title: Synthesis and biological evaluation of novel 5(H)-phenanthridin-6-ones, 5(H)-phenanthridin-6-one diketo acid, and polycyclic aromatic diketo acid analogs as new HIV-1 integrase inhibitors.
abstract: A new series of phenanthridinone derivatives, and diketo acid analogs, as well as related phenanthrene and anthracene diketo acids have been synthesized and evaluated as HIV integrase (IN) inhibitors. Several new beta-diketo acid analogs with the phenanthridinone scaffold replaced by phenanthrene, anthracene or pyrene exhibited the highest IN inhibitory potency. There is a general selectivity against the integrase strand transfer step. The most potent IN was 2,4-dioxo-4-phenanthren-9-yl-butyric acid (27f) with an IC(50) of 0.38microM against integrase strand transfer. The phenanthrene diketo acids 27d-f were more potent (IC(50)=2.7-0.38microM) than the corresponding phenanthridinone diketo acid 16 (IC(50)=65microM), suggesting that the polar amide bridge in the phenanthridinone system decreases inhibitory activity relative to the more lipophilic phenanthrene system. This might have to do with the possible binding of the aryl group of the compounds binding to a lipophilic pocket at the integrase active site as suggested by the docking simulations. Molecular modeling also suggested that effectiveness of chelation of the active site Mg(2+) contributes to IN inhibitory potency. Finally, some of the potent compounds inhibited HIV-1 replication in human peripheral blood mononuclear cells (PBMC) with EC(50) down to 8microM for phenanthrene-3-(2,4-dioxo)butyric acid (27d), with a selectivity index of 10 against PBMCs.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Shivaputra
authors.initials: S
authors.lastname: Patil
authors.forename: Shantaram
authors.initials: S
authors.lastname: Kamath
authors.forename: Tino
authors.initials: T
authors.lastname: Sanchez
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: John K
authors.initials: JK
authors.lastname: Buolamwini
mesh_terms: D000818:Animals; D002087:Butyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007651:Keto Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008274:Magnesium; D008958:Models, Molecular; D015394:Molecular Structure; D010616:Phenanthrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010617:Phenanthridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014709:Vero Cells / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: C518545:2,4-dioxo-4-phenanthren-9-yl-butyric acid; D002087:Butyrates; D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D010616:Phenanthrenes; D010617:Phenanthridines; D019427:HIV Integrase; D008274:Magnesium