Α-aminophosphonate Derivatives Research Articles

Evaluation of the toxicity of a new series of α-aminophosphonate derivatives in a target (Ephestia Kuehniella) and non-target (Lumbricus rubellus) population

Evaluation of the toxicity of a new series of α-aminophosphonate derivatives in a target (Ephestia Kuehniella) and non-target (Lumbricus rubellus) population

Facile one pot three component synthesis, characterization, and molecular docking simulations of novel α-aminophosphonate derivatives based pyrazole moiety as potential antimicrobial agent.

An efficient method has been developed for the synthesis of novel α-aminophosphonates (AAP) (3a-m) through a one-pot three-component reaction of 1,3-disubstituted-1H-pyrazol-5-amine, aromatic aldehydes, and phosphite using lithium perchlorate as catalyst. All newly synthesized compounds were characterized via different spectroscopic techniques. The synthesized compounds' mode of action was investigated using molecular docking against the outer membrane protein A (OMPA) and exo-1,3-beta-glucanase, with interpreting their pharmacokinetics aspects. The results of the antimicrobial effectiveness of these compounds revealed a broad spectrum of their biocidal activity and this in-vitro study was in line with the in- silico results. Additionally, it has been demonstrated that these compounds exhibited a minimum inhibitory concentration (MIC) with significant activity at low concentrations (7.5-30.0 mg/mL). Further, the radical scavenging (DPPH*) activity of the synthesized compounds fluctuated, with compounds 3h, 3a, and 3f showing the highest antioxidant activity. Overall, the formulated compounds can be employed as antimicrobial and antioxidant agents in medical applications.

Crystal Structure, quantum chemical analysis and apoptotic propensity of diaryl substituted α-aminophosphonates as selected C[sbnd]P bonded systems

Three component Kabachnik-Fields reaction under sonochemical conditions was utilized for synthesizing library of electronically diverse aryl substituted α-aminophosphonates as representative carbon phosphorus bonded systems. Single crystal X-ray structures of four novel α-aminophosphonate derivatives with comprehensive Hirshfeld surface analysis for highlighting influence of different functionalities over α-aminophosphonate motif on the crystal packing pattern and formation of molecular assemblies via supramolecular aggregation have been presented. Solid state absorption and photoluminescence studies corroborated electronic and crystal packing influences. The computational methodologies for evaluating quantum chemical descriptors of electronic properties of α-aminophosphonates were bench marked. The bioactivity potential of synthesized library of α- aminophosphonates was evaluated from their cytotoxic propensity towards human cancer lines in NCI-60 panel via SRB assay. The screened derivatives showed a range of cytotoxicity against cancer cell lines in NCI-60 panel. Compound 3 exhibited highest cell growth inhibition in prostate cancer cells with IC50 value of 10.94 μM. For mechanistic insights apoptotic propensity was evaluated using caspase-3 enzyme assay in PC-3 cells. The onset of apoptosis via caspase-3 activation was evidenced as a major pathway from morphological changes under fluorescence microscope with and without DAPI staining. The triggering of apoptosis via caspase 3 activation by the lead compound 3 was also confirmed from western blot analysis of PARP-1 in PC-3 cancer cells. Furthermore, the anti-metastatic potential of compound 3 can be predicted from its efficacy in restricting the migration of PC-3 cancer cells under in vitro conditions observed from wound healing assay.

Inhibition Profiles of Some Novel Sulfonamide-Incorporated α-Aminophosphonates on Human Carbonic Anhydrases.

A series of hitherto unknown sulfonamide-incorporated α-aminophosphonate derivatives were synthesized through the one-pot, two-step FeCl3-catalyzed coupling of 4-aminobenzenesulfonamide with the appropriate benzaldehydes and diethyl phosphite. The new sulfonamides inhibition studies were performed on four carbonic anhydrase isoforms, i.e., the cytosolic human (h) hCA I and II (off-targets) as well as transmembrane cancer-related hCA IX and XII (targets). Among the synthesized compounds, derivative 23 resulted in the most selective compound against both cancer-associated isoforms over the off-target hCA I (hCA I/IX = 78; hCA I/XII = 458) and hCA II (hCA II/IX = 10; hCA II/XII = 56) and the binding mode of both enantiomers R and S was investigated in silico.

2-Hydroxymethyl-18-crown-6 as an efficient organocatalyst for α-aminophosphonates synthesized under eco-friendly conditions, DFT, molecular docking and ADME/T studies

Eco-friendly and simple procedure has been developed for the synthesis of α-aminophosphonates that act as topoisomerase II α-inhibiting anticancer agent, using 2-hydroxymethyl-18-crown-6 as an unexpected homogeneous organocatalyst in multicomponents reaction of aromatic aldehyde, aniline and diethylphosphite in one pot via Kabachnik–Fields reaction. This efficient method proceeds with catalytic amount, transition metal-free, at room temperature within short reaction time, giving the α-aminophosphonates derivatives (4a–r) in high chemical yields (up to 80%). Theoretical DFT calculations of three compounds (4p, 4q and 4r) were carried out in a gas phase at CAM-B3LYP 6-31G (d,p) basis set to predict the molecular geometries and chemical reactivity descriptors. The frontier orbital energies (HOMO/LUMO) were described the charge transfer and used to predict structure-activity relationship study. Molecular electrostatic potential (MEP) has also been analyzed. Molecular docking studies are implemented to analyze the binding energy and compared with Adriamycin against 1ZXM receptor which to be considered as antitumor candidates. In silico pharmacological ADMET properties as Drug likeness and oral activity have been carried out based on Lipinski’s rule of five. Communicated by Ramaswamy H. Sarma

Synthesis and anti-Alzheimer potential of novel α-amino phosphonate derivatives and probing their molecular interaction mechanism with acetylcholinesterase

Pleiotropic interference may be a prerequisite for the efficient limitation of the progression of multi-factorial diseases such as Alzheimer's disease (AD). Concept of designing the single chemical entity acting on two or more targets of interest has potential advantage in AD therapy. In line with this, rational design and synthesis of frame work of hybrids bearing 2,3-disubstituted quinazolinone, vanillin and α-amino phosphonate scaffolds (5a─v) were carried out. A congeneric set of twenty-two synthetic derivatives (5a─v) were evaluated for their cholinesterase inhibitory, antioxidant, DNA nicking, DNA protection, neuroprotective and Aβ aggregation modulatory activities. Amongst tested activities, the most significant and worth mentioning is that the analogues 5m, 5p and 5u were found to be the most potent, selective, and mixed type inhibitors of EeAChE with IC50 values of 0.296 ± 0.030, 0.289 ± 0.027, and 0.306 ± 0.028 μM, respectively. Further, the biophysical approaches indicated that the compounds 5m, 5p, and 5u have a strong binding affinity towards AChE. Kinetic and Molecular docking studies have revealed that the most active congeners were well oriented in the AChE active site by interacting with both catalytic active site (CAS) and peripheral anionic site (PAS). A few parameters derived from molecular dynamics (MD) simulation trajectories emphasized the stability of AChE-5p and 5m complexes throughout the 100 ns simulations, and the local conformational changes of the residues of AChE validate the stability of AChE-5p and 5m complexes. Further, these derivatives significantly impacted ABTS radical scavenging capacities and maximal DNA protection activity. Importantly, Thioflavin T (ThT) assay and FE-SEM study demonstrated compounds 5m, 5p and 5u as effective Aβ1−42 fibril modulators at molecular level by the formation of micro size co-assembled mature structures, thus efficiently abolishing the cytotoxicity of Aβ1–42. Finally, these active compounds are determined to be non-toxic and highly neuroprotective against H2O2-induced cell death in SK-N-SH cell lines. Furthermore, in silico ADMET prediction studies have revealed that the targeted analogues satisfied most of the characteristics of CNS acting drugs. These multi-functional efficacies indicated worthiness of these α-amino phosphonate derivatives being chosen for further pharmacokinetics, toxicity, and behavioral research to test their potential for AD treatment.

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.

One-pot synthesis and fluorescent property of novel syringaldehyde α-aminophosphonate derivatives

Seven novel syringaldehyde α-aminophosphonate derivatives (1–7) were synthesized based on syringaldehyde together with different aryl amines and diethyl phosphite in a one-pot, solvent free, and catalyst free reaction. All of the obtained compounds were characterized by analysis of their 1H NMR and 13C NMR, IR spectra, and FT mass spectra. The UV and fluorescence emission spectra of 1–7 were investigated in the concentration range of 0.1–250 μM. As the results, the maximum emission wavelength of 1–7 was observed between 600 and 700 nm under the exciting wavelength of 250 nm for 1–5 and 300 nm for 6 and 7. The emission intensity is the strongest at a concentration of 60 μM for 2, 3, and 5–7, 30 μM for 1, and 0.1 μM for 4.

Thermoresponsive nanofibers loaded with antimicrobial α-aminophosphonate-o/w emulsion supported by cellulose nanocrystals for smart wound care patches

Long-term topical application of antibiotics on wounds has led to the emergence of drug-resistant bacterial infections. Antibiotic incorporation into the wound dressing requires enormous advancement of the field to ensure that the needed dose is released when the infection arises. This study synthesized a series of antimicrobial α-aminophosphonate derivatives, and the most effective compound was incorporated into thermoresponsive wound dressing patches. Wound dressing mats were fabricated by needleless electrospinning, and the resultant nanofiber mats were coated with a thermoresponsive eicosane/cellulose nanocrystals o/w system loaded with active α-aminophosphonate derivatives. Chemical, physical, thermal, and antimicrobial properties of the wound dressings were characterized wound dressings. Using SEM analysis, Nanofibers spun with 20 % w/v solutions were selected for drug-emulsion loading since they showed lower diameters with higher surface area.Furthermore, the drug-emulsion coating on the electrospun dressings improved the hydrophilicity of the wound dressings, and the thermoresponsive behavior of the mats was proved using differential scanning calorimetry data. Finally, the drug-loaded electrospun meshes were found active against tested microorganisms, and clear inhibition zones were observed. In conclusion, this novel approach of synthesizing a new family of antimicrobial molecules and their incorporation into nanofibers from renewable sources exhibits great potential for smart and innovative dressings.

Self-crosslinked polyvinyl alcohol/cellulose nanofibril cryogels loaded with synthesized aminophosphonates as antimicrobial wound dressings.

Microbial infection is the most common obstacle in the wound healing process, leading to wound healing impairment and complications and ultimately increasing morbidity and mortality. Due to the rising number of pathogens evolving resistance to the existing antibiotics used for wound care, alternative approaches are urgently required. In this study, α-aminophosphonate derivatives as antimicrobial agents were synthesized and incorporated into self-crosslinked tri-component cryogels composed of fully hydrolyzed polyvinyl alcohol (PVA-F), partially hydrolyzed polyvinyl alcohol (PVA-P), and cellulose nanofibrils (CNFs). Initially, the antimicrobial activity of four α-aminophosphonate derivatives against selected skin bacterial species was tested and their minimum inhibitory concentration was determined based on which the most effective compound was loaded into the cryogels. Next, the physical and mechanical properties of cryogels with various blending ratios of PVA-P/PVA-F and fixed amounts of CNFs were assessed, and drug release profiles and biological activities of drug-loaded cryogels were analyzed. Assessment of α-aminophosphonate derivatives showed the highest efficacy of a cinnamaldehyde-based derivative (Cinnam) against both Gram-negative and Gram-positive bacteria compared to other derivatives. The physical and mechanical properties of cryogels showed that PVA-P/PVA-F with a 50/50 blending ratio had the highest swelling ratio (1600%), surface area (523 m2 g-1), and compression recoverability (72%) compared to that with other blending ratios. Finally, antimicrobial and biofilm development studies showed that the cryogel loaded with a Cinnam amount of 2 mg (relative to polymer weight) showed the most sustained drug release profile over 75 h and had the highest efficacy against Gram-negative and Gram-positive bacteria. In conclusion, self-crosslinked tri-component cryogels loaded with the synthesized α-aminophosphonate derivative, having both antimicrobial and anti-biofilm formation properties, can have a significant impact on the management of uprising wound infection.

One-pot synthesis of pyrazolo[4,3-d]thiazole derivatives containing α-aminophosphonate as potential Mur A inhibitors against MDR pathogens with radiosterilization and molecular modeling simulation.

The present study involves the synthesis of a new series of α-aminophosphonate derivatives in good yields with a simple workup via the Kabachnik-Fields reaction using lithium perchlorate (LiClO4) as a catalyst to facilitate the reaction. All the newly synthesized compounds were confirmed using various physical, spectroscopic, and analytical data, and the obtained results correlated with the proposed molecular structure. The in vitro antimicrobial activities of each compound were evaluated against different clinical isolates. The results indicated that among these derivatives, two compounds (5a and 5b) were the most active and displayed potent activity with MICs in the range from 0.06 to 0.25 μg mL-1 compared with fosfomycin and fluconazole as standard antibiotics. Moreover, the synthesized phosphonates displayed a broad spectrum of bactericidal and fungicidal activities depending on MICs, MBCs/MFCs, and the time-kill kinetics. In addition, the checkerboard assay showed synergistic and partial synergistic activities between the active compounds combined with fosfomycin and fluconazole. Furthermore, the SEM images showed distinct ruptures of the OM integrity of the FOS-R E. coli at their MICs, which was further indicated by the increased EtBr accumulation within the bacterial cells. Moreover, active derivatives revealed MurA inhibitory activity with IC50 values of 3.8 ± 0.39 and 4.5 ± 0.23 μM compared with fosfomycin (IC50 = 12.7 ± 0.27 μM). To our surprise, exposing 5a and 5b compounds to different gamma radiation doses revealed that 7.0 kGy eradicated the microbial load completely. Finally, the results of quantum chemical study supported the binding mode obtained from the docking study performed inside the active site of MurA (PDB: 1UAE), suggesting that these phosphonates may be promising safe candidates for MDR infection therapy clinical trials with no toxic effects on the normal human cells.

Design, Synthesis, and Spectroscopic Studies of Some New α-Aminophosphonate Analogues Derived from 4-Hydroxybenzaldehyde with Special Reference to Anticancer Activity.

IntroductionAs biological activity components, α-aminophosphonates and their moieties play important roles in medicinal chemistry. Alpha-phosphonic acids are significant α-amino acid counterparts. Due to its strong biological activity, this class of molecule has recently been discovered to have numerous medical applications.Results and DiscussionA new class of α-aminophosphonates and arylidene derivatives was synthesized. Various spectroscopic and elemental analyses were used to confirm the prepared products. The produced materials were tested as anticancer against breast carcinoma cells and normal human cells (PBMC). Besides the analysis results, it was found that (7b, 4c, 5k, 6, 5a, 7c, 5f, 5b, and 5g) against MCF-7 line cells. As a reference anticancer drug, 5-fluorouracil was used. The anticancer activities showed that the compounds 7b, 4c, containing α-aminophosphonate and Schiff base groups, respectively, showed high inhibition activity against the MCF-7 cell line, with 94.32% and 92.45% inhibition compared to the inhibition by 5-FU with 96.02% inhibition. The results showed that the compounds 5k, 7b, 6, and 5a, respectively, had very low activity against normal human cells PBMC, with 12.77%, 13%, 13.13%, and 17.88% inhibition compared to the inhibition by 5-FU with 12.50% inhibition. The binding energy for non-bonding interactions between the ligand (studied compounds) and receptor, thymidylate synthase, was determined using molecular docking (pdb code: 1AN5).Conclusionα-aminophosphonate derivatives, arylidines, and disphosphonate derivatives derived from 4-hydroxybenzaldehyde were synthesized, purified, elucidated by spectroscopic analysis, and finally tested against carcinoma breast cancer to give high to moderate to low activity.

A green and novel method for the preparation of α-aminophosphonates using eggshell as catalyst. X-ray study

An efficient and eco-friendly green methodology is developed for the synthesis of series of α-aminophosphonate derivatives from diverse aldehydes, anilines and triethyl phosphite by using environmentally benign and cost-effective Eggshells as solid heterogeneous base catalyst. The reaction is conducted by the stepwise one pot condensation through Kabachnick–Fields addition reaction in ethanol at room temperature during 25–30 min. High yield, short reaction time, solvent-free condition, waste to wealth, and optimization with the design of experiment are the major advantages of this method. In addition, this study examines the influence of different solvents, temperature and the amount of catalyst on the yield of the reaction. A single crystal of (2S)- diethyl (phenyl) ((4-fluorophenyl)-aminophosphonate (3g) has been obtained after recrystallization from ethanol/dichloromethane (9/1) and selected for X-ray diffraction study. Compound 3g crystallizes in the monoclinic space group P21/c. The structure of the obtained compounds was confirmed by 1H, 13C, and 31P NMR spectroscopy, IR spectroscopy, as well as elemental analysis.

Diethyl α-aminophosphonate containing lubricating additives synthesized from (3-aminophenyl)boronic acid pinacol ester

In this paper, (3-aminophenyl)boronic acid pinacol ester was employed as a raw material to react with different aromatic aldehydes. Then diethyl phosphite was introduced to produce the addition reaction of carbon nitrogen double bond to prepare four diethyl α-aminophosphonate derivatives, which were diethyl[phenyl({[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino})methyl]phosphonate (BNP1), diethyl[(4-methoxyphenyl)({[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino})methyl]phosphonate (BNP2), diethyl [(4-nitrophenyl)({[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino})methyl]phosphonate (BNP3), and diethyl[(4-methylphenyl)({[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino})methyl]phosphonate (BNP4). The prepared compounds were characterized by 1H and 13C NMR, MS, FT-IR and PL (Photoluminescence Spectroscopy). Four derivatives perform high thermal stability. In addition, it exhibits good friction properties for rapeseed oil (RSO) at low concentrations. Compared with BNP1, BNP2 and BNP4, BNP3 exhibits best on friction-reducing and anti-wear performances attributed to the strong electron withdrawing ability of the nitro group in BNP3, which is also reflected in the solid-state fluorescence. Therefore, the four diethyl α-aminophosphonate derivatives have potential industrial applications as lubricant additives.

Relationship between Structure and Antibacterial Activity of α-Aminophosphonate Derivatives Obtained via Lipase-Catalyzed Kabachnik-Fields Reaction.

We reported a new method dealing with the synthesis of novel pharmacologically relevant α-aminophosphonate derivatives via a lipase-catalyzed Kabachnik−Fields reaction with yields of up to 93%. The advantages of this protocol are excellent yields, mild reaction conditions, low costs, and sustainability. The developed protocol is applicable to a range of H-phosphites and organic amines, providing a wide substrate scope. A new class of α-aminophosphonate analogues possessing P-chiral centers was also synthesized. The synthesized compounds were characterized on the basis of their antimicrobial activities against E. coli. The impact of the various alkoxy groups on antimicrobial activity was demonstrated. The crucial role of the substituents, located at the aromatic rings in the phenylethyloxy and benzyloxy groups, on the inhibitory action against selected pathogenic E. coli strains was revealed. The observed results are especially important because of increasing resistance of bacteria to various drugs and antibiotics.

Discovery of Novel α-Aminophosphonates with Hydrazone as Potential Antiviral Agents Combined With Active Fragment and Molecular Docking.

A series of novel α-aminophosphonate derivatives containing hydrazone were designed and synthesized based on active fragments. Bioassay results demonstrated that title compounds possessed good activities against tobacco mosaic virus. Among them, compounds 6a, 6g, 6i, and 6j were equivalent to the commercial antiviral agents like dufulin. On structure optimization-based molecular docking, compound 6k was synthesized and displayed excellent activity with values of 65.1% curative activity, 74.3% protective activity, and 94.3% inactivation activity, which were significantly superior to the commercial antiviral agents dufulin and ningnanmycin. Therefore, this study indicated that new lead compounds could be developed by adopting a joint strategy with active fragments and molecular docking.

A convenient synthesis, biological activity and X-ray crystallography of novel α-aminophosphonate derivatives

A new series of novel α-aminophosphonate derivatives have been synthesized by new rapid and convenient approach, based on the stepwise one pot reaction of 2-hydroxyaniline, aromatic aldehydes and triethyl phosphite. The structures of all compounds have been identified by appropriate spectroscopic methods such as FTIR, 1H, 13C, 31P NMR and ESI-MS. The crystal structure of diethyl-(2-fluorophenyl)-(2-hydroxy-4-methylphenyl)amino phosphonate has been determined, it crystallizes in the P-1 space group. In vitro antifungal activity of the synthesized compounds were tested against wheat fusarium (Fusarium oxysporum) and compared with standard antifungal drug Chlorpyriphos EC to explore their potential antifungal activity. We also measured the antioxidant activity of these molecules, compared with vitamin C as standard antioxidant.

Synthesis of α-Aminophosphonates Derivatives by Using Novel Nano-Catalyst through Kabachnik-Fields Reaction

The novel Nano-catalyst (PAni-Mn) as the first multifunctional catalyst is described for efficient synthesis of α-Aminophosphonates by Kabachnik-Field reaction. This reaction is a Multicomponent reactions in which three- components i e. substituted aldehyde, aniline and dialkylphosphite are combining to form α-Aminophosphonates. The four α-Aminophosphonates were synthesized in good to high yield under solvent free condition at room temperature. The novel Nano-catalyst i.e. Doped Polyaniline with Manganese (PAni-Mn) has been synthesized first and characterized by elemental analysis FT-IR, SEM, TEM, X-ray diffraction technique. This catalyst provides high surface area, increase catalytic activity, easily separated and recycled. It increases the yield of α-Aminophosphonates. α-Aminophosphonates are bioisosteres of amino acids analogous, which has important application in Industrial, Agricultural and Medicinal field, due to their biological and physical properties, They are also use full as synthetic intermediates..

Design, synthesis and biological evaluation of furan based α-aminophosphonate derivatives as anti-Alzheimer agent

Design, synthesis and biological evaluation of furan based α-aminophosphonate derivatives as anti-Alzheimer agent

Ultrasound-Promoted Kabachnik–Fields Synthesis of Novel Chromonyl α-Aminophosphonate Derivatives Incorporating Nitrogen Heterocycles Using CdI2 Nanoparticles as an Efficient Catalyst: Evaluation of Their Antifungal Properties

Ultrasound-Promoted Kabachnik–Fields Synthesis of Novel Chromonyl α-Aminophosphonate Derivatives Incorporating Nitrogen Heterocycles Using CdI2 Nanoparticles as an Efficient Catalyst: Evaluation of Their Antifungal Properties