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
• adenin analogy a deriváty   metabolismus   farmakologie   MeSH
• adenylátcyklasový toxin antagonisté a inhibitory   metabolismus   MeSH
• antibakteriální látky metabolismus   farmakologie   MeSH
• Bordetella pertussis účinky léků   růst a vývoj   patogenita   MeSH
• Caco-2 buňky MeSH
• inhibiční koncentrace 50 MeSH
• lidé MeSH
• makrofágy účinky léků   mikrobiologie   MeSH
• mikrobiální testy citlivosti MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• organofosfonáty farmakologie   MeSH
• prekurzory léčiv metabolismus   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 9-(2-(phosphonomethoxy)ethyl)adenine diphosphate MeSH Prohlížeč
• adefovir dipivoxil MeSH Prohlížeč
• adenin MeSH
• adenylátcyklasový toxin MeSH
• antibakteriální látky MeSH
• organofosfonáty MeSH
• prekurzory léčiv 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
• adenin analogy a deriváty   chemie   MeSH
• antivirové látky chemická syntéza   chemie   toxicita   MeSH
• cidofovir MeSH
• Cytomegalovirus účinky léků   MeSH
• cytosin analogy a deriváty   chemie   MeSH
• HIV účinky léků   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• organofosfonáty chemie   MeSH
• prekurzory léčiv chemická syntéza   chemie   toxicita   MeSH
• Simplexvirus účinky léků   MeSH
• virus varicella zoster účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adefovir MeSH Prohlížeč
• adenin MeSH
• antivirové látky MeSH
• cidofovir MeSH
• cytosin MeSH
• organofosfonáty MeSH
• prekurzory léčiv MeSH