Synthesis of Diketoacid based HIV-1 integrase inhibitors

Replication of retroviruses depends on the integration of a double stranded DNA copy of the retroviral genome into the host cell nuclear DNA. Integration requires the virus-encoded protein integrase (IN). This enzyme represents an attractive target for therapy because of its essential role in viral replication cycle and the lack of cellular counterpart. IN mediates the integration of retroviral DNA into host chromosomes by two distinct processes known as 3’-processing (3’-P) and strand transfer (ST), respectively. Initially, the enzyme recognizes the LTR terminal of the viral DNA, from which removes the last two nucleotides (GT), thus leaving two recessed 3’-OH ends (3’-P reaction). Then, IN catalyzes the joining of the processed 3’-ends to the 5’-ends of the host DNA (ST reaction). The integration reaction is completed by the removal of unpaired nucleotides and gap repair by cellular enzymes that lead to provirus formation.1 The two most predominant classes of inhibitors are polyhydroxylated aromatic compounds and aryl -diketoacids (ADK). ADK-based inhibitors show selective inhibition of the ST reaction and may function by competing with host DNA in binding to the IN-proviral DNA complex. Moreover, they bind the catalytic triad “DD35E motif” required for catalysis by coordination of divalent metal ions (Mg2+ in vivo, Mn2+ in vitro). 2 All the former examples of ADK inhibitors share a common -diketopropyl moiety linking to an aryl or heteroaryl system and the carboxy or tetrazole group. Structural modifications to both these latter substituents were planned in order to evaluate effects on HIV-1 IN inhibitory potency.