ABSTRACT
A novel synthesis of mappicine ketone, which possesses strong selective activity against the herpes viruses HSV-1 and HSV-2, including those Acyclovir-resistant, and human cytomegalovirus (HCMV) has been efficiently accomplished. The synthesis highlights a new pyridone approach that effectively combines a double, intramolecular Michael addition in a conjugated ester-conjugated amide with oxidation-decarboxylation of the resulting piperidone.
Subject(s)
Antiviral Agents/chemical synthesis , Indolizines/chemical synthesis , Quinolines/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Herpesviridae/drug effects , Indolizines/chemistry , Indolizines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Spectrum AnalysisABSTRACT
Styrylquinoline derivatives, known to be potent inhibitors of HIV-1 integrase, have been experimentally tested for their inhibitory effect on the disintegration reaction catalyzed by catalytic cores of HIV-1 and Rous sarcoma virus (RSV) integrases. A modified docking protocol, consisting of coupling a grid search method with full energy minimization, has been specially designed to study the interaction between the inhibitors and the integrases. The inhibitors consist of two moieties that have hydroxyl and/or carboxyl substituents: the first moiety is either benzene, phenol, catechol, resorcinol, or salicycilic acid; the hydroxyl substituents on the second (quinoline) moiety may be in the keto or in the enol forms. Several tautomeric forms of the drugs have been docked to the crystallographic structure of the RSV catalytic core. The computed binding energy of the keto forms correlates best with the measured inhibitory effect. The docking procedure shows that the inhibitors bind closely to the crystallographic catalytic Mg(2+) dication. Additional quantum chemistry computations show that there is no direct correlation between the binding energy of the drugs with the Mg(2+) dication and their in vitro inhibitory effect. The designed method is a leading way for identification of potent integrase inhibitors using in silico experiments.
Subject(s)
Enzyme Inhibitors/chemistry , HIV Integrase Inhibitors/chemistry , HIV Integrase/metabolism , HIV-1/enzymology , Models, Molecular , Quinolines/chemistry , Algorithms , Avian Sarcoma Viruses/enzymology , Binding Sites , DNA/metabolism , Enzyme Inhibitors/metabolism , HIV Integrase/chemistry , HIV Integrase Inhibitors/metabolism , Integrases/metabolism , Magnesium/metabolism , Molecular Conformation , Molecular Structure , Quinolines/metabolism , Recombinant Proteins/metabolism , Static Electricity , Structure-Activity Relationship , ThermodynamicsABSTRACT
Our prior studies showed that polyhydroxylated styrylquinolines are potent HIV-1 integrase (IN) inhibitors that block the replication of HIV-1 in cell culture at nontoxic concentrations. To explore the mechanism of action of these inhibitors, various novel styrylquinoline derivatives were synthesized and tested against HIV-1 IN and in cell-based assays. Regarding the in vitro experiments, the structural requirements for biological activity are a carboxyl group at C-7, a hydroxyl group at C-8 in the quinoline subunit, and an ancillary phenyl ring. However the in vitro inhibitory profile tolerates deep alterations of this ring, e.g. by the introduction of various substituents or its replacement by heteroatomic nuclei. Regarding the ex vivo assays, the structural requirements for activity are more stringent than for in vitro inhibition. Thus, in addition to an o-hydroxy acid group in the quinoline, the presence of one ortho pair of substituents at C-3' and C-4', particularly two hydroxyl groups, in the ancillary phenyl ring is imperatively required for inhibitory potency. Starting from literature data and the SARs developed in this work, a putative binding mode of styrylquinoline inhibitors to HIV-1 IN was derived.
Subject(s)
Anti-HIV Agents/chemical synthesis , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase/metabolism , HIV-1/drug effects , Quinolines/chemical synthesis , Styrenes/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Catalytic Domain , Cell Line , HIV Integrase/chemistry , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , Humans , Protein Binding , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity Relationship , Styrenes/chemistry , Styrenes/pharmacology , Virus ReplicationABSTRACT
On the basis of the fact that several polynucleotidyl transferases, related to HIV integrase, contain in their active site two divalent metal cations, separated by ca. 4 A, new potential HIV integrase inhibitors were designed, in which a quinoline substructure is linked to an aryl nucleus possessing various hydroxy substitution patterns, by means of an ethylenic spacer. Although the most active compounds contain the catechol structure, this group is not essential for the activity, since compound 21 that lacks such a moiety is a potent drug, implicating the presence of a different pharmacophore. The most promising styrylquinolines thus synthesized inhibit HIV-1 integrase in vitro at micromolar or submicromolar concentrations and block HIV replication in CEM cells, with no significant cellular toxicity in a 5-day period assay. These inhibitors are active against integrase core domain-mediated disintegration, suggesting that fragment 50-212 is their actual target. These new styrylquinolines may provide lead compounds for the development of novel antiretroviral agents for AIDS therapeutics, based upon inhibition of HIV integrase. They might also be used in the elucidation of the mechanism of inhibition of this enzyme; e.g., they could serve as candidates for cocrystallization studies with HIV integrase.