SYNTHESIS, COMPUTATIONAL STUDIES AND HIV-1 NEUTRALIZATION ASSAY OF NOVEL MARAVIROC RELATED COMPOUNDS

The AIDS disease is caused by the Human Immunodeficiency Virus (HIV), a retrovirus with RNA genome.[1] The UNAIDS Report 2009 estimated that 33.4 million people worldwide were living with HIV at the end of 2008.[2] Since the AIDS pandemic remains one of the leading global public health threats, the discovery and development of new antiretroviral drugs with reduced toxicity, enhanced potency, different mechanisms of action, and reduced prevalence of adverse drug-drug interactions remain a very high priority. In particular, a promising area of investigation is the identification of agents that inhibit viral attachment and entry into host cells[3] in order to block HIV infection at the early stages. Maraviroc (Selzentry), belongs to the family of entry inhibitor, it is a negative allosteric modulator of coreceptor CCR5 [4], it was approved by the U.S. Food and Drug Administration (FDA) in August 2007 for treatment-experienced people who have HIV strains that are resistant to multiple antiretroviral drugs and for people with drug-sensitive HIV strains, such as those starting antiretroviral therapy for the first time. Maraviroc is the only entry inhibithor approved for the HIV therapy. In this context we have synthesized analogs of compound 1 introducing different changes in the chemical structure instead of the azabyciclo group. The new compounds of general formula 2 were synthesized and their biological activity evaluated. Finally, in an attempt to correlate the geometrical features of these compounds to their HIV-1 inhibitory activity, a modeling study was carried out to ascertain their conformational preferences The chemistry, the computational and biological data will be discussed in the poster.