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 (IC50 = 0.9 lM vs. 0.54 lM, 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.
Design and synthesis of novel dihydroquinoline-3-carboxylic acids as HIV-1 integrase inhibitors / Sechi, Mario; Giuseppe, Rizzi; Alessia, Bacchi; Mauro, Carcelli; Dominga, Rogolino; Nicolino, Pala; TINO W., SANCHEZ C; Laleh, Taheri; Raveendra, Dayam; Nouri, Neamati. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 17:(2009), pp. 2925-2935.