levels by specifically down-modulating cell-surface and intracellular CD4. An effective five-step synthesis of CADA in 30% overall yield is reported. This synthesis has also been modified to produce more than 50 analogues. Many tail-group analogues have been made by removing the benzyl tail of CADA and replacing it with various alkyl, acyl, alkoxycarbonyl and aminocarbonyl substituents. A series of sidearm analogues, including two unsymmetrical compounds, have also been prepared by modifying the CADA synthesis, replacing the toluenesulfonyl sidearms with other sulfonyl groups. Testing 30 of these compounds in MT-4 cells shows a wide range of CD4 down-modulation potency, which correlates with ability to inhibit HIV-1. Three-dimensional quantitative structure−activity relationship (3D-QSAR) models were constructed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The X-ray crystal structures of four compounds, including CADA, show the same major conformation of the central 12-membered ring. The solid-state structure of CADA was energy minimized and used to generate the remaining 29 structures, which were similarly minimized and aligned to produce the 3D-QSAR models. Both models indicate that steric bulk of the tail group, and, to a lesser extent, the sidearms mainly determine CD4 down-modulation potency in this series of compounds.