- Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol-dependent cytolysins
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Certain species of pathogenic bacteria damage tissues by secreting cholesterol-dependent cytolysins, which form pores in the plasma membranes of animal cells. However, reducing cholesterol protects cells against these cytolysins. As the first committed st
- Pospiech, Mateusz,Owens, Sian E.,Miller, David J.,Austin-Muttitt, Karl,Mullins, Jonathan G. L.,Cronin, James G.,Allemann, Rudolf K.,Sheldon, I. Martin
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- Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii
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As an extension of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically evaluated against Trypanosoma cruzi and Toxoplasma gondii,
- Galaka, Tamila,Falcone, Bruno N.,Li, Catherine,Szajnman, Sergio H.,Moreno, Silvia N.J.,Docampo, Roberto,Rodriguez, Juan B.
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p. 3663 - 3673
(2019/07/10)
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- The preparation of N-substituted aminomethylidenebisphosphonates and their tetraalkyl esters via reaction of isonitriles with trialkyl phosphites and hydrogen chloride. Part 1
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The reaction of isonitriles with trialkyl phosphites in the presence of hydrogen chloride gives tetraalkyl N-substituted aminomethylidenebisphosphonates via N-methylideneaminium (isonitrilium) salts. Hydrolysis or dealkylation of these tetraalkyl esters gives N-substituted aminomethylidenebisphosphonic acids in high yields.
- Goldeman, Waldemar,Kluczyński, Artur,Soroka, Miros?aw
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p. 5290 - 5292
(2012/11/13)
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- Effects of Bisphosphonates on the Growth of Entamoeba histolytica and Plasmodium Species in Vitro and in Vivo
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The effects of a series of 102 bisphosphonates on the inhibition of growth of Entamoeba histolytica and Plasmodium falciparum in vitro have been determined, and selected compounds were further investigated for their in vivo activity. Forty-seven compounds tested were active (IC50 50 ~ 4-9 μM) were nitrogen-containing bisphosphonates with relatively large aromatic side chains. Simple n-alkyl-1-hydroxy-1,1-bisphosphonates, known inhibitors of the enzyme farnesylpyrophosphate (FPP) synthase, were also active, with optimal activity being found with C9-C10 side chains. However, numerous other nitrogen-containing bisphosphonates known to be potent FPP synthase inhibitors, such as risedronate or pamidronate, had little or no activity. Several pyridine-derived bisphosphonates were quite active (IC50 ~ 10-20 μM), and this activity was shown to correlate with the basicity of the aromatic group, with activity decreasing with increasing pKa values. The activities of all compounds were tested versus a human nasopharyngeal carcinoma (KB) cell line to enable an estimate of the therapeutic index (TI). Five bisphosphonates were selected and then screened for their ability to delay the development of amebic liver abscess formation in an E. histolytica infected hamster model. Two compounds were found to decrease liver abscess formation at 10 mg/kg ip with little or no effect on normal liver mass. With P. falciparum, 35 compounds had IC50 values 50 values around 1 μM. Five compounds were again selected for in vivo investigation in a Plasmodium berghei ANKA BALB/c mouse suppressive test. The most active compound, a C9 n-alkyl side chain containing bisphosphonate, caused an 80% reduction in parasitemia with no overt toxicity. Taken together, these results show that bisphosphonates appear to be useful lead compounds for the development of novel antiamebic and antimalarial drugs.
- Ghosh, Subhash,Chan, Julian M. W.,Lea, Christopher R.,Meints, Gary A.,Lewis, Jared C.,Tovian, Zev S.,Flessner, Ryan M.,Loftus, Timothy C.,Bruchhaus, Iris,Kendrick, Howard,Croft, Simon L.,Kemp, Robert G.,Kobayashi, Seike,Nozaki, Tomoyoshi,Oldfield, Eric
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p. 175 - 187
(2007/10/03)
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- 3-D QSAR Investigations of the Inhibition of Leishmania major Farnesyl Pyrophosphate Synthase by Bisphosphonates
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We report the activities of 62 bisphosphonatesas inhibitors of the Leishmania major mevalonate/isoprene biosynthesis pathway enzyme, farnesyl pyrophosphate synthase. The compounds investigated exhibit activities (IC 50 values) ranging from ~100 nM to ~80 μM (corresponding to Ki values as low as 10 nM). The most active compounds were found to be zoledronate (whose single-crystal X-ray structure is reported), pyridinyl-ethane-1-hydroxy-1,1-bisphosphonates or picolyl aminomethylene bisphosphonates. However, N-alicyclic amino-methylene bisphosphonates, such as incadronate (N-cycloheptyl aminomethylene bisphosphonate), as well as aliphatic aminomethylene bisphosphonates containing short (n = 4, 5) alkyl chains, were also active, with 1C50 values in the 200-1700 nM range (corresponding to Ki values of ~20-170 nM). Bisphosphonates containing longer or multiple (N,N-) alkyl substitutions were inactive, as were aromatic species lacking an o- or m-nitrogen atom in the ring, or possessing multiple halogen substitutions or a p-amino group. To put these observations on a more quantitative structural basis, we used three-dimensional quantitative structure-activity relationship techniques: comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), to investigate which structural features correlated with high activity. Training set results (N = 62 compounds) yielded good correlations with each technique (R2 = 0.87 and 0.88, respectively), and were further validated by using a training/test set approach. Test set results (N = 24 compounds) indicated that IC50 values could be predicted within factors of 2.9 and 2.7 for the CoMFA and CoMSIA methods, respectively. The CoMSIA fields indicated that a positive charge in the bisphosphonate side chain and a hydrophobic feature contributed significantly to activity. Overall, these results are of general interest since they represent the first detailed quantitative structure-activity relationship study of the inhibition of an expressed farnesyl pyrophosphate synthase enzyme by bisphosphonate inhibitors and that the activity of these inhibitors can be predicted within about a factor of 3 by using 3D-QSAR techniques.
- Sanders, John M.,Gómez, Aurora Ortiz,Mao, Junhong,Meints, Gary A.,Van Brussel, Erin M.,Burzynska, Agnieszka,Kafarski, Pawel,González-Pacanowska, Dolores,Oldfield, Eric
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p. 5171 - 5183
(2007/10/03)
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- 1-Aminoalkane-1,1-diphosphonic acids and their salts
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A process for the production of 1-aminoalkane-1,1-diphosphonates of the formula SPC1 Wherein R1 is a member selected from the group consisting of hydrogen, lower alkyl and phenyl, R2 and R 3 are members selected from the group consisting of hydrogen, alkyl having 1 to 22 carbon atoms, cycloalkyl having 5 to 6 carbon atoms, phenyl, alkylphenyl having 7 to 18 carbon atoms, phenylalkyl having 7 to 18 carbon atoms and together with the nitrogen atom, piperidino, pyrrolidino and morpholino, and X is a member selected from the group consisting of hydrogen, alkali metal, ammonium, pyridinium, guanidinium and mono-, di-, and tri-lower-alkanol-ammonium with the proviso that at least one of R1, R2 and R3 is other than hydrogen, which consists essentially in reacting a phosphorus trihalide selected from the group consisting of phosphosus trichloride and phosphorus tribromide with a monocarboxylic acid amide of the formula SPC2wherein the molecular weight of said carboxylic acid amide is over 46 and R1, R2 and R 3 have the above assigned meanings, at a temperature of from 0° to 75°C, subjecting the resultant reaction product to hydrolysis, and recovering said 1-aminoalkane-1,1-diphosphonates. The 1-aminoalkane-1,1-diphosphonates, some of which are novel, are capable of forming complexes with heavy metals.
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