ABSTRACT
The discovery and SAR study of a series of 4,6-diamino-1,3,5-triazin-2-ol compounds as novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are reported. The lead compounds in this series showed excellent activity against wild-type and drug-resistant RT enzymes and viral strains. In addition, compounds from this series demonstrated favorable pharmacokinetic profile in rat. A preliminary modeling study was conducted to understand the binding mode of this series of compounds.
Subject(s)
Drug Discovery , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Triazines/chemical synthesis , Triazines/pharmacology , Animals , Models, Molecular , Rats , Reverse Transcriptase Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Solid phase, solution, and hybrid approaches to the synthesis of small focused libraries of alpha,alpha-disubstituted-alpha-acylaminoketones have been explored. Solution and hybrid approaches that used support-bound reagents and scavenger resins were the most productive.
ABSTRACT
Two new classes of diphenylether inhibitors of p38alpha MAP kinase are described. Both chemical classes are based on a common diphenylether core that is identified by simulated fragment annealing as one of the most favored chemotypes within a prominent hydrophobic pocket of the p38alpha ATP-binding site. In the fully elaborated molecules, the diphenylether moiety acts as an anchor occupying the deep pocket, while polar extensions make specific interactions with either the adenine binding site or the phosphate binding site of ATP. The synthesis, crystallographic analysis, and biological activity of these p38alpha inhibitors are discussed.
Subject(s)
Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Ethers/chemistry , Ethers/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/classification , Structure-Activity RelationshipABSTRACT
Heterocyclic demonstration libraries for agrochemical screening were prepared from the common intermediates 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles (1), using standard solution-phase techniques. A total of 18 screening libraries were prepared in good to excellent yields. Several members of these libraries were active in the first level of agrochemical screening, especially in the fungicide screen.
Subject(s)
Chemistry, Pharmaceutical , Combinatorial Chemistry Techniques , Heterocyclic Compounds/chemical synthesis , Nitriles/chemistry , Pyridones/chemistry , Cyclization , Drug Evaluation, Preclinical , Fungicides, Industrial/analysis , Fungicides, Industrial/pharmacology , Molecular Weight , StereoisomerismABSTRACT
Two new solid-phase syntheses of substituted pyrazoles are described. The first includes supporting an o-hydroxyacetophenone on Merrifield resin, Vilsmeier-Haack formylation on the methyl group and cyclization with a substituted hydrazine to afford a pyrazole ring with two diversity centers. The second starts from o-hydroxyacetophenone supported on Wang resin, which undergoes a Claisen condensation with a carboxylic acid ester to yield a 1,3-dicarbonyl compound that cyclizes to a pyrazole using a hydrazine. Both methods have been used to synthesize two small pyrazole libraries.
Subject(s)
Acetophenones/chemistry , Combinatorial Chemistry Techniques , Pyrazoles/chemical synthesis , Animals , Biochemistry/methods , Drug Design , Drug Evaluation, Preclinical/methods , Fungicides, Industrial/chemistry , Fungicides, Industrial/pharmacology , Herbicides/chemistry , Herbicides/pharmacology , Insecticides/chemistry , Insecticides/pharmacology , Structure-Activity RelationshipABSTRACT
A library of 35 cis-1-benzoyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolines was prepared. The compounds bore various substitutuents on the benzoyl ring, at the 4-position of the phenylamino ring and at the 6-position of the tetrahydroquinoline ring. The compounds were assayed for their ability to cause expression of a reporter gene downstream of an ecdysone response element in a mammalian cell line engineered to express the ecdysone receptor from Aedes aegypti. In general, compounds with small lipophilic substituents at the meta and para-positions of the benzoyl ring and hydrogen or fluorine at the 4-position of the phenylamino ring and the 6-position of the tetrahydroquinoline ring were the most potent.
Subject(s)
Ecdysone/metabolism , Gene Expression Regulation/drug effects , Quinolines/chemical synthesis , Quinolines/pharmacology , Aedes/metabolism , Animals , Dose-Response Relationship, Drug , Ecdysone/genetics , Isomerism , Ligands , Quinolines/chemistry , Receptors, Steroid/drug effects , Receptors, Steroid/metabolism , Structure-Activity Relationship , Transcriptional Activation/drug effectsABSTRACT
A lead discovery library and a follow-up focused library of alpha-acylaminoketones were designed based on known dibenzoylhydrazine ecdysone agonists, including GS(TM)-E. The compounds were assayed in mammalian cells expressing the ecdysone receptor from Bombyx mori for their ability to cause expression of a reporter gene downstream of an ecdysone response element. The most potent alpha-acylaminoketones were comparable to GS(TM)-E in this assay.
Subject(s)
Amines/chemical synthesis , Amines/pharmacology , Gene Expression/drug effects , Ketones/chemical synthesis , Ketones/pharmacology , Animals , Bombyx/metabolism , Cells, Cultured , Ecdysone/pharmacology , Indicators and Reagents , Lethal Dose 50 , Mice , Molecular Conformation , Receptors, Steroid/antagonists & inhibitors , Structure-Activity Relationship , beta-Galactosidase/biosynthesis , beta-Galactosidase/geneticsABSTRACT
A library of 422 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides was prepared in five steps using solution-phase chemistry. The first step in the synthesis was the reaction of ethyl 2-ethoxymethylene-3-oxo-4,4,4-trifluorobutanoate with thiosemicarbazide, which is reported in the literature to afford a 1:1 mixture of ethyl 1-thiocarbamoyl-5-(trifluoromethyl)pyrazole-4-carboxylate and ethyl 1-thiocarbamoyl-3-(trifluoromethyl)pyrazole-4-carboxylate. We reassigned the structure of the product to be a single compound, ethyl 5-hydroxy-1-thiocarbamoyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-4-carboxylate. This common intermediate was diversified by reaction with 17 alpha-bromoketones affording, in two steps, 17 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxylic acids. Scavenger resins were used to facilitate formation and purification of up to 27 amides from each of these acids in the last step. In addition, the Curtius reaction was applied to 12 of the acids followed by quenching with alcohols to afford a 108-member carbamate library. Certain compounds in the two libraries were toxic to C. elegans.
Subject(s)
Amides/chemical synthesis , Combinatorial Chemistry Techniques/methods , Drug Design , Hydrocarbons, Fluorinated/chemistry , Pyrazoles/chemical synthesis , Thiazoles/chemical synthesis , Amides/pharmacology , Animals , Antinematodal Agents/chemical synthesis , Antinematodal Agents/pharmacology , Caenorhabditis elegans/drug effects , Carbamates/chemistry , Carbamates/pharmacology , Drug Evaluation, Preclinical , Nematoda/drug effects , Pyrazoles/pharmacology , Thiazoles/pharmacologyABSTRACT
The preparation in multigram scale of two metabolites 3-(3,5-dichloro-4-methyl-benzoylamino)-2-hydroxy-3-methyl-pentanoic acid and 3-(3,5-dichloro-benzoylamino)-3-methyl-2-oxo-butyric acid isolated from soil treated with either Zoxium fungicide or Kerb herbicide was efficiently accomplished using a common 5-step synthetic process starting from easily available raw materials.