New Antiviral INSTIs: Design, Synthesis And Biological Evaluation.

The Highly Active Antiretroviral Therapy (HAART)1 includes a combination of two or more drugs that act against three viral enzymes: reverse transcriptase, protease, and integrase (IN). The latter catalyzes the integration of the viral DNA with host DNA and was recently identified as a target for a promising class of drugs, the Integrase Strand Transfer Inhibitors (INSTI).2 Currently, three drugs that seem to inhibit efficiently IN-HIV-1, namely Raltegravir, Elvitegravir and Dolutegravir, have been approved by FDA (American Food and Drug Administration) for therapeutic use3. Nonetheless, the outbreak of drug resistance during the therapeutic approach requires the continuous design of new antivirals. As a part of a research programme focused on the development of new INSTI structures, we report herein design and synthesis of a series of novel cytosine- as well as guanine-based systems (as depicted in the figure), originating from preliminary conformational analysis which showed that both cores provide adequate facial orientation in the bioactive conformation, in the presence of functional groups suitable for the insertion of additional structural elements. All the synthesized products were tested to assess their biological activity in vitro, at Xpress Bio-laboratories in Maryland (USA). In addition, molecular docking analyses have suggested the possibility to improve their potential inhibitory activity by structural modifications on the side chains. Thereafter, the second part we have exploited the developed procedure to prepare a second generation of pyrimidine based molecules, currently under biological evaluation.