Aminophosphonic Derivatives Research Articles

Microwave-Assisted Synthesis of Aminophosphonic Derivatives and Their Antifungal Evaluation against Lomentospora prolificans.

Lomentospora prolificans is a pathogenic and multidrug-resistant fungus that can infect both immunocompetent and immunocompromised patients, with mortality rates up to 87%. The World Health Organization (WHO) included this fungal species in its first list of 19 priority fungal pathogens, which focused on fungal pathogens that can cause invasive acute and subacute systemic fungal infections. Therefore, there is a growing interest in finding new therapeutic alternatives. In this work, the synthesis of twelve α-aminophosphonates by the microwave-assisted Kabachnik-Fields reaction and twelve α-aminophosphonic acids by a monohydrolysis reaction is reported. All compounds were evaluated by the agar diffusion method as a preliminary screening in comparison with voriconazole, showing inhibition halos for compounds 7, 11, 13, 22 and 27. The five active compounds in the preliminary tests were evaluated against five strains of L. prolificans following protocol M38-A2 from CLSI. The results showed that these compounds exhibit antifungal activity in the concentration range of 900->900 μg/mL. Cytotoxicity against healthy COS-7 cells was also evaluated by the MTT assay, and it was shown that compound 22 was the least cytotoxic, with a viability of 67.91%, comparable to the viability exhibited by voriconazole (68.55%). Docking studies showed that the possible mechanism of action of the active compounds could be through the inhibition of the enzyme lanosterol-14-alpha-demethylase in an allosteric hydrophobic cavity.

Effect of mono- vs. bi-functionality of aminophosphonate derivatives on the enhancement of U(VI) sorption: physicochemical properties and sorption performance

Aminophosphonates are excellent complexing agents for numerous metal ions (including uranyl). Based on this property, two sorbents have been synthesized using simple one-pot reaction: thiocarbazide (amine source), p-phthaldehyde (di-aldehyde), and trimethylphosphite (phosphorous precursor) are mixed with different molar ratios to produce bis- (2:1:2) and mono (1:1:1) α-aminophosphonate-based derivatives (B-AmPh and M-AmPh, respectively). Materials are characterized using XRD, BET, SEM, titration, elemental, FTIR, and XPS analyses to evaluate the effect of substitution rate on the physicochemical properties. FTIR and XPS are also used for elucidating binding mechanisms. Sorption properties of the materials have been tested for U(VI): the pH effect is completed by investigating uptake kinetics and sorption isotherms. At pH 4.5 (and T: 55 °C), sorption capacity increases from 0.89 to 1.22 mmol/g with the increase in the substitution degree (M-AmPh < B-AmPh). This increase is not correlated to the fraction of grafted reactive groups, meaning that steric hindrance probably contributes to limiting the accessibility and availability of aminophosphonate moieties. Pseudo-second order and Crank equation preferentially fit kinetic profiles. Langmuir equation successfully describes sorption isotherms. Sorption process is systematically endothermic and spontaneous: enthalpy and entropy changes decrease with the substitution rate. Uranium successfully desorbed using HCl (0.2 M); allows six cycles of re-use with limited loss in sorption/desorption efficiencies. The sorbents were used for U(VI) recovery from acidic leachate of uranium ore. This test shows remarkable affinity and selectivity of B-AmPh for uranium; however, after elution and precipitation the U concentrate contains about 10 % of impurities.

Cytotoxic Activity of α-Aminophosphonic Derivatives Coming from the Tandem Kabachnik-Fields Reaction and Acylation.

Encouraged by the significant cytotoxic activity of simple α-aminophosphonates, a molecular library comprising phosphonoylmethyl- and phosphinoylmethyl-α-aminophosphonates, a tris derivative, and N-acylated species was established. The promising aminophosphonate derivatives were subjected to a comparative structure-activity analysis. We evaluated 12 new aminophosphonate derivatives on tumor cell cultures of different tissue origins (skin, lung, breast, and prostate). Several derivatives showed pronounced, even selective cytostatic effects. According to IC50 values, phosphinoylmethyl-aminophosphonate derivative 2e elicited a significant cytostatic effect on breast adenocarcinoma cells, but it was even more effective against prostatic carcinoma cells. Based on our data, these new compounds exhibited promising antitumor activity on different tumor types, and they might represent a new group of alternative chemotherapeutic agents.

Novel Synthesis, Docking studies and Antitumor Evaluation of Pyrazolo- and Pyrazolo Aminophosphonate Derivatives Derived from N-Heterocyclic Amines

Novel Synthesis, Docking studies and Antitumor Evaluation of Pyrazolo- and Pyrazolo Aminophosphonate Derivatives Derived from N-Heterocyclic Amines

CO2 Adsorption on the N- and P-Modified Mesoporous Silicas.

SBA-15 and MCM-48 mesoporous silicas were modified with functionalized (3-aminopropyl)triethoxysilane (APTES) by using the post-synthesis method, thus introducing N- and P-containing groups to the pore surface. The structure of the newly synthesized modifiers (aldimine and aminophosphonate derivatives of (3-aminopropyl)triethoxysilane and their grafting onto the porous matrix were proved by applying multinuclear NMR and FTIR spectroscopies. The content of the grafted functional groups was determined via thermogravimetric analysis. The physicochemical properties of the adsorbent samples were studied by nitrogen physisorption and UV–Vis spectroscopy. The adsorption capacity of CO2 was measured in a dynamic CO2 adsorption regime. The modified silicas displayed an enhanced adsorption capacity compared to the initial material. The 13C NMR spectra with high-power proton decoupling proved the presence of physically captured CO2. A value of 4.60 mmol/g was achieved for the MCM-48 material grafted with the Schiff base residues. The total CO2 desorption was achieved at 40 °C. A slight decrease of about 5% in CO2 adsorption capacities was registered for the modified silicas in three adsorption/desorption cycles, indicating their performance stability.

Design and synthesis of novel 20(S)-α-aminophosphonate derivatives of camptothecin as potent antitumor agents

29 novel 20(S)-aminophosphonate derivatives of camptothecin were synthesized via a FeCl3 - catalyzed one-pot reaction. All of these compounds displayed similar or superior cytotoxic activity in comparison with that of Irinotecan against Hep3B, MCF-7, A-549, MDA-MB-231, KB, and multidrug-resistant (MDR) KB-vin cell lines. Out of them, compound B07 exhibited significant cytotoxicity and 10-fold improvement in activity compared to Irinotecan. Mechanistically, B07 not only induced cell apoptosis and cell cycle arrest in Hep3B and MCF-7 cells, but also inhibited Topoisomerase I activity in the cell and cell-free system in a manner similar to that of Irinotecan. In both xenograft and primary HCC mouse models, B07 showed significant anti-tumor activity and was more potent than Irinotecan. Additionally, the acute toxicity assay showed that B07 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the FVB/N mice. Therefore, these findings indicate that compound B07 could be a potential Topoisomerase I poison drug candidate for further clinical trial.

Discovery of novel sulfonamide-containing aminophosphonate derivatives as selective COX-2 inhibitors and anti-tumor candidates

As an essential enzyme with a variety of physiological functions, Cyclooxygenase-2 (COX-2) is also closely related to carcinoma due to the observed overexpression. In this work, a novel series of sulfonamide-containing aminophosphonate derivatives (A1-A25) were developed as selective COX-2 inhibitors and anti-cancer candidates. The top hit compound A23 presented applicative COX-2 inhibitory activity (IC50 = 0.28 µM) and anti-proliferative capability against several cancer cell lines (IC50 = 2.34–16.43 µM for HeLa, MCF-7, HCT116 and HepG2 cells). Among them, A23 has the most significant inhibitory effect on HCT116 cells, which were comparable with that of the positive controls respectively (eg: IC50 = 8.73 µM for HCT116). The binding pattern of A23 was inferred by the molecular docking simulation. Moreover, A23 could induce the apoptosis via a mitochondrion-dependent mode and cause the arrest of the cell-cycle in G1 stage. A further investigation in the checkpoints of apoptosis indicated that the node Bcl-2 might connect the selective COX-2 inhibition and the anti-tumor activity. Therefore, this work brought new information for developing COX-2 inhibitors in anti-tumor therapies in future.

Discovery of novel aminophosphonate derivatives containing pyrazole moiety as potential selective COX-2 inhibitors

Cyclooxygenase is critical for maintaining physiological functions, whereas overexpression of COX-2 was closely implicated in various cancers. In this study, a series of novel aminophosphonate derivatives containing pyrazole moiety were synthesized with their anti-cancer activity evaluated. In vitro assays of the target compounds showed that Z21 displayed excellent COX-2 inhibitory activity against COX-2 (IC50 = 0.22 ± 0.04 µM) and anti-proliferative activity against MCF-7 cell (IC50 = 4.37 ± 0.49 µM). The apoptosis induction of compound Z21 was confirmed by flow cytometry and polymerase chain reaction. Further investigation demonstrated that compound Z21 induced apoptosis of MCF-7 cells through a mitochondrion-dependent pathway and involved cell-cycle arrest in G2 phase. Overall, these results provided some new insights into the design of therapeutic drugs for COX-2 inhibitors and indicated the connection between selective COX-2 inhibition and the anti-tumor activity.

Cytotoxic Action of N-aryl, Furan-derived Aminophosphonates against HT29 and HCT116 Cancer Cell Lines

The anticancer activity of aminophosphonic derivatives has been described extensively, some recent papers included furan-derived aminophosphonates and their cytostatic action against various cancer cells. A series of twelve furan-derived dibenzyl and diphenyl aminophosphonates 2a-f and 3a-f was synthesized and tested in aspect of their cytotoxic action on two cell lines of colorectal cancer: HT29 and HCT116. Seven of them are new compounds, while the rest five have already been published by us, together with their cytotoxic action against squamous esophageal cancer cells. To estimate the cytotoxicity effect of tested compounds MTT test was used. Pro-apoptotic activity of five selected compounds was evaluated using APC Annexin V Apoptosis Detection Kit on a flow cytometer. Quantification of caspases 3/7 activity was performed using Caspase-Glo® 3/7 Assay Kit. Five of these aminophosphonates showed significant cytotoxicity higher than those of cisplatin. Simultaneous evaluation of their cytotoxicity against PBLs revealed that these compounds are rather not harmful for regular human lymphocytes. Tests on apoptosis vs. their necrotic actions on cells were performed with selected compounds showing the most significant cytotoxicity against cancer cells and all tested compounds did not induce significant increase of necrosis in cells, whereas they showed moderate-to-strong proapoptotic actions even at the lowest applied concentration. Caspase 3/7 activity results confirmed proapoptotic properties of tested aminophosphonates. From among studied compounds, dibenzyl N-phenyl substituted amino(2-furyl)methylphsophonates were found to be more potent compounds in aspect of their antiproliferative action than the corresponding diphenyl derivatives.

New aminophosphonate derivatives on the basis of 1-vinylsulfonyl-2-arylpyrrolidine

New water soluble 1-vinylsulfonyl-2-arylpyrrolidine derivatives were obtained through aza-Michael reaction of 4-chloro-6-[1-(vinylsulfonyl)pyrrolidin-2-yl]benzene-1,3-diol with secondary aminophosphonates in water-ethanol medium in the presence of triethylamine.

Effect of New Thiophene-Derived Aminophosphonic Derivatives on Growth of Terrestrial Plants. Part 2. Their Ecotoxicological Impact and Phytotoxicity Test Toward Herbicidal Application in Agriculture.

Background: The aim of this work was to evaluate phytotoxicity of the thiophene derivatives against three persistent weeds of a high degree of resistance (Galinsoga parviflora Cav., Rumex acetosa L., and Chenopodium album) as well as their ecotoxicological impact on Heterocypris incongruens. In addition, Aliivibrio fischeri was measured. Two of eight described aminophosphonates, namely dimethyl N-(2-methoxyphenyl)amino(2-thienyl)methylphosphonate (2d) and dimethyl N-(tert-butyl)- (2-thienyl)methylphosphonate (2h), have never been reported before. Methods: The phytotoxicity of tested aminophosphonates toward their potential application as soil-applied herbicides was evaluated according to the OECD 208 Guideline. Ecotoxicological properties of investigated compounds were made using the OSTRACODTOXKITTM and Microtox® tests. Results: Obtained results showed that four aminophosphonates have interesting herbicidal properties and N-(2-methylphenyl)amino- (2-thienyl)methylphosphonate (2a) was found to kill efficiently the most resistant plant Chenopodium album. None of the tested compounds showed important toxicity against Aliivibrio fischeri. However, their toxic impact on Heterocypris incongruens was significantly elevated. Conclusions: The aminophosphonate 2a showed herbicidal potential and it is not toxic against tested bacteria (EC50 over 1000 mg/L). It was found to be moderately toxic against ostracods [mortality 48% at 10 mg/kg of soil dry weight (s.d.w.)] and this problem should be solved by the use of the controlled release from a polymeric carrier.

Analysis and application of the SRBSDV P9-1 octamer crystal structure for the target of α-amino phosphonate derivatives

// Yan Ding 1 , Xiangyang Li 1 , Kai Chen 1 , Guoping Zhang 1 , Liangzhi Luo 1 , Deyu Hu 1 and Baoan Song 1 1 State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, PR China Correspondence to: Baoan Song, email: basong@gzu.edu.cn Xiangyang Li, email: xyli1@gzu.edu.cn Keywords: targets; SRBSDV P9-1; octamers; bind to; &alpha;-amino phosphonate derivatives Received: October 17, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: December 05, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: January 13, 2018 ABSTRACT Southern rice black-streaked dwarf virus (SRBSDV) P9-1 octameric protein accumulates viroplasms in SRBSDV-infected plant and insect cells, our previous studies found &alpha;-amino phosphonate drug&mdash;dufulin had a micromole affinity with SRBSDV P9-1. Now we focus our studies on the SRBSDV P9-1 crystal structure and use it as the target for &alpha;-amino phosphonate derivatives. The structure of the SRBSDV P9-1 cylindrical octamer was determined to a 2.2 &Aring; resolution using X-ray crystallography, this structure was composed of nine &alpha;-helices, nine &beta; -sheets and a series of interconnecting loops. The structures of all eight subunits were nearly identical, except for some differences in the &beta; -sheet core. There were six different sites (R20K, V109D, F164T, V123L, C124L and V128T) present between the SRBSDV P9-1 and the previously reported RBSDV P9-1 crystal structure. Fluorescence titration, isothermal calorimetry and microscale thermophoresis experiments showed that &alpha;-amino phosphonate derivatives GUFCC-013 and GUFCC-023 bound to SRBSDV P9-1 with micromole binding affinities. These results will provide important help for the further improvement of the lead compound and develop the potential anti-SRBSDV drugs.

Synthesis of Two Novel Homologous Polyphosphoesters Containing Aminophosphonate Units and Cytotoxicity of Some Low‐Molecular and Polymeric Aminophosphonate Derivatives

Two novel polyphosphoesters containing anthracene‐ and furan‐derived aminophosphonate moieties, namely, poly[oxyethylene(aminophosphonate‐co‐H‐phosphonate)]s P-12 and P-13, were synthesized through an addition of poly(oxyethylene H‐phosphonate) to 9‐anthrylidene‐furfurylamine and characterized. The novel polyphosphoester P-12 and a series of previously described anthracene‐derived compounds including Schiff bases S‐1 and S‐2, α‐aminophosphonates A-3–A-6, bis‐aminophosphonate B-6, two enantiomers A-5a and A-5b, and polyphosphoesters P-8–P-11 containing aminophosphonate units were screened for antitumor activity against a panel of human leukemic cell lines, using cisplatin as a reference cytotoxic agent. As concluded from the cytotoxicity assays, both precursors S-1 and S-2 presented similar cytotoxicity profiles that are cisplatin‐like only in the REH cell line. Leader compound of the α‐aminophosphonates is A-4 with cell death‐inducing properties fully equaling those of the referent drug in all of the screened leukemic cell lines with the only exception being the AML histological subtype HL‐60. Some of the polymeric analogues elicited moderate (P-10 and P-12) to low (P-11) cytotoxic activity, whereas the polyphosphoesters P-8 and P-9 produced in vitro antitumor effects largely surpassing cisplatin’s. The compounds P-8, P-9, and A-4 could be potential new materials for anticancer therapeutic purposed.

Aminophosphinates against Helicobacter pylori ureolysis-Biochemical and whole-cell inhibition characteristics.

Urease is an important virulence factor from Helicobacter pylori that enables bacterial colonization of human gastric mucosa. Specific inhibition of urease activity can be regarded as a promising adjuvant strategy for eradication of this pathogen. A group of organophosphorus inhibitors of urease, namely, aminophosphinic acid and aminophosphonic acid derivatives, were evaluated in vitro against H. pylori urease. The kinetic characteristics of recombinant enzyme activity demonstrated a competitive reversible mode of inhibition with Ki values ranging from 0.294 to 878 μM. N-n-Hexylaminomethyl-P-aminomethylphosphinic acid and N-methylaminomethyl-P-hydroxymethylphosphinic acid were the most effective inhibitors (Ki = 0.294 μM and 1.032 μM, respectively, compared to Ki = 23 μM for the established urease inhibitor acetohydroxamic acid).The biological relevance of the inhibitors was verified in vitro against a ureolytically active Escherichia coli Rosetta host that expressed H. pylori urease and against a reference strain, H. pylori J99 (CagA+/VacA+). The majority of the studied compounds exhibited urease-inhibiting activity in these whole-cell systems. Bis(N-methylaminomethyl)phosphinic acid was found to be the most effective inhibitor in the susceptibility profile studies of H. pylori J99. The cytotoxicity of nine structurally varied inhibitors was evaluated against four normal human cell lines and was found to be negligible.

Structure based design, synthesis and biological evaluation of amino phosphonate derivatives as human glucokinase activators

Glucokinase (GK) is a potential therapeutic target of type 2 diabetes and GK activators (GKAs) represent a promising class of small organic molecules which enhance GK activity. Based on the configuration and conformation of the allosteric site of GK, we have designed a novel class of amino phosphonate derivatives in order to develop potent GKAs. The QSAR model developed using numerous descriptors revealed its potential with the best effective statistical values of RMSE=1.52 and r2=0.30. Moreover, application of this model on the present test set GKAs proved to be worthy to predict their activities as a better linear relationship was observed with RMSE=0.14 and r2=0.88. ADME studies and Lipinski filters encouraged them as safer therapeutics. The molecular dynamics and docking studies against the GK allosteric site revealed that all GKAs bind with best affinities and the complexes are strengthened by H-bonding, phosphonate salt bridges, hydrophobic and arene cat ionic interactions. Finally, in vitro evaluation with human liver GK revealed their potential to increase the GK activity by different folds. The results from QSAR, ADME, molecular docking and in vitro assays strongly suggested that the present molecules could be used as effective and safer therapeutics to control and manage type 2 diabetes.

The Effect of New Thiophene-Derived Aminophosphonic Derivatives on Growth of Terrestrial Plants: A Seedling Emergence and Growth Test.

The aim of this work was to synthesize selected thiophene-derived aminophosphonic systems and evaluate the phytotoxicity of newly obtained products according to the OECD 208 Guideline. Seven new thiophene-derived N-substituted dimethyl aminomethylphosphonic acid esters 2a–h were synthesized by the addition of an appropriate phosphite to azomethine bond of starting Schiff bases 1a–h, and NMR spectroscopic properties of aminophosphonates were investigated. These eight compounds were analyzed in regard to their phytotoxicity towards two plants, radish (Raphanus sativus) and oat (Avena sativa). On the basis of the obtained results, it was found that tested aminophosphonates 2a–h showed an ecotoxicological impact against selected plants, albeit to various degrees.

The synthesis of phosphorylated silsesquioxanes and the investigation of the ability to aggregation and interaction with aromatic dicarboxylic acids

For the first time, silsesquioxanes containing aminophosphonate fragments were synthesized by condensation of the aminophosphonate derivatives with trialkoxysilane moieties under acid catalysis conditions. According to 29Si NMR, IR-spectroscopies, the silsesquioxane obtained have ladder-like structure with T4 and T6 silicon atoms. Information obtained from the MALDI-TOF mass spectra was used to deduce the structure of both oligomeric derivatives and the silsesquioxane framework. The morphology of the polysilsesquioxanes formed was investigated by transmission electron microscopy. The T6-silsesquioxanes bearing aminophosphonate moieties contrary to T4-silsesquioxanes tend to form aggregates of prolate shape. Their aggregation behavior was analyzed by the dynamic light scattering method. T6-silsesquioxane tends to form submicron-sized aggregates in aqueous solutions. The ability of these silsesquioxanes to recognize aromatic dicarboxylic acids was studied by the UV-spectroscopy.

Catalytic Asymmetric 1,2‐Addition of α‐Isothiocyanato Phosphonates: Synthesis of Chiral β‐Hydroxy‐ or β‐Amino‐Substituted α‐Amino Phosphonic Acid Derivatives

Abstractα‐Amino phosphonic acid derivatives are considered to be the most important structural analogues of α‐amino acids and have a very wide range of applications. However, approaches for the catalytic asymmetric synthesis of such useful compounds are very limited. In this work, simple, efficient, and versatile organocatalytic asymmetric 1,2‐addition reactions of α‐isothiocyanato phosphonate were developed. Through these processes, derivatives of β‐hydroxy‐α‐amino phosphonic acid and α,β‐diamino phosphonic acid, as well as highly functionalized phosphonate‐substituted spirooxindole, can be efficiently constructed (up to 99 % yield, d.r. &gt;20:1, and &gt;99 % ee). This novel method provides a new route for the enantioselective functionalization of α‐phosphonic acid derivatives.

Low cytotoxicity and clastogenicity of some polymeric aminophosphonate derivatives

Poly(oxyethylene aminophosphonate)s synthesized on the basis of biodegradable poly(phosphorester)s and Schiff bases were tested in vitro for antitumor activity against a panel of six human epithelial cancer cell lines, for cytotoxicity to mouse fibroblast cells and in vivo for clastogenicity and antiproliferative effects. The polymers showed lower cytotoxicity, both in vivo and in vitro and lower clastogenicity in vivo than the corresponding low-molecular aminophosphonates. The biological activities of the tested polymers correlate with their low in vitro antitumor activity.

Exploring the Isomer Dependent SERS Spectra of (diphenylphosphoryl)(pyridin-2, -3, and -4-yl)methanol Adsorbed on Gold Nanocolloids

The surface-enhanced Raman scattering (SERS) spectra of three aminophosphonate derivatives of pyridine: (diphenylphosphoryl)(pyridin-2-yl)methanol (α-Pyr), (diphenylphosphoryl)(pyridin-3-yl)methanol (β-Pyr), and (diphenylphosphoryl)(pyridin-4-yl)methanol (γ-Pyr) were measured after immobilization onto colloidal gold surface. Changes in the wavenumber, broadness, and enhancement between the corresponding Raman and SERS bands allowed to deduce orientation of theα-,β-, andγ-isomers (α-,β-, andγ-refer to the position of the substituent relative to the ring nitrogen atom) of aminophosphonate derivatives of pyridine on the gold surface. Briefly, it was demonstrated that theα-Pyr andβ-Pyr show the same mode of adsorption, whereas the adsorption process of theγ-Pyr isomer differs in this regard that pyridine assists in the interaction with the gold surface.