Synthesis and biological evaluation of novel dialkyl (4-amino-5H-chromeno[2,3-d]pyrimidin-5-yl)phosphonates.

This study reports the design and synthesis of novel dialkyl (4-amino-5H-chromeno[2,3-d]pyrimidin-5-yl)phosphonates as potential antitumor agents against A549 (lung cancer), DU-145 (prostate cancer), PC-3 (prostate cancer), HeLa (cervical cancer) and MCF-7 (breast cancer), cell lines evidenced from the in vitro antitumor studies performed by MTT assay (across 10-30 µM concentrations). The structural eminence of these synthesized molecules has emanated by designing the structural core by uniting the chromene, pyrimidine and phosphonate moieties into one, which has augmented their novelty and made them unreported. Further the deep structural activity relationship study investigations articulated that the title compounds are promising drug-like compounds and potential inhibitor of histidine amino acid residue present on the respective enzymatic proteins [3QJZ (A549), 3VHE (DU-145), 3V49 (PC-3), 3F81 (HeLa), & 3R7Q (MCF-7)] of the cell lines screened and are identified as responsible for the multi-faceted antitumor activities predicted in vitro. The obtained results were further supported by molecular docking studies, QSAR, ADMET, and bioactivity studies which have supported them as potential BBB penetrable molecules and proficient CNS active neuro-protective agents during drug delivery.

Green Biosynthesis, Antioxidant, Antibacterial, and Anticancer Activities of Silver Nanoparticles of Luffa acutangula Leaf Extract.

Studies on green biosynthesis of newly engineered nanoparticles for their prominent medicinal applications are being the torch-bearing concerns of the state-of-the-art research strategies. In this concern, we have engineered the biosynthesized Luffa acutangula silver nanoparticles of flavonoid O-glycosides in the anisotropic form isolated from aqueous leave extracts of Luffa acutangula, a popular traditional and ayurvedic plant in south-east Asian countries. These were structurally confirmed by Ultraviolet-visible (UV-Vis), Fourier transform infrared spectroscopy accessed with attenuated total reflection (FTIR-ATR) spectral analyses followed by the scanning electron microscopic (SEM) and the X-ray diffraction (XRD) crystallographic studies and found them with the face-centered cubic (fcc) structure. Medicinally, we have explored their significant antioxidant (DPPH and ABTS assays), antibacterial (disc diffusion assay on E. coli, S. aureus, B. subtilis, S. fecilis, and S. boydii), and anticancer (MTT assay on MCF-7, MDA-MB-231, U87, and DBTRG cell lines) potentialities which augmented the present investigation. The molecular docking analysis of title compounds against 3NM8 (DPPH) and 1DNU (ABTS) proteins for antioxidant activity; 5FGK (Gram-Positive Bacteria) and 1AB4 (Gram-Negative Bacteria) proteins for antibacterial activity; and 4GBD (MCF-7), 5FI2 (MDA-MB-231), 1D5R (U87), and 5TIJ (DBTRG) proteins for anticancer activity has affirmed the promising ligand-protein binding interactions among the hydroxy groups of the title compounds and aspartic acid of the concerned enzymatic proteins. The binding energy varying from -9.1645 to -7.7955 for Cosmosioside (1, Apigenin-7-glucoside) and from -9.2690 to -7.8306 for Cynaroside (2, Luteolin-7-glucoside) implies the isolated compounds as potential bioactive compounds. In addition, the performed studies like QSAR, ADMET, bioactivity properties, drug scores, and toxicity risks confirmed them as potential drug candidates and aspartic acid receptor antagonists. This research auxiliary augmented the existing array of phytological nanomedicines with new drug candidates that are credible with multiple bioactivities.

Excellency of pyrimidinyl moieties containing α-aminophosphonates over benzthiazolyl moieties for thermal and structural stability of stem bromelain.

An efficient approach has been made for the synthesis of a series of novel di α-aminophosphonates by the reaction of terephthalaldehyde with various pyrimidine/benzthiazole amines and diethyl phosphite using sulfonated graphitic carbon nitride - SA@g-C3N4 as catalyst under room temperature and solvent free conditions. Later, the different effects of these newly synthesized α-aminophosphonates as a function of concentration gradient has been scrutinized on the thermal and structural stability of stem bromelain (SBM) through combining the results of various spectroscopic techniques like UV-vis, steady state fluorescence and circular dichroism (CD). Lastly the competitive and distinctive behaviour of α-aminophosphonates towards the stability of SBM has been envisaged using molecular docking simulations which suggest that nature of α-aminophosphonates plays a crucial role for their interactions with SBM. Molecular docking results clearly show that α-aminophosphonates with pyrimidine ring are having more number of hydrogen bonding interaction with amino acid residues of SBM than α-aminophosphonates with benzthiazolyl ring. Sequentially for thermal and structure stability of SBM, concentration of α-aminophosphonates plays an inexorable role and through these results it must be concluded that most of the α-aminophosphonates are stabilizing the SBM upto the 0. 1 mM concentration.

Prospects to the formation and control of potential dimer impurity E of pantoprazole sodium sesquihydrate.

Pantoprazole sodium, a substituted benzimidazole derivative, is an irreversible proton pump inhibitor which is primarily used for the treatment of duodenal ulcers, gastric ulcers, and gastroesophageal reflux disease (GERD). The monographs of European Pharmacopoeia (Ph. Eur.) and United States Pharmacopoeia (USP) specify six impurities, viz.; impurities A, B, C, D, E and F, respectively for its active pharmaceutical ingredient (API). The identification and synthesis of all impurities except impurity E are well described in the literature; however, there is no report related to impurity E. The prospects to the formation and controlling of impurity E up to ≤0.03% in the synthesis of pantoprazole sodium sesquihydrate (PAN) were discussed in detail for the first time. The present work described the journey towards the successful development of an optimal preparation procedure of dimer impurity E. The most plausible mechanism involved in the formation of impurity E has been proposed.

Environmentally Benign and Facile Process for the Synthesis of Pantoprazole Sodium Sesquihydrate: Phase Transformation of Pantoprazole Sodium Heterosolvate to Pantoprazole Sodium Sesquihydrate.

A cost-effective, scalable, and environmentally benign process is herein reported for the synthesis of pantoprazole sodium sesquihydrate: 5-(difluromethoxy)-2-[{(3,4-dimethoxy-2-pyridinyl)methyl}sulfinyl]-1H-benzimidazole sodium sesquihydrate. At least two of the three main synthetic steps (coupling and oxidation) have been carried out for the first time in water, with no need to isolate and purify the intermediates, affording the corresponding pantoprazole sodium in good yield and purity. Minimum organic solvents, in terms of both the number of solvents and the volume of solvent used, are employed to make this process both economical and environment friendly. Furthermore, in situ transformation of pantoprazole sodium heterosolvate, due to the association between molecules of water and solvent used, to pantoprazole sodium sesquihydrate is described.

TiO2-SO4(2-) Catalyzed Synthesis and Antimicrobial Activity / Molecular Docking Studies of ß-Indolylnitroalkanes.

Michael addition of indole derivatives with various substituted nitrostyrenes to yield ß- indolylnitroalkanes is accomplished effectively under solvent free conditions using TiO2-SO4(2-) as efficient catalyst at 60 º C. All the synthesized compounds were screened for their antibacterial activity through in silico and in vitro methods. The molecular docking studies against FabH enzyme, a potential drug target of bacterial fatty acid biosynthetic pathway indicated the scope of developing them a new class of antimicrobial agents. Among the title compounds, 5h exhibited the highest dock score and the highest antibacterial activity when compared with other compounds and the standard drug Ampicillin. In addition, the compounds 5d, 5e, 5g, 5h, 5i, 5j and 5l showed significant inhibitory activity at different dose concentrations under in vitro conditions against the specified bacterial strains thus qualifying for further clinical evaluation so that they can be used as effective anti-bacterial agents.

Palladium-catalyzed regioselective domino cyclization of cyclohexadienones.

A mild and efficient Pd-catalyzed arylative domino carbocyclization of cyclohexadienone-containing 1,6-enynes is described. The reaction tolerates a variety of functionalized boronic acids to afford a cis-fused bicyclic framework containing an α,ß-unsaturated ketone with excellent regio- and diastereoselectivity in good yields. The tandem process proceeds with ß-arylation of propargylic ether followed by conjugate addition of a vinyl palladium intermediate and subsequent protonolysis of a palladium enolate.

Diastereoselective synthesis of (+)-pseudohygroline via proline-catalyzed alpha-hydroxylation.

A highly diastereoselective total synthesis of (+)-pseudohygroline (1) starting from D-proline is described using Wittig olefination and MacMillan-alpha-hydroxylation as key reactions. (+)-Pseudohygroline is an important molecule in alkaloid chemistry as it was prepared as part of the first chemical proof of the absolute stereochemistry of biosynthetically important (+)-hygroline (2) and (+)-hygrine (3).

Binding and molecular dynamics studies of 7-hydroxycoumarin derivatives with human serum albumin and its pharmacological importance.

Human serum albumin (HSA) is one of the most widely studied proteins and is an important plasma protein responsible for binding and transport of many exogenous and endogenous drugs. Coumarin derivatives play a critical role as anticancer, antidiabetic, anticoagulant, and analgesic agents. Here we have studied the cytotoxic activity of 7-hydroxycoumarin derivatives (7HC-1, 7HC-2, and 7HC-3) on mouse macrophage (RAW 264.7) cell lines. These studies revealed that 7-hydroxycoumarin derivatives caused an increased inhibition in growth of inflamed macrophages in a concentration-dependent manner with an IC50 of 78, 63, and 50 µM. Further studies, using fluorescence, circular dichroism spectroscopy, molecular docking, and molecular dynamics methods, show binding of 7HC (umbelliferone) derivatives with HSA at physiological pH 7.2. The binding constant of 7HC derivatives with HSA obtained from fluorescence emission was found to be K7HC-1 = 4.6 ± 0.01 × 10(4) M(-1), K7HC-2 = 1.3 ± 0.01 × 10(4) M(-1), and K7HC-3 = 7.9 ± 0.01 × 10(4) M(-1) which corresponds to -6.34 kcal/mol, -5.58 kcal/mol, and -6.65 kcal/mol of free energy. In contrast, the binding of these coumarin derivatives (7HC-1, 7HC-2, and 7HC-3) was almost negligible with α-1-glycoprotein (AGP). Circular dichroism (CD) studies revealed a decreased α-helix content with an increase in the ß-sheets and random coils in HSA upon interaction with coumarin derivatives, suggesting a partial unfolding of the HSA secondary structure. Site probe studies with phenylbutazone (Site I) and ibuprofen (Site II) indicated that 7HC derivatives specifically bind to sub domains IIIA and IIIB of HSA which is further corroborated by molecular dynamics and docking studies suggesting that binding is specific in nature. The values of free energies and binding constants coincide for both experimental and in silico analysis and suggest that there are hydrophobic interactions when coumarin derivatives bind to HSA. Molecular dynamics studies showed that the HSA-coumarin complex reaches an equilibration state at around 3.5 ns which indicates that the HSA-coumarin complexes were stable. Thus these interactions play a central role in development of coumarin derivative-inspired drugs.

Biogenic silver nanoparticles using Rhinacanthus nasutus leaf extract: synthesis, spectral analysis, and antimicrobial studies.

Nanotechnology is gaining momentum due to its ability to transform metals into nanoparticles. The synthesis, characterization, and applications of biologically synthesized nanomaterials have become an important branch of nanotechnology. Plant extracts are a cost-effective, ecologically friendly, and efficient alternative for the large-scale synthesis of nanoparticles. In this study, silver nanoparticles (AgNps) were synthesized using Rhinacanthus nasutus leaf extract. After exposing the silver ions to the leaf extract, the rapid reduction of silver ions led to the formation of AgNps in solution. The synthesis was confirmed by ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, and transmission electron microscopy. The in vitro antimicrobial activity of the AgNps synthesized using R. nasutus leaf extract was investigated against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli, Aspergillus niger, and Aspergillus flavus using a disc diffusion method. The AgNps showed potential activity against all of the bacterial strains and fungal colonies, indicating that R. nasutus has the potential to be used in the development of value-added products in the biomedical and nanotechnology-based industries.

Design, synthesis, antioxidant, and anti-breast cancer activities of novel diethyl(alkyl/aryl/heteroarylamino)(4-(pyridin-2-yl)phenyl)methylphosphonates.

A series of new diethyl(alkyl/aryl/heteroarylamino)(4-(pyridine-2-yl)phenyl)methylphosphonates (4a-t) were synthesized via three-component Kabachnik-Field's reaction of 4-(pyridin-2-yl)benzaldehyde, diethylphosphite and various primary amines, catalyzed by cupric acetate monohydrate [Cu(OAc)(2) ∙ H(2)O] under solvent-free and microwave irradiation conditions. Their computational docking analysis supported them as good therapeutic agents to the breast cancer aromatase enzyme and ascertained 4a, 4h, 4m, 4n, and 4t as potential molecules with good binding affinities varying from -9.0 to -9.6 kcal/mol and containing the 4-(pyridine-2-yl)phenyl moiety as a pharmacophore. Their in vitro screening performed for the anti-cell proliferation activity against MBC-MCF7 cells by MTT and Trypan blue assays confirmed 4m, 4n, and 4q as promising compounds to sustain a low percentage of cell viability at 20 µg/mL concentration. These compounds were also evaluated for their antioxidant activity by the DPPH method and the results established that compounds 4m, 4n, and 4q show around 10% higher activity than the standard antioxidant ascorbic acid.

Green synthesis and bioactivity of 2-amino-4H-chromen-4-yl-phosphonates.

A simple and efficient one pot synthesis of 2-amino-4H-chromen-4-yl phosphonate derivatives has been accomplished by the condensation of salicylaldehyde, malononitrile/ethylcyanoacetate and triethyl phosphite/trimethyl phosphite in the presence of molecular iodine as catalyst in water at room temperature. All the reactions were very clean and the products were obtained in very good to excellent yields. The title compounds are characterized by IR, 1H-, 13C-, 31P-NMR and mass spectra, also studied their antimicrobial and antioxidant activity.

Total synthesis of (+)-anamarine.

Total synthesis of (+)-anamarine a polyoxygenated δ-pyranone natural product was accomplished via cross-metathesis protocol starting from 3-butene-1-ol and glycidol. Other key features of this synthetic strategy include use of Sharpless asymmetric epoxidation, dihydroxylation, and deoxygenation-isomerization through allene rearrangement.

One-step synthesis and bioassay of N-phosphoramidophosphonates.

A simple one-step synthesis was accomplished for the preparation of N-phosphoramidophosphonates by a direct reaction of phosphoramidate (1) with heterocyclic aldehydes (2a-j) and dialkyl phosphites at 60-70 degrees C in the presence of tetramethylguanidine. The tetramethylguanidine not only catalyses this reaction but also helps to form pure products in high yields in lesser time. They exhibited good insecticidal and antioxidant properties.

Synthesis, anti-bacterial and anti-oxidant properties of thiadiazaphosphol-2-ones.

4-Amino-5-phenyl-4H-1,2,4-triazole-3-thiol (1) underwent facile condensation with various phosphorus dichlorides (2a-j) in the presence of triethylamine in dry tetrahydrofuran at 60-65 degrees C and afforded corresponding thiadiazaphosphol-2-ones (3a-j). Their chemical structures were characterized using IR, (1)H-, (13)C-, (31)P-NMR and Mass spectral studies. All the title compounds were screened for antioxidant properties by radical scavenging methods such as 1,1-diphenyl-2-picryl hydrazyl (DPPH), hydroxyl and lipid peroxidation. They exhibited potent in vitro antioxidant activity dose dependently. Their bioassay showed them to possess significant antibacterial activity.