| Abstract
| - The dicaffeoylquinic acids (DCQAs) and dicaffeoyltartaric acids (DCTAs) are potent and selectiveinhibitors of human immunodeficiency virus type 1 (HIV-1) integrase. They also inhibit HIV-1replication at nontoxic concentrations. Since integrase is an excellent target for anti-HIVtherapy, structure−activity relationships were employed to synthesize compounds with: (1)improved potency against HIV-1 integrase, (2) improved anti-HIV effect in tissue culture, and(3) increased selectivity as indicated by low cellular toxicity. Thirty-four analogues of the DCTAsand DCQAs were synthesized and tested for cell toxicity, anti-HIV activity, and inhibition ofHIV-1 integrase. Seventeen of the 34 analogues had potent activity against HIV-1 integraseranging from 0.07 to >10 μM. Seventeen analogues that were synthesized or purchased hadno inhibitory activity against integrase at concentrations of 25 μM. Of the biologically activeanalogues, 7 of the 17 inhibited HIV replication at nontoxic concentrations. The most potentcompounds were d-chicoric acid, meso-chicoric acid, bis(3,4-dihydroxydihydrocinnamoyl)-l-tartaric acid, digalloyl-l-tartaric acid, bis(3,4-dihydroxybenzoyl)-l-tartaric acid, dicaffeoylglycericacid, and bis(3,4-dihydroxyphenylacetyl)-l-tartaric acid. Anti-HIV activity of the activecompounds in tissue culture ranged from 35 to 0.66 μM. Structure−activity relationshipsdemonstrated that biscatechol moieties were absolutely required for inhibition of integrase,while at least one free carboxyl group was required for anti-HIV activity. These datademonstrate that analogues of the DCTAs and the DCQAs can be synthesized which haveimproved activity against HIV integrase.
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