Anti-AIDS Agents. 37. Synthesis and Structure−Activity Relationships of (3‘R,4‘R)-(+)-cis-Khellactone Derivatives as Novel Potent Anti-HIV Agents

To explore the structural requirements of (+)-cis-khellactone derivatives as novel anti-HIV agents, 24 monosubstituted 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives were synthesized asymmetrically. These compounds included 4 isomeric monomethoxy analogues (3−6), 4 isomeric monomethyl analogues (7−10), 4 4-alkyl/aryl-substituted analogues (11−14), and 12 4-methyl-(+)-cis-khellactone derivatives (15−26) with varying 3',4'-substituents. These (+)-cis-khellactone derivatives were screened against HIV-1 replication in acutely infected H9 lymphocytes. The results demonstrated that the (3'R,4'R)-(+)-cis-khellactone skeleton, two (S)-(−)-camphanoyl groups at the 3'- and 4'-positions, and a methyl group on the coumarin ring, except at the 6-position, were optimal structural moieties for anti-HIV activity. 3-Methyl- (7), 4-methyl- (8), and 5-methyl- (9) 3',4'-di-O-(S)-camphanoyl-(3'R,4'R)-(+)-cis-khellactone showed EC50 and therapeutic index values of <5.25 × 10-5 μM and >2.15 × 106, respectively, in H9 lymphocytes, which are much better than those of DCK and AZT in the same assay. Furthermore, 8 and 9 also showed potent inhibitory activity against HIV-1 replication in the CEM-SS cell line, and most monosubstituted DCK analogues were less toxic than DCK in both assays.