Anti-AIDS agents.: 42.: Synthesis and anti-HIV activity of disubstituted (3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone analogues

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 x 10(-6) muM and a therapeutic index of > 2.08 x 10,(7) 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.