RESUMO
Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
Assuntos
Antidepressivos Tricíclicos/síntese química , Encéfalo/efeitos dos fármacos , Química Farmacêutica/métodos , Receptores de Serotonina/química , Antagonistas da Serotonina/síntese química , Animais , Antidepressivos Tricíclicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/química , Humanos , Ligação de Hidrogênio , Microssomos/efeitos dos fármacos , Modelos Químicos , Conformação Molecular , Isoformas de Proteínas , Ratos , Antagonistas da Serotonina/farmacologiaRESUMO
The antimicrobial natural product chuangxinmycin has been found to be a potent and selective inhibitor of bacterial tryptophanyl tRNA synthetase (WRS). A number of analogues have been synthesised. The interaction with WRS appears to be highly constrained, as only sterically smaller analogues afforded significant inhibition. The only analogue to show inhibition comparable to chuangxinmycin also had antibacterial activity. WRS inhibition may contribute to the antibacterial action of chuangxinmycin.
