ABSTRACT
4-Amino- and 4-guanidino-4H-pyran-6-carboxamides 4 and 5 related to zanamivir (GG167) are a new class of inhibitors of influenza virus sialidases. Structure--activity studies reveal that, in general, secondary amides are weak inhibitors of both influenza A and B viral sialidases. However, tertiary amides, which contain one or more small alkyl groups, show much greater inhibitory activity, particularly against the influenza A virus enzyme. The sialidase inhibitory activities of these compounds correlate well with their in vitro antiviral efficacy, and several of the most potent analogues displayed useful antiviral activity in vivo when evaluated in a mouse model of influenza A virus infection. Carboxamides which were highly active sialidase inhibitors in vitro also showed good antiviral activity in the mouse efficacy model of influenza A infection when administered intranasally but displayed modest activity when delivered by the intraperitoneal route.
Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Guanidines/pharmacology , Influenza A virus/drug effects , Influenza B virus/drug effects , Neuraminidase/antagonists & inhibitors , Pyrans/pharmacology , Sialic Acids/pharmacology , Administration, Intranasal , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Guanidines/chemical synthesis , Guanidines/chemistry , Guanidines/pharmacokinetics , Influenza A virus/enzymology , Influenza B virus/enzymology , Injections, Intraperitoneal , Mice , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/enzymology , Pyrans/chemical synthesis , Pyrans/chemistry , Pyrans/pharmacokinetics , Sialic Acids/chemistry , Sialic Acids/pharmacokinetics , Structure-Activity Relationship , ZanamivirABSTRACT
A series of cephalosporins containing a novel 7-[2-(Z)-(2-amino-thiazol-4- yl)-3-(dimethoxy-phosphoryl)-acryloylamino] group were prepared and their antibacterial activity measured against a range of pathogens. In general the compounds displayed a broad spectrum of activity against both Gram positive and Gram negative organisms, except Pseudomonas aeruginosa. Activity against the latter could be achieved by introducing a catechol moiety at the 3 position of the cephalosporin. The methyl phosphonates in general were stable to a wide range of beta-lactamases, including the TEM enzymes and the Enterobacter cloacae P99 chromosomal enzyme. In addition, they showed the advantage of being highly water soluble.
Subject(s)
Cephalosporins/chemical synthesis , Cephalosporins/pharmacology , Organophosphonates/chemical synthesis , Organophosphonates/pharmacology , Animals , Cephalosporins/chemistry , Female , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Magnetic Resonance Spectroscopy , Mice , Microbial Sensitivity Tests , Staphylococcal Infections/drug therapy , Vinyl Compounds/chemical synthesis , Vinyl Compounds/pharmacologyABSTRACT
In order to identify a suitable peptide substrate for human immunodeficiency virus-1 (HIV-1) proteinase, a range of peptides from various cleavage sites within the gag-pol polyprotein were assayed by HPLC for specific cleavage. The peptide with the optimal combination of favorable kinetics and good solubility was based on the N-terminus cleavage site of HIV-1 proteinase (KQGTVSFNF*PQIT). The HPLC assay, using the above peptide, was developed into a rapid isocratic method in order to analyze inhibition kinetics. An assay suitable for high-throughput screening was developed using a radioactively labeled peptide with the same sequence, coupled to a solid phase. Using this assay, a C2-symmetric HIV-1 proteinase inhibitor derived from penicillin was discovered during random screening of a compound library. A chemical synthesis program developed this structure into a series of potent inhibitors. The lead structures were highly selective for HIV-1 proteinase with good antiviral activity in vitro against HIV and no cytotoxicity. The HPLC assay was used to demonstrate that these compounds are competitive tight-binding inhibitors of HIV-1 proteinase.
