ABSTRACT
Human immunodeficiency virus type-1 integrase is an essential enzyme for effective viral replication and hence a valid target for the design of inhibitors. We report here on the design and synthesis of a novel series of phthalimide analogues as integrase inhibitors. The short synthetic pathway enabled us to synthesize a series of analogues with a defined structure diversity. The presence of a single carbonyl-hydroxy-aromatic nitrogen motif was shown to be essential for the enzymatic activity and this was confirmed by molecular docking studies. The enzymatically most active compound from this series is 7-(3,4-dichlorobenzyl)-5,9-dihydroxypyrrolo[3,4-g]quinoxaline-6,8-dione (15l) with an IC(50) value of 112 nM on the HIV-1 integrase enzyme, while ((7-(4-chlorobenzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione (15k)) showed an EC(50) of 270 nM against HIV-1 in a cell-based assay.
Subject(s)
Anti-HIV Agents/chemical synthesis , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase/metabolism , Heterocyclic Compounds, 3-Ring/chemical synthesis , Phthalimides/chemical synthesis , Pyrroles/chemical synthesis , Quinoxalines/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Binding Sites , Cell Line , HIV Integrase/chemistry , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Models, Molecular , Phthalimides/chemistry , Phthalimides/pharmacology , Protein Binding , Pyrroles/chemistry , Pyrroles/pharmacology , Quinoxalines/chemistry , Quinoxalines/pharmacology , Structure-Activity RelationshipABSTRACT
On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an improved broad spectrum activity and acceptable pharmacokinetic properties. Several of these compounds display an exceptional broad spectrum activity against a panel of highly cross-resistant mutants. Certain members of these series exhibit favorable pharmacokinetic profiles in rat and dog. Crystal structures and molecular modeling were used to rationalize the broad spectrum profile resulting from the extension into the P2' pocket of the HIV-1 protease.
Subject(s)
Benzoxazoles/chemical synthesis , Drug Resistance, Multiple, Viral , HIV Protease Inhibitors/chemical synthesis , HIV-1/drug effects , Sulfonamides/chemical synthesis , Thiazoles/chemical synthesis , Animals , Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Binding Sites , Calorimetry , Cell Line , Crystallography, X-Ray , Dogs , Drug Stability , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , Humans , In Vitro Techniques , Microsomes, Liver/metabolism , Models, Molecular , Rats , Rats, Wistar , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thermodynamics , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.
