ABSTRACT
Glycobiology opens a wide field for new therapeutic approaches. However, the complexity and unavailability of various carbohydrate test compounds has excluded this class of natural products from modern screening systems. Alternatively, glycomimetics are considered to be more drug-like candidates for development. By means of multicomponent condensations (MCCs) utilizing suitable carbohydrate synthons, rapid and effective access to glycoconjugate libraries can be obtained. The flexibility of MCCs allows the assembly of diverse carbohydrate containing libraries. It may be assumed that MCCs containing carbohydrate moieties will play an important role in glycomimetic chemistry and biology.
Subject(s)
Biochemistry/methods , Combinatorial Chemistry Techniques , Glycoconjugates/chemical synthesis , Aldehydes/chemistry , Amines/chemistry , Carboxylic Acids/chemistry , Cyanides/chemistry , Glycoconjugates/chemistry , Glycosylation , Templates, GeneticABSTRACT
The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.
Subject(s)
Antiviral Agents/therapeutic use , DNA Helicases/antagonists & inhibitors , Enzyme Inhibitors/therapeutic use , Herpes Simplex/drug therapy , Pyridines/therapeutic use , Thiazoles/therapeutic use , Acyclovir/therapeutic use , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , DNA Primase , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Female , Guinea Pigs , Herpes Simplex/enzymology , Herpes Simplex/pathology , Humans , Infant, Newborn , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Pregnancy , Pyridines/chemistry , Pyridines/pharmacokinetics , Safety , Sulfonamides , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Viral ProteinsABSTRACT
Four-component reactions: The Ugi reaction of four suitably functionalized carbohydrate derivatives (as a per-O-benzylated amine, an aldehyde, a carboxylic acid, and an isocyanide) allow the effective assembly of diverse compound libraries. The complex glycoconjugates formed can be deprotected (see the picture for an example), and the resulting glycomimetics are of high interest for screening purposes.
