Design And Synthesis Of1,3-diketo And Phophoryl Compounds As HIV-1Integrase Inhibitors

Human immunodeficiency virus type1(HIV-1) is the causative pathogen of AIDS. The viral enzyme integrase (IN), a crucial enzyme for the viral replication, has lower toxicity and higher selectivity because there is no counterpart in human cell. It is a hot target for the development of new anti HIV-1inhibitors.The diketo acid moiety was believed to be the most crucial pharmacophore for the inhibition of viral replication. S-1360, is the first IN inhibitor for human clinical trials. Unfortunately, it failed in efficacy tests for infected patients due to its metabolic instability. We synthesized new compounds that possess the diketo bioisostere and polyhydroxy-phenyl. The1,2,3-triazole ring is not only a hydrogen-bond donor but also as a linking unit in the structure scaffold. Its planar structure may facilitate the π stacking interaction with target enzymes. Therefore, in order to verify how the function group of hydroxyl on aromatic rings and halogen on aromatic rings effect the inhibitory activities, we designed and synthesized28targeting compounds as new integrase inhibitors.Elvitegravir (GS-9137), the first quinolone carboxylic acid developed by Gilead. It has entered the Ⅲ clinical trials. Among these, the quinolone carboxylic acid is the crucial pharmacophore. Phosphoryl is the bioisostere of carbonyl. Research shows phosphoyl in stead of carbonyl could improve the anti-HTV activity. We designed and synthesized3new quinolone phosphoryl compounds.All targeting compounds and intermediates are identified by1H NMR,13C NMR and ESI-MS. Their bioactivity against HIV is in test.