Adenylate cyclase toxin (ACT) is the key virulence factor of Bordetella pertussis that facilitates its invasion into the mammalian body. 9-[2-(Phosphonomethoxy)ethyl]adenine diphosphate (PMEApp), the active metabolite of the antiviral drug bis(POM)PMEA (adefovir dipivoxil), has been shown to inhibit ACT. The objective of this study was to evaluate six novel amidate prodrugs of PMEA, both phenyloxy phosphonamidates and phosphonodiamidates, for their ability to inhibit ACT activity in the J774A.1 macrophage cell line. The two phenyloxy phosphonamidate prodrugs exhibited greater inhibitory activity (50% inhibitory concentration [IC50] = 22 and 46 nM) than the phosphonodiamidates (IC50 = 84 to 3,960 nM). The inhibitory activity of the prodrugs correlated with their lipophilicity and the degree of their hydrolysis into free PMEA in J774A.1 cells. Although the prodrugs did not inhibit ACT as effectively as bis(POM)PMEA (IC50 = 6 nM), they were significantly less cytotoxic. Moreover, they all reduced apoptotic effects of ACT and prevented an ACT-induced elevation of intracellular [Ca(2+)]i. The amidate prodrugs were less susceptible to degradation in Caco-2 cells compared to bis(POM)PMEA, while they exerted good transepithelial permeability in this assay. As a consequence, a large amount of intact amidate prodrug is expected to be available to target macrophages in vivo. This feature makes nontoxic amidate prodrugs attractive candidates for further investigation as novel antimicrobial agents.

• MeSH
• Adenine analogs & derivatives   metabolism   pharmacology   MeSH
• Adenylate Cyclase Toxin antagonists & inhibitors   metabolism   MeSH
• Anti-Bacterial Agents metabolism   pharmacology   MeSH
• Bordetella pertussis drug effects   growth & development   pathogenicity   MeSH
• Caco-2 Cells MeSH
• Inhibitory Concentration 50 MeSH
• Humans MeSH
• Macrophages drug effects   microbiology   MeSH
• Microbial Sensitivity Tests MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Organophosphonates pharmacology   MeSH
• Prodrugs metabolism   pharmacology   MeSH
• Cell Survival drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 9-(2-(phosphonomethoxy)ethyl)adenine diphosphate MeSH Browser
• adefovir dipivoxil MeSH Browser
• Adenine MeSH
• Adenylate Cyclase Toxin MeSH
• Anti-Bacterial Agents MeSH
• Organophosphonates MeSH
• Prodrugs MeSH

New Adefovir (PMEA) prodrugs with a pro-moiety consisting of decyl or decyloxyethyl chain bearing hydroxyl function(s), hexaethyleneglycol or a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl unit were prepared starting from the tetrabutylammonium salt of the phosphonate drug and an appropriate alkyl bromide or tosylate. Analogously, two esters of Cidofovir [(S)-HPMPC] bearing a hexaethyleneglycol moiety were prepared. The activity of the prodrugs was evaluated in vitro against different virus families. A loss in the antiviral activities of the hydroxylated decyl or decyloxyethyl esters and hexaethyleneglycol esters of PMEA against human immunodeficiency virus (HIV) and herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (CMV)] occurred in comparison with the parent compound. On the other hand, the (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of PMEA showed significant activities against HIV and herpesviruses. (S)-HPMPC prodrugs exhibited anti-cytomegalovirus activities in the same range as the parent drug, whereas the anti-HSV and anti-VZV activities were one- to seven-fold lower than that of Cidofovir.

• MeSH
• Adenine analogs & derivatives   chemistry   MeSH
• Antiviral Agents chemical synthesis   chemistry   toxicity   MeSH
• Cidofovir MeSH
• Cytomegalovirus drug effects   MeSH
• Cytosine analogs & derivatives   chemistry   MeSH
• HIV drug effects   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Organophosphonates chemistry   MeSH
• Prodrugs chemical synthesis   chemistry   toxicity   MeSH
• Simplexvirus drug effects   MeSH
• Herpesvirus 3, Human drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• adefovir MeSH Browser
• Adenine MeSH
• Antiviral Agents MeSH
• Cidofovir MeSH
• Cytosine MeSH
• Organophosphonates MeSH
• Prodrugs MeSH