Synthesis of prodrug-type anti-HIV agents conjugating a REVERSE transcriptase inhibitor to a HIV-1 integrase inhibitor by a spontaneously cleavable linker.

Based on the prodrug concept as well as the combination of two different classes of anti-HIV agents, we have designed and synthesized a series of anti-HIV double-drugs consisting of a nucleoside reverse transcriptase inhibitor (NRTI) conjugated with an integrase inhibitor (INI) through a spontaneously cleavable linker in an effort to enhance the antiviral activity. These conjugates combined in their structure a dideoxy-didehydro-nucleoside (ddN) such as d4T and an INI such as alpha, gamma-diketo acid (DKA) analogues of L-708,906 and L-731,988 linked through an appropriate self-immolative spacer. Among these novel bis-substrate inhibitors, several conjugates exhibited antiviral activity but this effect was accompanied for some of them by an increased cytotoxicity by comparison to d4T, DKA or even some precursors. These compounds are nevertheless interesting candidates for further investigations.