Design, Synthesis, and Biological Evaluation of Novel Hybrid Dicaffeoyltartaric/Diketo Acid and Tetrazole-Substituted l-Chicoric Acid Analogue Inhibitors of Human Immuno

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• 作者：David C. Crosby ; Xiangyang Lei ; Charles G. Gibbs ; Brenda R. McDougall ; W. Edward Robinson ; Jr. ; Manfred G. Reinecke
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：November 25, 2010
• 年：2010
• 卷：53
• 期：22
• 页码：8161-8175
• 全文大小：1102K
• 年卷期：v.53,no.22(November 25, 2010)
• ISSN：1520-4804

文摘

Fourteen analogues of the anti-HIV-1 integrase (IN) inhibitor l-chicoric acid (L-CA) were prepared. Their IC₅₀ values for 3′-end processing and strand transfer against recombinant HIV-1 IN were determined in vitro, and their cell toxicities and EC₅₀ against HIV-1 were measured in cells (ex vivo). Compounds 1−6 are catechol/β-diketoacid hybrids, the majority of which exhibit submicromolar potency against 3′-end processing and strand transfer, though only with modest antiviral activities. Compounds 7−10 are L-CA/p-fluorobenzylpyrroloyl hybrids, several of which were more potent against strand transfer than 3′-end processing, a phenomenon previously attributed to the β-diketo acid pharmacophore. Compounds 11−14 are tetrazole bioisosteres of L-CA and its analogues, whose in vitro potencies were comparable to L-CA but with enhanced antiviral potency. The trihydroxyphenyl analogue 14 was 30-fold more potent than L-CA at relatively nontoxic concentrations. These data indicate that L-CA analogues are attractive candidates for development into clinically relevant inhibitors of HIV-1 IN.