Anti-AIDS Agents. 42. Synthesis and Anti-HIV Activity of Disubstituted (3‘R,4‘R)-3‘,4‘-Di-O-(S)-camphanoyl-(+)-cis-khellactone Analogues

• Published in: Journal of medicinal chemistry 2001-03, Vol.44 (5), p.664-671
• Main Authors: Xie, Lan, Takeuchi, Yasuo, Cosentino, L. Mark, McPhail, Andrew T, Lee, Kuo-Hsiung
• Format: Article
• Language: English
• 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; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cell Line; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - pharmacology; Crystallography, X-Ray; HIV-1 - drug effects; Humans; Inhibitory Concentration 50; Medical sciences; Pharmacology. Drug treatments; Structure-Activity Relationship; T-Lymphocytes - cytology; T-Lymphocytes - virology; Virus Replication
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000070g

A series of disubstituted 3‘,4‘-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogues (1 − 10) were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. 5-Methoxy-4-methyl DCK (8) was the most promising compound with an EC50 value of 7.21 × 10-6 μM and a therapeutic index of >2.08 × 10, which were much better than those of lead compound DCK in the same assay. Another six disubstituted DCK analogues (1 − 5 and 7) were more potent than AZT but less active than DCK. Conformational analysis suggested that resonance of the coumarin system is an essential structural feature for potent anti-HIV activity. Steric compression of C(4) and C(5) substituents of the coumarin moiety can reduce the overall planarity and thus resonance of the coumarin nucleus, resulting in a decrease or lack of anti-HIV activity.