Structure-activity relationships: Analogues of the dicaffeoylquinic and dicaffeoyltartaric acids as potent inhibitors of human immunodeficiency virustype 1 integrase and replication

The dicaffeoylquinic acids (DCQAs) and dicaffeoyltartaric acids (DCTAs) are potent and selective inhibitors of human immunodeficiency virus type 1 (HI V-1) integrase. They also inhibit HIV-1 replication at nontoxic concentrati ons; Since integrase is an excellent target for anti-HIV therapy, structure -activity relationships were employed to synthesize compounds with: (1) imp roved potency against HIV-1 integrase, (2) improved anti-HIV effect in tiss ue culture, and (3) increased selectivity as indicated by low cellular toxi city. Thirty-four analogues of the DCTAs and DCQAs were synthesized and tes ted for cell toxicity, anti-HIV activity, and inhibition of HIV-1 integrase . Seventeen of the 34 analogues had potent activity against HIV-1 integrase ranging from 0.07 to >10 mu M. Seventeen analogues that were synthesized o r purchased had no inhibitory activity against integrase at concentrations of 25 mu M. Of the biologically active analogues, 7 of the 17 inhibited HIV replication at nontoxic concentrations. The most potent compounds were D-c hicoric acid, meso-chicoric acid, bis(3,4-dihydroxydihydrocinnamoyl)-L-tart aric acid, digalloyl-L-tartaric acid, bis(3,4-dihydroxybenzoyl)-L-tartaric acid, dicaffeoylglyceric acid, and bis(3,4-dihydroxyphenylacetyl)-L-tartari c acid. Anti-HIV activity of the active compounds in tissue culture ranged from 35 to 0.66 mu M. Structure-activity relationships demonstrated that bi scatechol moieties were absolutely required for inhibition of integrase, wh ile at least one free carboxyl group was required for anti-HIV activity. Th ese data demonstrate that analogues of the DCTAs and the DCQAs can be synth esized which have improved activity against HIV integrase.