Synthesis,molecular docking studies,and antimicrobial evaluation of new structurally diverse ureas

A series of new urea derivatives (3a-p) have been synthesized from readily available isocyanates and amines in good to high yields. All synthesized compounds were fully characterized using ¹H NMR, ¹³C NMR, IR, and mass spectrometry. Additionally, the structure of the compound (3n) was confirmed by single-crystal X-ray diffraction. Furthermore, all compounds were evaluated for antimicrobial activity against five bacteria and two fungi. Last but not the least, molecular docking studies with Candida albicans dihydropteroate synthetase were performed and the results are presented herein.     

Chloro-fac-tricarbonylrhenium(I) complexes of asymmetric azines derived from 6-acetyl-1,3,7-trimethylpteridine-2,4(1H,3H)-dione with hydrazine and aromatic aldehydes: Preparation, structural characterization and biological activity against several human tumor cell lines

A number of new asymmetric azines derived from hydrazine and 6-acetyl-1,3,7-trimethyllumazine (lumazine = pteridine-2,4(1H,3H)-dione) and its derivatives with several aromatic aldehydes have been prepared and characterized by usual procedures (XRD, IR, ¹H and ¹³C NMR). These were reacted with [ReCl(CO)₅] to give the corresponding mononuclear chloro-fac-tricarbonylrhenium(I) [ReCl(CO)₃L] compounds. The complexes were characterized by elemental analysis, thermogravimetry (TG) and differential scanning calorimetry (DSC), IR, ¹H and ¹³C NMR. Furthermore, single-crystal X-ray diffraction studies have also allowed to report two different coordination modes of the ligands, which are strongly influenced by the basicity of the heteroatoms on the aromatic aldehyde; thus, the hydrazones derived from hydrazine and hydroxyaldehydes are linked to Re(I) through N5 atom from the pyrazine ring and the N61 one from the hydrazino group, whereas with the ligand derived from pyridin-2-carbaldehyde, the N62 atom of the hydrazino group and the N1 from the pyridine moiety are preferred ligand-to-metal binding sites. The study of the effects of the compounds on the growth of four human tumor cell lines (neuroblastoma NB69, glioma U373, and breast cancer MCF-7 and EVSA-T) suggests a modulator behaviour, according to the concentration, of cell growth due to their estrogen-like characteristics.     

Synthesis,structure analysis,antitumor evaluation and 3D-QSAR studies of 3,6-disubstituted-dihydro-1,2,4,5-tetrazine derivatives

3,6-Diaryl-dihydro-1,2,4,5-tetrazine derivatives were synthesized and their structures were confirmed by single-crystal X-ray diffraction. Monosubstituted dihydrotetrazines are the 1,4-dihydro structure, but disubstituted dihydrotetrazines are the 1,2-dihydro structure. The results of further research indicated there may be a rearrangement during the synthesis process of disubstituted dihydrotetrazines. Their antitumor activities were evaluated against A-549 and P388 cells in vitro. The results showed several compounds to be endowed with cytotoxicity in the low micromolar range. Two compounds were highly effective against A-549 cell and IC₅₀ values were 0.575 and 2.08 μM, respectively. Three-dimensional quantitative structure–activity relationship (3D-QSAR) studies of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 37 1,2,4,5-tetrazine derivatives with antitumor activity against A-549 cell. Models with good predictive abilities were generated with the cross validated q² values for CoMFA and CoMSIA being 0.744 and 0.757, respectively. Conventional r² values were 0.978 and 0.988, respectively, the predicted R² values were 0.916 and 0.898, respectively. The results provide the tool for guiding the design and synthesis of novel and more potent tetrazine derivatives.     

Selective carboxypropionylation of chitosan: synthesis, characterization, blood compatibility, and degradation

Two water-soluble chitosan (WSC) derivatives of N-succinyl-chitosan (NSCS) and N,O-succinyl-chitosan (NOSCS) with a degree of substitution (DS) that ranged form 0.28 to 0.61 were selectively synthesized by varying the molar ration of succinic anhydride and chitosan. The chemical structure and physical properties of the chitosan derivatives were characterized by FT-IR, ¹H NMR, and XRD. XRD analysis showed that the derivatives were amorphous. The lysozyme enzymatic degradation results revealed that the NSCS was of higher susceptibility to lysozyme. The degradation rate and the solubility of the chitosan derivatives were strongly determined by the degree of substitution and the position of the substitution. The results of antithrombotic properties, hemolytic properties and anticoagulant properties of WSCs indicated that the blood compatibility was dramatically improved, and the carboxyl group introduced on the C-6 or C-2 hydroxyl group appeared to impact anticoagulant activity in different ways.     

Synthesis,characterization, antifungal evaluation and 3D-QSAR study of phenylhydrazine substituted tetronic acid derivatives

A series of 3-(1-(2-(substituted phenyl)hydrazinyl)alkylidene)furan-2,4(3H,5H)-diones were designed and prepared using two synthetic routes. Their structures were confirmed by FT-IR, ¹H NMR, ¹³C NMR, MS, elemental analysis and single-crystal X-ray diffraction. Their bioactivity was evaluated against Botrytis cinerea in vitro. Most target compounds exhibited remarkable antifungal activity. Two compounds 7f and 7h were highly effective and their EC₅₀ values were 0.241 μg/mL and 0.167 μg/mL, respectively, close to that of the control drug procymidone. 3D-QSAR studies of CoMFA and CoMSIA were carried out. Models with good predictive ability were generated with the cross validated q² values for CoMFA and CoMSIA being 0.565 and 0.823. Conventional r² values were 0.983 and 0.945, respectively. The results provided a practical tool for guiding the design and synthesis of novel and more potent tetronic acid derivatives containing substituted phenylhydrazine moiety.     

A novel templates of piperazinyl-1,2-dihydroquinoline-3-carboxylates: Synthesis,anti-microbial evaluation and molecular docking studies

A series of piperazinyl-1,2-dihydroquinoline carboxylates were synthesized by the reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylates with various piperazines and their structures were confirmed by ¹H NMR, ¹³C NMR, IR and mass spectral analysis. All the synthesized compounds were screened for their in vitro antimicrobial activities. Further, the in silico molecular docking studies of the active compounds was performed to explore the binding interactions between piperazinyl-1,2-dihydroquinoline carboxylate derivatives and the active site of the Staphylococcus aureus (CrtM) dehydrosqualene synthase (PDB ID: 2ZCQ). The docking studies revealed that the synthesized derivatives showed high binding energies and strong H-bond interactions with the dehydrosqualene synthase validating the observed antimicrobial activity data. Based on antimicrobial activity and docking studies, the compounds 9b and 10c were identified as promising antimicrobial lead molecules. This study might provide insights to identify new drug candidates that target the S. aureus virulence factor, dehydrosqualene synthase.     

Understanding the structure-activity relationship of betulinic acid derivatives as anti-HIV-1 agents by using 3D-QSAR and docking

Novel anti-HIV-1 agents derived from betulinic acid have been greatly concerned. 3D-QSAR and molecular docking studies were applied to rationalize the structural requirements responsible for the anti-HIV activity of these compounds. The CoMFA and CoMSIA models resulted from 28 molecules gave r _cv² values of 0.599 and 0.630, r ² values of 0.994 and 0.958, respectively. To estimate the predictive ability of the 3D-QSAR model, an external validation was employed. Based on the contour maps generated from both CoMFA and CoMSIA, we have identified some key features in the betulinic acid derivatives that are responsible for the anti-HIV activity. Molecular docking was used to explore the binding mode between these derivatives and HIV gp120. We have therefore designed a series of novel betulinic acid derivatives by utilizing the SAR results revealed in the present study, which were predicted with excellent potencies in the developed models. The results provide a valuable method to design new betulinic acid derivatives as anti-HIV-1 agents.     

Novel heterometallic palladium-silver complex

The reaction between Pd₃(OOCMe)₆ and Ag₂(OOCMe)₂ afforded the first palladium-silver heterometallic acetate-bridged complex Pd^II[(μ-OOCMe)₂Ag^I(HOOCMe)₂]₂ (1). The molecular geometry and electronic structure of 1 were studied by single-crystal XRD and quantum-chemical DFT calculations. Thermal transformations of 1in vacuo and under Ar, H₂ produced PdAg alloy nanoparticles characterized with powder XRD and EXAFS.     

Synthesis and biological activities of novel pyrazolomatrine derivatives

In continuation of our program aimed at the development of new natural product-based pesticides, a series of novel pyrazolomatrine derivatives were prepared by structural modifications of matrine, isolated as a quinolizidine alkaloid from the roots of Sophora flave. Their structures were confirmed by ¹H NMR, HRMS, etc. Moreover, the steric structures of three compounds were determined by single-crystal X-ray diffraction. Among all derivatives, 19-(naphthyl-2-oyl)pyrazolomatrine (5y) showed 3.13-fold more potent acaricidal activity than its precusor matrine against Tetranychus cinnabarinus; 19-(4-methylbenzoyl)pyrazolomatrine (5j) and 19-(3,5-dimethylbenzoyl)pyrazolomatrine (5k) displayed the promising aphicidal activity against Aphis citricola van der. Their structure-activity relationships were also observed.     

Selective small molecule inhibitors of the potential breast cancer marker,human arylamine N-acetyltransferase 1, and its murine homologue,mouse arylamine N-acetyltransferase 2

The identification, synthesis and evaluation of a series of rhodanine and thiazolidin-2,4-dione derivatives as selective inhibitors of human arylamine N-acetyltransferase 1 and mouse arylamine N-acetyltransferase 2 is described. The most potent inhibitors identified have submicromolar activity and inhibit both the recombinant proteins and human NAT1 in ZR-75 cell lysates in a competitive manner. ¹H NMR studies on purified mouse Nat2 demonstrate that the inhibitors bind within the putative active site of the enzyme.     

Metabolism of 4-hydroxybenzaldehyde, 3-bromo-4-hydroxybenzaldehyde and bromide by cell-free fractions of the marine red alga Odonthalia floccosa

Cell-free fractions from Odonthalia floccosa incubated with 4-hydroxybenzaldehyde-[U-¹⁴C], 3-bromo-4-hydroxybenzaldehyde-[U-¹⁴C] and ⁸²Br^? formed the dibromo-dihydroxybenzaldehyde derivatives of the bromophenols (brominated benzylalcohols) which were also identified as naturally occurring products.     

Synthesize and characterization of organic-soluble acylated chitosan

Acylated chitosan was synthesized by reaction of chitosan and stearoyl chloride. The chemical structures and physical properties of the prepared compounds were confirmed by Fourier transform infrared (FT-IR), ¹H Nuclear Magnetic Resonance (¹H NMR) spectroscopy, X-ray diffraction (XRD) and Thermogravimetric (TG) techniques. The degree of substitution (DS) was calculated by ¹H NMR and ranged from 1.8 to 3.8. The synthesized compounds exhibited an excellent solubility in organic solvents. XRD analysis showed that they had high crystalline structure. TG results demonstrated that thermal stability of the prepared compounds was lower than that of chitosan, the weight loss decreased with increase of DS. This procedure could be a facile method to prepare organic-soluble chitosan derivatives.     

Dibrefeldins A and B,A pair of epimers representing the first brefeldin A dimers with cytotoxic activities from Penicillium janthinellum

Dibrefeldins A and B (1 and 2), two unexpected brefeldin A (BFA) dimers, as well as brefeldin F (3), brefeldin G (4), and 14-hydroxy-BFA (5), three new BFA derivatives, together with three new naturally occurring BFA derivatives (6–8) and four known analogues (9–12), were isolated from the fungus Penicillium janthinellum. Dibrefeldins A and B (1 and 2) represent the first examples of BFA dimers formed by an esterification between two BFA monomer units. Brefeldin F (3) has an α,β-unsaturated γ-lactone ring, and this moiety was first discovered in naturally occurring BFA derivatives. The structures and relative/absolute configurations of these derivatives were elucidated by extensive spectroscopic methods, ¹³C NMR calculations, and single-crystal X-ray diffraction. Compounds 1, 2, 8, and 9 showed excellent cytotoxic activities against six cancer cell lines with IC₅₀ values ranging from 0.01 to 4.45 μM.     

Synthesis,characterization, in vitro cytotoxicity and antimicrobial investigation and evaluation of physicochemical properties of novel 4-(2-methylacetamide)benzenesulfonamide derivatives

In this study, several sulfonamide derivatives, 4-(2-methylacetylamino)benzenesulfonamides were synthesized. Chemical structures of the derivatives were characterized by ¹H NMR, ¹³C NMR, LC–MS–MS, UV–Vis, FTIR, photoluminescence and elemental analysis. Sulfanilamide was reacted with 2-bromopropionyl bromide, in the presence of pyridine, to form bromo-substituted sulfonamide key intermediates, which were subsequently treated with secondary amines to obtain novel sulfonamide derivatives. All the synthesized compounds were evaluated for in vitro antimicrobial activities and cytotoxicity. Increases in ring size, and rings bearing a nitrogen heteroatom led to improvements in antimicrobial activities. As the presence of CA IX and CA XII enzymes have been implicated in some cancerous tumors, the studies presented herein focuses on targeting these enzymes. It was found that the synthesized derivatives had in vitro anti-cancer properties, where compounds (3–6) were found to be active against all cancerous cells, and no cytotoxic effects on normal cells were observed.     

Incorporation of 14CO2, 14C-phenylalanine and 14C-cinnamate into soluble and insoluble cinnamic derivatives in Mentha arvensis

With the successful development of methods for the isolation and purification of ethanol-insoluble cinnamic acid esters in mint it became possible to initiate kinetic, isotopic studies on purified, ‘insoluble’ derivatives of caffeic acid, ferulic acid and p-coumaric acid. Pulse-feeding experiments were conducted with ¹⁴CO₂, phenylalanine-U-¹⁴C and cinnamic acid-3-¹⁴C. The ferulic acid derivative exhibited a significant turnover as compared to the other insoluble derivatives which were relatively stable. Time-course tracer studies were performed to compare the turnover of soluble caffeic acid derivatives with ‘insoluble’ forms of caffeic acid. Caffeic acid associated with a macromolecular fraction consistently showed a higher specific activity than either soluble caffeic acid or the caffeic acid associated with a second insoluble derivative.     

Synthesis,Anti-Oomycete and Anti-fungal Activities of Novel Cinchona Alkaloid Derivatives Containing Sulfonate Moiety

Using cinchona alkaloid as the lead compound, twenty-four cinchona alkaloid sulfonate derivatives ( 1 a – l , 2 a – c , 3 a – c , 4 a – c , and 5 a – c ) were designed and prepared by modifying their C9 position, and structurally confirmed by ¹H-NMR, ¹³C-NMR, HR-MS and melting points. Moreover, the stereochemical configurations of compounds 1 f and 1 l were unambiguously confirmed by single-crystal X-ray diffraction. Furthermore, we determined the anti-oomycete and anti-fungal activities of these target compounds against Phytophthora capsici and Fusarium graminearum in vitro. The results showed that two compounds 4 b and 4 c exhibited prominent anti-oomycete activity, and the median effective concentration (EC₅₀) values of 4 b and 4 c against P. capsici were 22.55 and 16.32 mg/L, respectively. This study suggested that when the C9 position of cinchona alkaloid sulfonate derivatives is in the S configuration and the 6′-position methoxy group is not present, the anti-oomycete activity is superior. In addition, five compounds 1 e , 1 f , 1 k , 3 c and 4 c displayed significant anti-fungal activity, with EC₅₀ values of 43.64, 45.07, 80.18, 48.58 and 41.88 mg/L against F. graminearum, respectively. This result indicates that only when a specific substituent is introduced into the structural framework of the target compound, the corresponding compound exhibits significant inhibitory activity against fungi.     

Ce−ZSM-5: A Highly Capable Catalyst for the Construction of Acridines in Water and Their Computational Study against DNA Gyrase Protein

Cerium doped ZSM-5 (Ce−ZSM-5) as an environmentally benign and reusable catalyst for the construction of acridines in aqueous medium. This method produced corresponding acridines with good yields and shorter reaction times. Also avoids the use of hazardous solvents and involves a simple work-up process. The solid catalyst was prepared by doping Ce ions with ZSM-5 (Zeolite Socony Mobil-5) and confirmed by XRD, BET SA-PSD and SEM. The synthesised acridine derivatives were confirmed by ¹H-NMR, ¹³C-NMR and FT-IR spectroscopic data. The docking studies of the synthesised compounds are performed by the PyRx auto dock tool against DNA gyrase protein. The products 5a and 6d are found to be the best fit ligands against DNA gyrase protein.     

Synthesis, spectral and electrochemical properties of cyclotriphosphazene appended with six metalloporphyrins

The metal derivatives (Co^II, Ni^II, Cu^II, Zn^II and Sn^IV) of hexaporphyrinato cyclotriphosphazene systems were prepared by treating the hexaporphyrin assembly on cyclotriphosphazene ring with the appropriate metal salt under standard metallation conditions. The complete metallation of all six porphyrin units in hexaporphyrin assembly required 10-12 h reflux as judged by the absorption spectroscopy. The metal derivatives were confirmed by molecular ion peak in mass spectra for all compounds. ³¹P and ¹H NMR spectra for Ni(II), Zn(II) and Sn(IV) derivatives and ESR spectra for Cu(II) derivative also confirmed the complete metallation of all six porphyrin units. The hexametalloporphyrin assemblies are freely soluble in common organic solvents. The spectral, electrochemical and fluorescence studies indicate that the six porphyrin units in assemblies interact very weakly and retain their individual characteristic features in the ground and excited states.     

Studies on the properties of 1,N 6 -ethenoadenine derivatives of various coenzymes

Several fluorescent 1,N⁶-ethenoadenine derivatives were synthesized, including ?-AMP's, ?-DPN⁺, and ?-FAD, and some of their physicochemical and biological properties were studied in some detail. In contrast to the high fluorescence quantum yields of the mononucleotide derivatives, the dinucleotide derivatives exhibit extremely low quantum yields. NMR data indicate that the intramolecular folding of the ?-dinucleotides is not much different from that of the natural coenzymes in solution, and thus cannot account for the low quantum yields of the ?-compounds. It is postulated that the discrepancy is caused by dynamic quenching effects.The interaction of the ?-dinucleotides with various dehydrogenases causes a much larger quenching of the tryptophan fluorescence than is observed with the natural coenzymes, indicating that the quenching of the protein fluorescence may not be due solely to the nicotinamide moiety but involves the adenine portion of the coenzyme as well.?-DPN⁺ and ?-cAMP were shown to be biologically active in a variety of enzymatic systems, and may be useful in kinetic as well as in structural studies of various enzyme systems.     

Regioselective facile one-pot Friedländer synthesis of sugar-based heterocyclic biomolecules

Regioselective facile one-pot synthesis of 16 different sugar-based quinoline, naphthyridine, and xanthone derivatives is reported. The compounds are characterized by NMR spectroscopy and elemental analysis. The β-Anomeric form of the sugar moiety was identified from ¹H NMR studies. Antimicrobial studies of these sugar-heterocyclic derivatives, 3a, 3b, 3f, 5c, 7a, 7b, and 7c show excellent activity against different microbes.