Sechi Mario, Rizzi Giuseppe, Bacchi Alessia, Carcelli Mauro, Rogolino Dominga, Pala Nicolino, Sanchez Tino W, Taheri Laleh, Dayam Raveendra, Neamati Nouri
Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Via Muroni 23/A, 07100 Sassari, Italy.
Bioorg Med Chem. 2009 Apr 1;17(7):2925-35. doi: 10.1016/j.bmc.2008.10.088. Epub 2008 Nov 6.
Previously, we discovered linomide analogues as novel HIV-1 integrase (IN) inhibitors. Here, to make possible structure-activity relationships, we report on the design and synthesis of a series of substituted dihydroquinoline-3-carboxylic acids. The crystal structure of the representative compound 2c has also been solved. Among the eight new analogues, 2e showed a potency in inhibiting IN strand transfer catalytic activity similar to the reference diketo acid inhibitor L-731,988 (IC(50)=0.9 microM vs. 0.54 microM, for 2e and L-731,988, respectively). Furthermore, none of the compounds showed significant cytotoxicity in two tested cancer cell lines. These compounds represent an interesting prototype of IN inhibitors, potentially involved in a metal chelating mechanism, and further optimization is warranted.
此前，我们发现利诺米德类似物是新型HIV-1整合酶（IN）抑制剂。在此，为了建立构效关系，我们报道了一系列取代二氢喹啉-3-羧酸的设计与合成。还解析了代表性化合物2c的晶体结构。在这八个新类似物中，2e在抑制IN链转移催化活性方面表现出的效力与参考二酮酸抑制剂L-731,988相似（2e和L-731,988的IC(50)分别为0.9 microM和0.54 microM）。此外，这些化合物在两种测试癌细胞系中均未表现出明显的细胞毒性。这些化合物代表了一种有趣的IN抑制剂原型，可能涉及金属螯合机制，值得进一步优化。
