Compounds with a phosphonate group, i.e., -P(O)(OH)2 group attached directly to the molecule via a P-C bond serve as suitable non-hydrolyzable phosphate mimics in various biomedical applications. In principle, they often inhibit enzymes utilizing various phosphates as substrates. In this review we focus mainly on biologically active phosphonates that originated from our institute (Institute of Organic Chemistry and Biochemistry in Prague); i.e., acyclic nucleoside phosphonates (ANPs, e.g., adefovir, tenofovir, and cidofovir) and derivatives of non-nucleoside phosphonates such as 2-(phosphonomethyl) pentanedioic acid (2-PMPA). Principal strategies of their syntheses and modifications to prodrugs is reported. Besides clinically used ANP antivirals, a special attention is paid to new biologically active molecules with respect to emerging infections and arising resistance of many pathogens against standard treatments. These new structures include 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines or so-called "open-ring" derivatives, acyclic nucleoside phosphonates with 5-azacytosine as a base moiety, side-chain fluorinated ANPs, aza/deazapurine ANPs. When transformed into an appropriate prodrug by derivatizing their charged functionalities, all these compounds show promising potential to become drug candidates for the treatment of viral infections. ANP prodrugs with suitable pharmacokinetics include amino acid phosphoramidates, pivaloyloxymethyl (POM) and isopropoxycarbonyloxymethyl (POC) esters, alkyl and alkoxyalkyl esters, salicylic esters, (methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL) esters and peptidomimetic prodrugs. We also focus on the story of cytostatics related to 9-[2-(phosphonomethoxy)ethyl]guanine and its prodrugs which eventually led to development of the veterinary drug rabacfosadine. Various new ANP structures are also currently investigated as antiparasitics, especially antimalarial agents e.g., guanine and hypoxanthine derivatives with 2-(phosphonoethoxy)ethyl moiety, their thia-analogues and N-branched derivatives. In addition to ANPs and their analogs, we also describe prodrugs of 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a potent inhibitor of the enzyme glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA). Glutamate carboxypeptidase II inhibitors, including 2-PMPA have been found efficacious in various preclinical models of neurological disorders which are caused by glutamatergic excitotoxicity. Unfortunately its highly polar character and hence low bioavailability severely limits its potential for clinical use. To overcome this problem, various prodrug strategies have been used to mask carboxylates and/or phosphonate functionalities with pivaloyloxymethyl, POC, ODOL and alkyl esters. Chemistry and biological characterization led to identification of prodrugs with 44-80 fold greater oral bioavailability (tetra-ODOL-2-PMPA).

• Klíčová slova
• 2-PMPA, FOLH1, GCPII, acyclic nucleoside phosphonates, antivirals, prodrugs, prostate-specific membrane antigen, protides,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Nucleos(t)ide analogues entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line monotherapies for chronic hepatitis B (CHB). Multiple HBV genotypes/subgenotypes have been described, but their impact on treatment response remains largely elusive. We investigated the effectiveness of ETV/TDF on HBV/D-subgenotypes, D1/D2/D3/D5, studied the structural/functional differences in subgenotype-specific reverse transcriptase (RT) domains of viral polymerase, and identified novel molecules with robust inhibitory activity on various D-subgenotypes. Transfection of Huh7 cells with full-length D1/D2/D3/D5 and in vitro TDF/ETV susceptibility assays demonstrated that D1/D2 had greater susceptibility to TDF/ETV while D3/D5 exhibited poorer response. Additionally, HBV load was substantially reduced in TDF-treated CHB patients carrying D1/D2 but minimally reduced in D3/D5-infected patients. Comparison of RT sequences of D-subgenotypes led to identification of unique subgenotype-specific residues, and molecular modeling/docking/simulation studies depicted differential bindings of TDF/ETV to the active site of their respective RTs. Replacement of signature residues in D3/D5 HBV clones with corresponding amino acids seen in D1/D2 improved their susceptibility to TDF/ETV. Using high throughput virtual screening, we identified N(9)-[3-fluoro-2-(phosphonomethoxy)propyl] (FPMP) derivatives of purine bases, including N6-substituted (S)-FPMP derivative of 2,6-diaminopurine (DAP) (OB-123-VK), as potential binders of RT of different D-subgenotypes. We synthesized (S)-FPMPG prodrugs (FK-381-FEE/FK-381-SEE/FK-382) and tested their effectiveness along with OB-123-VK. Both OB-123-VK and FK-381-FEE exerted similar antiviral activities against all D-subgenotypes, although FK-381-FEE was more potent. Our study highlighted the natural variation in therapeutic response of D1/D2/D3/D5 and emphasized the need for HBV subgenotype determination before treatment. Novel molecules described here could benefit future design/discovery of pan-D-subgenotypic inhibitors. IMPORTANCE Current treatment of chronic hepatitis B relies heavily on nucleotide/nucleoside analogs in particular, tenofovir disoproxil fumarate (TDF) and entecavir (ETV) to keep HBV replication under control and prevent end-stage liver diseases. However, it was unclear whether the therapeutic effects of TDF/ETV differ among patients infected with different HBV genotypes and subgenotypes. HBV genotype D is the most widespread of all HBV genotypes and multiple D-subgenotypes have been described. We here report that different subgenotypes of HBV genotype-D exhibit variable response toward TDF and ETV and this could be attributed to naturally occurring amino acid changes in the reverse transcriptase domain of the subgenotype-specific polymerase. Further, we identified novel molecules and also synthesized prodrugs that are equally effective on different D-subgenotypes and could facilitate management of HBV/D-infected patients irrespective of D-subgenotype.

• Klíčová slova
• antiviral activity, entecavir, hepatitis B virus D-subgenotypes, high throughput virtual screening, phosphonate prodrug, tenofovir,
• MeSH
• antivirové látky chemie   farmakologie   terapeutické užití   MeSH
• chronická hepatitida B farmakoterapie   virologie   MeSH
• genotyp MeSH
• guanin analogy a deriváty   chemie   farmakologie   terapeutické užití   MeSH
• inhibitory reverzní transkriptasy chemie   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• mutace MeSH
• organofosfonáty chemie   farmakologie   MeSH
• prekurzory léčiv MeSH
• proteinové domény MeSH
• racionální návrh léčiv * MeSH
• reverzní transkriptasa chemie   genetika   MeSH
• tenofovir chemie   farmakologie   terapeutické užití   MeSH
• virová léková rezistence účinky léků   genetika   MeSH
• virová nálož účinky léků   MeSH
• virus hepatitidy B účinky léků   enzymologie   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• entecavir MeSH Prohlížeč
• guanin MeSH
• inhibitory reverzní transkriptasy MeSH
• organofosfonáty MeSH
• prekurzory léčiv MeSH
• reverzní transkriptasa MeSH
• tenofovir MeSH

A series of acyclic nucleoside phosphonates (ANPs) was designed as inhibitors of bacterial adenylate cyclases (ACs), where adenine was replaced with 2-amino-4-arylthiazoles. The target compounds were prepared using the halogen dance reaction. Final AC inhibitors were evaluated in cell-based assays (prodrugs) and cell-free assays (phosphono diphosphates). Novel ANPs were potent inhibitors of adenylate cyclase toxin (ACT) from Bordetella pertussis and edema factor (EF) from Bacillus anthracis, with substantial selectivity over mammalian enzymes AC1, AC2, and AC5. Six of the new ANPs were more potent or equipotent ACT inhibitors (IC50 =9-18 nM), and one of them was more potent EF inhibitor (IC50 =12 nM), compared to adefovir diphosphate (PMEApp) with IC50 =18 nM for ACT and IC50 =36 nM for EF. Thus, these compounds represent the most potent ACT/EF inhibitors based on ANPs reported to date. The potency of the phosphonodiamidates to inhibit ACT activity in J774A.1 macrophage cells was somewhat weaker, where the most potent derivative had IC50 =490 nM compared to IC50 =150 nM of the analogous adefovir phosphonodiamidate. The results suggest that more efficient type of phosphonate prodrugs would be desirable to increase concentrations of the ANP-based active species in the cells in order to proceed with the development of ANPs as potential antitoxin therapeutics.

• Klíčová slova
• Acyclic nucleoside phosphonates, Adenylate cyclase, Bordetella pertussis, Inhibitors, Prodrugs,
• MeSH
• adenylátcyklasový toxin antagonisté a inhibitory   metabolismus   MeSH
• antigeny bakteriální metabolismus   MeSH
• Bacillus anthracis chemie   MeSH
• bakteriální toxiny antagonisté a inhibitory   metabolismus   MeSH
• Bordetella pertussis enzymologie   MeSH
• halogeny chemie   farmakologie   MeSH
• inhibitory adenylylcyklasy chemická syntéza   chemie   farmakologie   MeSH
• molekulární struktura MeSH
• organofosfonáty chemie   farmakologie   MeSH
• thiazoly chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2-aminothiazole MeSH Prohlížeč
• adenylátcyklasový toxin MeSH
• anthrax toxin MeSH Prohlížeč
• antigeny bakteriální MeSH
• bakteriální toxiny MeSH
• halogeny MeSH
• inhibitory adenylylcyklasy MeSH
• organofosfonáty MeSH
• thiazoly MeSH

A series of novel acyclic nucleoside phosphonates (ANPs) was synthesized as potential adenylate cyclase inhibitors, where the adenine nucleobase of adefovir (PMEA) was replaced with a 5-substituted 2-aminothiazole moiety. The design was based on the structure of MB05032, a potent and selective inhibitor of fructose 1,6-bisphosphatase and a good mimic of adenosine monophosphate (AMP). From the series of eighteen novel ANPs, which were prepared as phosphoroamidate prodrugs, fourteen compounds were potent (single digit micromolar or submicromolar) inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT), mostly without observed cytotoxicity in J774A.1 macrophage cells. Selected phosphono diphosphates (nucleoside triphosphate analogues) were potent inhibitors of ACT (IC50 as low as 37 nM) and B. anthracis edema factor (IC50 as low as 235 nM) in enzymatic assays. Furthermore, several ANPs were found to be selective mammalian AC1 inhibitors in HEK293 cell-based assays (although with some associated cytotoxicity) and one compound exhibited selective inhibition of mammalian AC2 (only 12% of remaining adenylate cyclase activity) but no observed cytotoxicity. The mammalian AC1 inhibitors may represent potential leads in development of agents for treatment of human inflammatory and neuropathic pain.

• Klíčová slova
• Acyclic nucleoside phosphonates, Adefovir, Adenylate cyclase, Bacillus anthracis, Bordetella pertussis, Inhibitors, Prodrugs,
• MeSH
• adenylátcyklasový toxin antagonisté a inhibitory   metabolismus   MeSH
• antibakteriální látky chemická syntéza   chemie   farmakologie   MeSH
• Bacillus anthracis účinky léků   MeSH
• Bordetella pertussis účinky léků   enzymologie   MeSH
• buněčné linie MeSH
• inhibitory adenylylcyklasy chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• myši MeSH
• neuralgie farmakoterapie   MeSH
• organofosfonáty chemie   farmakologie   MeSH
• thiazoly chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 2-aminothiazole MeSH Prohlížeč
• adenylátcyklasový toxin MeSH
• antibakteriální látky MeSH
• inhibitory adenylylcyklasy MeSH
• organofosfonáty MeSH
• thiazoly MeSH

With respect to the strong antiviral activity of (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine various types of its side chain fluorinated analogues were prepared. The title compound, (S)-1-[3-fluoro-2-(phosphonomethoxy)propyl]-5-azacytosine (FPMP-5-azaC) was synthesised by the condensation reaction of (S)-2-[(diisopropoxyphosphoryl)methoxy)-3-fluoropropyl p-toluenesulfonate with a sodium salt of 5-azacytosine followed by separation of appropriate N 1 and O 2 regioisomers and ester hydrolysis. Transformations of FPMP-5-azaC to its 5,6-dihydro-5-azacytosine counterpart, amino acid phosphoramidate prodrugs and systems with an annelated five-membered imidazole ring, i.e. imidazo [1,2-a][1,3,5]triazine derivatives were also carried out. 1-(2-Phosphonomethoxy-3,3,3-trifluoropropyl)-5-azacytosine was prepared from 5-azacytosine and trifluoromethyloxirane to form 1-(3,3,3-trifluoro-2-hydroxypropyl)-5-azacytosine which was treated with diisopropyl bromomethanephosphonate followed by deprotection of esters. Antiviral activity of all newly prepared compounds was studied. FPMP-5-azaC diisopropyl ester inhibited the replication of herpes viruses with EC50 values that were about three times higher than that of the reference anti-HCMV drug ganciclovir without displaying cytotoxicity.

• Klíčová slova
• 5-Azacytosine, Acyclic nucleoside phosphonates, Fluorinated nucleotides, Phosphonates, Prodrugs,
• Publikační typ
• časopisecké články MeSH

A series of 13 acyclic nucleoside phosphonates (ANPs) as bisamidate prodrugs was prepared. Five compounds were found to be non-cytotoxic and selective inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT) in J774A.1 macrophage cell-based assays. The 8-aza-7-deazapurine derivative of adefovir (PMEA) was found to be the most potent ACT inhibitor in the series (IC50 =16 nm) with substantial selectivity over mammalian adenylate cyclases (mACs). AC inhibitory properties of the most potent analogues were confirmed by direct evaluation of the corresponding phosphonodiphosphates in cell-free assays and were found to be potent inhibitors of both ACT and edema factor (EF) from Bacillus anthracis (IC50 values ranging from 0.5 to 21 nm). Moreover, 7-halo-7-deazapurine analogues of PMEA were discovered to be potent and selective mammalian AC1 inhibitors (no inhibition of AC2 and AC5) with IC50 values ranging from 4.1 to 5.6 μm in HEK293 cell-based assays.

• Klíčová slova
• Bacillus anthracis, Bordetella pertussis, adefovir, adenylate cyclase, inhibitors,
• MeSH
• adenin analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• adenylátcyklasy metabolismus   MeSH
• Bacillus anthracis enzymologie   MeSH
• Bordetella pertussis enzymologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• molekulární struktura MeSH
• organofosfonáty chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adefovir MeSH Prohlížeč
• adenin MeSH
• adenylátcyklasy MeSH
• inhibitory enzymů MeSH
• organofosfonáty MeSH

While noncanonic xanthine nucleotides XMP/dXMP play an important role in balancing and maintaining intracellular purine nucleotide pool as well as in potential mutagenesis, surprisingly, acyclic nucleoside phosphonates bearing a xanthine nucleobase have not been studied so far for their antiviral properties. Herein, we report the synthesis of a series of xanthine-based acyclic nucleoside phosphonates and evaluation of their activity against a wide range of DNA and RNA viruses. Two acyclic nucleoside phosphonates within the series, namely 9-[2-(phosphonomethoxy)ethyl]xanthine (PMEX) and 9-[3-hydroxy-2-(phosphonomethoxy)propyl]xanthine (HPMPX), were shown to possess activity against several human herpesviruses. The most potent compound was PMEX, a xanthine analogue of adefovir (PMEA). PMEX exhibited a single digit µM activity against VZV (EC50 = 2.6 µM, TK+ Oka strain) and HCMV (EC50 = 8.5 µM, Davis strain), while its hexadecyloxypropyl monoester derivative was active against HSV-1 and HSV-2 (EC50 values between 1.8 and 4.0 µM). In contrast to acyclovir, PMEX remained active against the TK- VZV 07-1 strain with EC50 = 4.58 µM. PMEX was suggested to act as an inhibitor of viral DNA polymerase and represents the first reported xanthine-based acyclic nucleoside phosphonate with potent antiviral properties.

• Klíčová slova
• Acyclic nucleoside phosphonates, HCMV, PMEX, VZV, antiviral, xanthine,
• MeSH
• antivirové látky chemická syntéza   chemie   farmakologie   MeSH
• Cytomegalovirus účinky léků   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• nukleosidy chemická syntéza   chemie   farmakologie   MeSH
• organofosfonáty chemická syntéza   chemie   farmakologie   MeSH
• virus varicella zoster účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• xanthin chemická syntéza   chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antivirové látky MeSH
• nukleosidy MeSH
• organofosfonáty MeSH
• xanthin MeSH

New 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidine (PMEO-DAPy) and 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (PME-5-azaC) prodrugs were prepared with a pro-moiety consisting of carbonyloxymethyl esters (POM, POC), alkoxyalkyl esters, amino acid phosphoramidates and/or tyrosine. The activity of the prodrugs was evaluated in vitro against different virus families. None of the synthesized prodrugs demonstrated activity against RNA viruses but some of them proved active against herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV)]. The bis(POC) and the bis(amino acid) phosphoramidate prodrugs of PMEO-DAPy inhibited herpesvirus replication at lower doses than the parent compound although the selectivity against HSV and VZV was only slightly improved compared to PMEO-DAPy. The mono-octadecyl ester of PME-5-azaC emerged as the most potent and selective PME-5-azaC prodrug against HSV, VZV and HCMV with EC50's of 0.15-1.12µM while PME-5-azaC only had marginal anti-herpesvirus activity. Although the bis(hexadecylamido-l-tyrosyl) and the bis(POM) esters of PME-5-azaC were also very potent anti-herpesvirus drugs, these were less selective than the mono-octadecyl ester prodrug.

• Klíčová slova
• 5-Azacytosine, Acyclic nucleoside phosphonates, Antivirals, HPMP-5-azaC, Open-ring, PME-azaC, PMEO-DAPy, Phosphonate, Prodrug,
• MeSH
• antivirové látky chemická syntéza   chemie   farmakologie   MeSH
• buněčné linie MeSH
• Cytomegalovirus účinky léků   MeSH
• lidé MeSH
• organofosfonáty chemická syntéza   chemie   farmakologie   MeSH
• prekurzory léčiv chemická syntéza   chemie   farmakologie   MeSH
• pyrimidinové nukleosidy chemie   MeSH
• Simplexvirus účinky léků   MeSH
• virus varicella zoster účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• organofosfonáty MeSH
• prekurzory léčiv MeSH
• pyrimidinové nukleosidy MeSH

Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF) are key virulence factors with adenylate cyclase (AC) activity that substantially contribute to the pathogenesis of whooping cough and anthrax, respectively. There is an urgent need to develop potent and selective inhibitors of bacterial ACs with prospects for the development of potential antibacterial therapeutics and to study their molecular interactions with the target enzymes. Novel fluorescent 5-chloroanthraniloyl-substituted acyclic nucleoside phosphonates (Cl-ANT-ANPs) were designed and synthesized in the form of their diphosphates (Cl-ANT-ANPpp) as competitive ACT and EF inhibitors with sub-micromolar potency (IC50 values: 11-622 nm). Fluorescence experiments indicated that Cl-ANT-ANPpp analogues bind to the ACT active site, and docking studies suggested that the Cl-ANT group interacts with Phe306 and Leu60. Interestingly, the increase in direct fluorescence with Cl-ANT-ANPpp having an ester linker was strictly calmodulin (CaM)-dependent, whereas Cl-ANT-ANPpp analogues with an amide linker, upon binding to ACT, increased the fluorescence even in the absence of CaM. Such a dependence of binding on structural modification could be exploited in the future design of potent inhibitors of bacterial ACs. Furthermore, one Cl-ANT-ANP in the form of a bisamidate prodrug was able to inhibit B. pertussis ACT activity in macrophage cells with IC50 =12 μm.

• Klíčová slova
• adenylate cyclase, anthrax, antibacterial agents, fluorescence, whooping cough,
• MeSH
• adenylátcyklasy metabolismus   MeSH
• Bordetella pertussis enzymologie   MeSH
• fluorescenční barviva chemická syntéza   chemie   farmakologie   MeSH
• inhibitory adenylylcyklasy chemická syntéza   chemie   farmakologie   MeSH
• makrofágy účinky léků   MeSH
• molekulární struktura MeSH
• myši MeSH
• nukleosidy chemická syntéza   chemie   farmakologie   MeSH
• organofosfonáty chemická syntéza   chemie   farmakologie   MeSH
• racionální návrh léčiv * MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adenylátcyklasy MeSH
• fluorescenční barviva MeSH
• inhibitory adenylylcyklasy MeSH
• nukleosidy MeSH
• organofosfonáty MeSH

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