ABSTRACT
Cinnoline or Benzo-pyridazine has its place in the family of fairly well-known benzfuseddiazine heterocycles. Because of its natural occurrence and synthetic exploration, cinnoline compounds validated its thought-provoking bioactivity through a number of research publications and patents during last few decades. A creative consideration has been rewarded to the synthesis of cinnoline based heterocyclic compounds, mostly due to their wide range of diverse pharmacological activities. The present review covers the principle approaches to the synthesis of cinnoline nucleus and almost all biological properties of 115 cinnoline derivatives reported during the last 65 years from natural and synthetic origin with 140 references.
Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Inflammatory Agents/pharmacology , Antifungal Agents/pharmacology , Antineoplastic Agents/pharmacology , Heterocyclic Compounds, 2-Ring/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aspergillus niger/drug effects , Candida albicans/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Cyclooxygenase 2/metabolism , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Humans , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular StructureABSTRACT
Pyrimidine-1,3-oxazolidin-2-arylimino hybrids have been synthesized as a new class of antibacterial agents. The synthetic approach exploits a Cu(II)-catalyzed intramolecular halkoxyhalogenation of alkynyl ureas, followed by a Suzuki coupling reaction with 2,4-dimethoxypyrimidin-5-boronic acid. Biological screenings revealed that most of the compounds showed moderate to good activity against two Gram-positive (B. subtilis, S. aureus) and three Gram-negative (P. aeruginosa, S. typhi, K. pneumonia) pathogenic strains. A molecular docking study, performed in the crystal structure of 50S ribosomal unit of Haloarcula marismortui, indicated that pyrimidine-oxazolidin-2-arylimino hybrids 8c and 8h exhibited a high binding affinity (-9.65 and -10.74 kcal/mol), which was in agreement with their good antibacterial activity. The obtained results suggest that the combination of pyrimidine and oxazolidone moieties can be considered as a valid basis to develop new further modifications towards more efficacious antibacterial compounds.
Subject(s)
Anti-Bacterial Agents , Bacteria/growth & development , Haloarcula marismortui , Heterocyclic Compounds, 2-Ring , Ribosome Subunits, Large, Archaeal/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/chemistry , Drug Evaluation, Preclinical , Haloarcula marismortui/chemistry , Haloarcula marismortui/growth & development , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacologyABSTRACT
We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.
Subject(s)
Antipsychotic Agents/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Imidazoles/chemistry , Pyrimidinones/chemistry , Receptor, Metabotropic Glutamate 5/chemistry , Allosteric Regulation , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacokinetics , Brain/metabolism , Drug Evaluation, Preclinical , Half-Life , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Locomotion/drug effects , Microsomes, Liver/metabolism , Protein Binding , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Rats , Receptor, Metabotropic Glutamate 5/metabolism , Structure-Activity RelationshipABSTRACT
[reaction: see text] The first asymmetric total synthesis of EI-1941-1, -2, and -3, inhibitors of the interleukin-1beta converting enzyme (ICE), has been accomplished, starting from a chiral epoxy iodoquinone 11, a key intermediate in our total synthesis of epoxyquinols A and B. Despite a failure to synthesize the inhibitors by our postulated biosynthetic route, we were able to diastereoselectively synthesize them via an intramolecular carboxypalladation with the key steps being a 6-endo cyclization mode followed by beta-hydride elimination. The investigation of the biological properties of EI-1941-1, -2, and -3 and their derivatives disclosed them to be potent and effective ICE inhibitors with less cytotoxicity than EI-1941-1 and -2 in a cultured cell system.
Subject(s)
Caspase Inhibitors , Cyclohexanones/chemical synthesis , Cyclohexanones/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Epoxy Compounds/chemical synthesis , Epoxy Compounds/pharmacology , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacology , Cell Line , Cell Survival/drug effects , Cyclohexanones/chemistry , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Epoxy Compounds/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Humans , Molecular Conformation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A library of 1,2,3-triazoles, isoxazoles, 1,2,4-oxadiazoles, and isoxazoline-containing 1,2-di-heterocyclic-substituted compounds with three points of diversity linked by an E double bond were prepared. Key steps include a 1,3-dipolar cycloaddition and Porco's two-step, one-pot condensation and alpha-alkylation reaction of selenium resins.
Subject(s)
Alkenes/chemistry , Alkenes/chemical synthesis , Combinatorial Chemistry Techniques/methods , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/chemical synthesis , Resins, Synthetic/chemistry , Selenium/chemistry , Drug Industry/methodsABSTRACT
CsOH- or Ag(2)O-mediated cycloalkylation of (alkylidene)bisperoxides 3 and 1,n-dihaloalkanes (n = 3-8) provided the corresponding medium-sized 1,2,4,5-tetraoxacycloalkanes 4-8 in moderate yields. Subsequent evaluation of the antimalarial activity of the cyclic peroxides 4-8 in vitro and in vivo revealed that 1,2,6,7-tetraoxaspiro[7.11]nonadecane 4a has considerable potential as a new, inexpensive, and potent antimalarial drug.
Subject(s)
Antimalarials/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemical synthesis , Spiro Compounds/chemical synthesis , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Cesium , Cyclization , Drug Evaluation, Preclinical , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Hydroxides , Malaria/drug therapy , Malaria/parasitology , Mice , Oxides , Plasmodium berghei , Plasmodium falciparum/drug effects , Silver Compounds , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis of a versatile L-rhamnose monosaccharide synthon is described. This synthon is used in the synthesis of a disaccharide containing the rare sugar, 6-deoxy-L-glucose, linked to the 3-C-hydroxymethyl group of methyl 2,3-O-isopropylidene 3-C-(hydroxymethyl)-beta-D-erythrofuranoside.