RESUMO
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.
Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Aspergillus niger/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura MolecularRESUMO
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.
Assuntos
Antibacterianos , Bactérias/crescimento & desenvolvimento , Haloarcula marismortui , Compostos Heterocíclicos com 2 Anéis , Subunidades Ribossômicas Maiores de Arqueas/química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/química , Avaliação Pré-Clínica de Medicamentos , Haloarcula marismortui/química , Haloarcula marismortui/crescimento & desenvolvimento , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologiaRESUMO
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.
Assuntos
Antipsicóticos/química , Compostos Heterocíclicos com 2 Anéis/química , Imidazóis/química , Pirimidinonas/química , Receptor de Glutamato Metabotrópico 5/química , Regulação Alostérica , Animais , Antipsicóticos/síntese química , Antipsicóticos/farmacocinética , Encéfalo/metabolismo , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Humanos , Imidazóis/síntese química , Imidazóis/farmacocinética , Locomoção/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ligação Proteica , Pirimidinonas/síntese química , Pirimidinonas/farmacocinética , Ratos , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-AtividadeRESUMO
[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.
Assuntos
Inibidores de Caspase , Cicloexanonas/síntese química , Cicloexanonas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Compostos de Epóxi/síntese química , Compostos de Epóxi/farmacologia , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cicloexanonas/química , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Compostos de Epóxi/química , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Conformação Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Alcenos/química , Alcenos/síntese química , Técnicas de Química Combinatória/métodos , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/síntese química , Resinas Sintéticas/química , Selênio/química , Indústria Farmacêutica/métodosRESUMO
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.
Assuntos
Antimaláricos/síntese química , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos de Espiro/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Césio , Ciclização , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Hidróxidos , Malária/tratamento farmacológico , Malária/parasitologia , Camundongos , Óxidos , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Compostos de Prata , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
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.