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 library 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. Under our conditions, a first generation of molecules were prepared and then tested to assess their biological activity in vitro, at Xpress Bio-laboratories (Maryland, USA). Molecular docking analysis prompted the possibility to improve their potential inhibitory activity by structural modifications at the side chains and, therefore, we have exploited our procedure to get a second generation of pyrimidine-based molecules that are presently under biological evaluation.