41468-36-4

The replacement of amino acids in peptides by phosphono-analogous (aminoalkyl)phosphonic acids 1, (2-aminoethyl)phosphonic acid (2) and substituted derivatives has been an important aspect of peptides research in the last years.In pantothenic acid (3), there is a peptide linkage between (2R)-2,4-dihydroxy-3,3-dimethylbutyric acid and the amino group of β-alanine, and in pantetheine (4), there is a second peptide linkage between the β-alanine and cysteamine.The synthesis of phosphono and phosphino analogues of pantothenic acid ethyl ester, where the β-alanine is replaced by the diethyl ester of (2-aminoethyl)phosphonic acid and the ethyl ester of (2-aminoethyl)methylphosphonic acid, respectively, and the syntheses of the phosphono analogue of pantetheine, where the β-alanine is replaced by (2-aminoethyl)phosphonic acid, are described.

Iron nanoparticles are highly-effective magnetic nanoparticles for T2 magnetic resonance imaging (MRI). However, the stability of their magnetic properties is dependent on good protection of the iron core from oxidation in aqueous media. Here we report the synthesis of custom-synthesized phosphonate-grafted polyelectrolytes (PolyM3) of various chain lengths, for efficient coating of iron nanoparticles with a native iron oxide shell. The size of the nanoparticle-polyelectrolyte assemblies was investigated by transmission electron microscopy and dynamic light scattering, while surface attachment was confirmed by Fourier transform infrared spectroscopy. Low cytotoxicity was observed for each of the nanoparticle-polyelectrolyte (“Fe-PolyM3”) assemblies, with good cell viability (>80%) remaining up to 100?μg?mL?1 Fe in HeLa cells. When applied in T2-weighted MRI, corresponding T2 relaxivities (r2) of the Fe-PolyM3 assemblies were found to be dependent on the chain length of the polyelectrolyte. A significant increase in contrast was observed when polyelectrolyte chain length was increased from 6 to 65 repeating units, implying a critical chain length required for stabilization of the α-Fe nanoparticle core.

The emergence and dissemination of metallo-β-lactamases (MBLs) producing Enterobacterales is a great concern for public health due to the limited therapeutic options. No MBL inhibitors are currently available in clinical practice. Herein, we synthesized a series of H2dpa derivatives containing pentadentate-chelating ligands and evaluated their inhibitory activity against MBLs. Related compounds inhibited clinically relevant MBLs (Imipenemase, New Delhi metallo-β-lactamase (NDM) and Verona integron-encoded metallo-β-lactamase) with IC50 values of 1–4.9 μM. In vitro, the most promising compounds, 5b and 5c, which had a chiral methyl at the acid adjacent to 5a, demonstrated potent synergistic activity against engineered strains, with fractional inhibitory concentration index values as low as 0.07–0.18. The addition of 5b and 5c restored meropenem efficacy against 42 MBL-producing Enterobacterales and Pseudomonas aeruginosa to satisfactory clinical levels. In addition, safety tests revealed that 5b/5c showed no toxicity in red blood cells, cell lines or mouse model. Further studies demonstrated that compounds 5b and 5c were non-competitive MBL inhibitors. In vivo compounds 5b and 5c potentiated meropenem efficacy and increased the survival rate from 0 to at least 83% in mice with sepsis caused by an NDM-1-positive clinical strain. The activity of the compounds exhibited consistency at the molecular, cellular, and in vivo levels. These data indicated that H2dpa derivatives 5b and 5c containing pentadentate-chelating ligands may be worthy of further study.

A series of N1-(phosphonoalkyl)uracils was prepared in a two-step reaction sequence from x- aminoalkylphosphonates and (E)-3-ethoxyacryloyl isocyanate followed by the uracil ring closure. Under standard conditions (NCS; NBS; I2/CAN) all N1-(phosphonoalkyl)uracils were transformed into the respective 5-halogeno derivatives to be later benzoylated at N3. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses. One compound was slightly active against human cytomegalovirus in HEL cell cultures (EC50 = 45 μM) while another showed weak activity against varicella-zoster virus (TK+ VZV strain OKA and TK- VZV strain 07-1) with EC50 = 43 and 53 μM, respectively. In addition, several compounds exhibited noticeable inhibitory effects on the proliferation of human cervical carcinoma cells (HeLa) at a concentration lower than 200 μM.

Three dipicolinic acid amine-derived compounds functionalized with a carboxylate (H3dpaa), phosphonate (H4dppa), and bisphosphonate (H7dpbpa), as well as their nonfunctionalized analogue (H2dpa), were successful

The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C-nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme.

The invention relates to compounds of formula (I) that are inhibitors of hypoxanthine and/or guanine purine phosphoribosyltransferases and to pharmaceutical compositions containing the compounds, processes for preparing the compounds, and methods of treating diseases or conditions in which it is desirable to inhibit hypoxanthine and/or guanine purine phosphoribosyltransferases. Such diseases include malaria.

The present disclosure is directed to corn- pounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders. The methods generally comprise administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that is designed to be substantially active in the gastrointestinal (GI) tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. More particularly, the method comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that inhibits NHE-3, -2 and/ or -8 mediated antiport of sodium and/or hydrogen ions in the GI tract and is designed to be substantially impermeable to the layer of epithelial cells, or more specifically the epithelium of the GI tract. As a result of the compound being substantially impermeable, it is not absorbed and is thus essentially systemically non-bioavailable, so as to limit the exposure of other internal organs (e.g., liver, heart, brain, etc.) thereto. The present disclosure is still further directed to a method wherein a mammal is administered such a compound with a fluid-absorbing polymer, such that the combination acts as described above and further provides the ability to sequester fluid and/or salt present in the GI tract

The present invention relates to new metal oxide nanoparticles coated with specific phosphonates, to the use of these nanoparticles as antimicrobials, especially in the home and personal care areas, to the production of such nanoparticles as well as to the new phosphonates and the corresponding process of production.

The nucleophile-assisted ring-opening reaction of phthalimides 1 has been studied. The reaction of phthalimides 1 with 0.5 equiv of hydrazine produced the novel bisphosphonates 2 in near quantitative yields whereas with 10-fold excess of hydrazine, diethyl aminoalkylphosphonates 3 was formed in 75% yields. The reaction of phthalimide 1b with 3-(aminopropyl)phosphine resulted in a novel compound 4a containing a P(III) hydride and a P(V) phosphonate within the same molecule. In addition, the reaction of 1b with 2- aminoethanol and 2-aminoethanethiol resulted in the formation of new phosphonates 4b,c. The reaction of bisphosphonates 2 with LiAlH4 in THF at 0 °C selectively reduced the phosphonate groups producing corresponding air- stable primary bisphosphines 6 in 80% yields. Further, the formylation of bisphosphines 6 under very mild conditions using 37% aqueous formaldehyde produced the corresponding novel water-soluble bisphosphine chelating agents 7 in near quantitative yields. All the new compounds have been characterized by 1H, 13C, 31P NMR, IR spectroscopy and mass spectrometry.

The synthesis and structure-stability relationships of a series of novel FK409 derivatives are described. The rates of decomposition in aqueous solution (pH 8.0, 30°C) were parallel with those of spontaneous NO release measured by ESR spectroscopy using carboxy-PTIO. The compounds can cover a wide range of NO releasing rates by appropriate modification of the molecule.

A series of phosphonic and phosphinic acid derivatives of glutathione were synthesized as potential inhibitors of glutathionylspermidine synthetase, an essential enzyme in the biosynthesis of trypanothione in trypanosomatids. The compounds showed moderate activity. Copyright

9-adenine, 9-adenine, 9-ethyl>adenine, and their diphosphates were synthesized.All three diphosphates were shown to incorporate into the 3'-te

A series of acyclic nucleosides and related α-phosphonyl acyclic analogues of dNTP with an amide bond have been prepared. Their antiviral and substrate properties were investigated.

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A new, simple method for the synthesis of aminoalkylphosphonic acids is based on the reduction of dialkoxyphosphorylcarboxamides with the borane-dimethyl sulfide complex.

Analogues of methotrexate (MTX) and aminopterin (AMT) with aminophosphonoalkanoic, aminoalkanesulfonic, and aminoalkanephosphonic acid side chains in place of glutamate were synthesized and tested as inhibitors of folylpolyglutamate synthetase (FPGS) from mouse liver. The aminophosphonoalkanoic acid analogues were also tested as inhibitors of dihydrofolate reductase (DHFR) from L1210 murine leukemia cells and as inhibitors of the growth of MTX-sensitive (L1210) and MTX-resistant (L1210/R81) cells in culture. The optimal number of CH2 groups in aminophosphonoalkanoic acid analogues of AMT was found to be two for both enzyme inhibition and cell growth inhibition but was especially critical for activity against FPGS. Deletion of the α-carboxyl also led to diminished anti-FPGS activity in comparison with previously studied homocysteic acid and 2-amino-4-phosphonobutyric acid analogues. In the aminoalkanesulfonic acid analogues of MTX without an α-carboxyl, anti-FPGS activity was low and showed minimal variation as the number of CH2 groups between the carboxamide and sulfonate moieties was changed from one to four. In similar aminoalkanephosphonic acid analogues of MTX, anti-FPGS activity was also low, was comparable for two and three CH2 groups between the carboxamide and phosphonate moieties, and was diminished by monoesterification of the phosphonate group. These effects demonstrate that the α-carboxyl group of folate analogues is involved in binding to the active site of FPGS, and that an α-carboxyl group should be retained as part of the structure of FPGS inhibitors.

Acylamino carboxylic acids were degradated by the Hunsdiecker-reaction; the bromo-derivatives were reacted with NaPO(OC2H5)2.Aminophosphonic acids were obtained by acidic hydrolysis, and half-blocked derivatives by the selective removal of masking substituents.Two phosphonopeptides were also prepared by this route.

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The reaction of phosphonic aldehydes with benzylamine in presence of NaBH3CN yields benzylaminoalkylphosphonates which, submitted to catalytic hydrogenation, lead to phosphonic amino esters.When reductive amination is carried out with H2/Pd reduction and debenzylation are observed simultaneously.In the absence of reducing agent the enaminobenzylphosphonate can be isolated and N-alkylated.Hydrolysis of phosphonic amino-esters with dilute HCl gives phosphonic amino acids.The order of occurence of each operation, as well as the choice of the catalyst is discussed.

The reactivity of diethyl-2-oxo ethyl- and 3-oxo propylphosphonates with ammonia, methyl and dimethylamine at pH 7 in the presence of sodium cyanohydridoborate via reductive amination of the carbonyl group has been reexamined.Reactions of diethyl-2-oxoethyl- and 3-oxopropylphosphonates with ammonia give imino-bis-(alkylphosphonates); methyl and dimethylamine give monocondensation products thus permitting the synthesis of N-substituted aminoalkylphosphonates.

The invention relates to a process for the manufacture of aminoalkyl-phosphonic acid esters by catalytic hydrogenation of cyanoalkylphosphonic acid esters. After having separated the catalyst and solvents, in general the crude product is distilled. The esters which can be obtained by the process of this invention are of importance as intermediate products, because all reactions of amines can be carried out with these products. They can also be used as additives for amine curing agents for epoxide resins in order to achieve flame-retarding properties.

The compounds of this invention are cephalosporins having various acylamino substituents at the 7-position and a phosphonoalkyl or esterified phosphonoalkyl substituted tetrazolylthiomethyl group at the 3-position of the cephem nucleus and intermediates for the preparation thereof. The 7-acylated compounds have antibacterial activity.