RESUMO
Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.
Assuntos
Benzimidazóis/farmacologia , Receptores Opioides kappa/agonistas , Sequência de Aminoácidos , Simulação por Computador , Humanos , Dados de Sequência Molecular , Receptores Opioides kappa/química , Homologia de Sequência de Aminoácidos , Relação Estrutura-AtividadeRESUMO
A highly efficient synthesis of enantiomerically pure (S) and (R)-isomers of N-(2,3-dihydroxypropyl)arylamides has been developed with good overall yields in a two step process. The key step involves the ring opening of the chiral epoxide with a nitrogen heterocyclic carbene (NHC) and further rearrangement to chiral N-(2,3-dihydroxypropyl)arylamides in high yields and enantioselectivity. During the reaction, no erosion in chiral purity was observed.
RESUMO
An efficient methodology for the synthesis of highly functionalized ellipticinium and ellipticine derivatives starting from the corresponding 2-bromocarbazoles via an AgOTf or CuI catalyzed electrophilic cyclization of 2-alkynyl-3-carbazolylaldimines is reported.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Química Farmacêutica/métodos , Elipticinas/síntese química , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase II/síntese química , Antineoplásicos Fitogênicos/farmacologia , Catálise , Ciclização , DNA Topoisomerases Tipo II/metabolismo , Elipticinas/farmacologia , Humanos , Estrutura Molecular , Neoplasias/enzimologia , Inibidores da Topoisomerase II/farmacologiaRESUMO
Three new species of Pentelicus Howard (Hymenoptera: Encyrtidae) are described from Tamil Nadu, India: P. funiculatus sp. nov., P. punctatus sp. nov. and P. depunctatus sp. nov. A revised key to the world species of Pentelicus is also provided.