Substituted Phenacyl Bromides Research Articles

Efficient One‐Pot Multicomponent Approach to 3‐Phenylpyrrolo[1,2‐a]Pyrazine and Novel 3‐Phenylpyrazino[1,2‐a]Indole in Aqueous Medium

AbstractA facile and atom‐efficient route via a new aqueous synthetic protocol for the greener and more efficient preparation of 3‐phenylpyrrolo[1,2‐a]pyrazine and 3‐phenylpyrazino[1,2‐a]indole by the one‐pot, three‐component method under mild reaction conditions is developed with substituted phenacyl bromides, aqueous ammonium hydroxide, and the corresponding 1H‐pyrrole‐2‐carbaldehyde and 1H‐indole‐2‐carbaldehyde. A reaction cascade consisting of N‐alkylation, imine formation, and annulation by condensation produces a sequence of three C−N bonds.

Synthesis, antibacterial, antifungal, antioxidant, cytotoxicity and molecular docking studies of thiazole derivatives

The emergence of numerous pandemics and microbial resistance has necessitated the development of novel heterocyclic compounds with potent biological effects. Five new (E)-2-((5-(1H-benzo[d]imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazineyl)-4-(aryl)thiazole derivatives (9a-e) were synthesized through a one pot multicomponent reaction involving 5-(1H-benzo[d]imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, thiosemicabazide and various substituted phenacyl bromides. FT-IR, 1H NMR, and 13C NMR spectroscopic techniques were used to characterize the newly synthesized benzimidazole-pyrazole clubbed thiazole hybrids. The synthesized compounds were screened for antibacterial activity against E. coli, B. subtilis, B. megaterium, and S. aureus and antifungal activity against A. niger, A. oryzae, Rhizophus spp., and C. albicans. All newly synthesized compounds exhibited potent antibacterial action against all tested strains. Besides, % radical scavenging activity was also evaluated and results showed good antioxidant potential of the synthesized compounds. The cytotoxicity study revealed that synthesized compounds has no to less toxicity as compared to standard Triton X 100. Molecular docking simulations against DNA gyrase (PDB: 4URO) revealed binding interactions and MESP plots confirmed the binding locations.

One-pot construction of novel trifluoromethyl dihydro-imidazo[1, 2-a]pyridine: A greener approach

A one-pot three-component method for the synthesis of 3-substituted 2- trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridin-3-yl analogues from 2-aminopyridine, substituted phenacyl bromides, and trifluoroacetaldehyde methyl hemiacetal (TFAMH) under solvent-free and the catalyst-free condition is described with good to excellent yield. This chemistry features the additive-free approach with the employment of safe, stable, and readily available starting materials with a wide substrate scope strategy.

Design, synthesis and biological evaluation of new series of benzotriazole-pyrazole clubbed thiazole hybrids as bioactive heterocycles: Antibacterial, antifungal, antioxidant, cytotoxicity study

The need for novel heterocyclic compounds with robust biological action is a result of the emergence of numerous pandemics and microbial resistance. To search antibacterial and antifungal lead compounds, a series of novel (E)-2-(2-((5-(1H-benzo[d][1,2,3]triazol-1-yl)-3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazinyl)-4-(aryl)thiazole derivatives were synthesized via three component reaction between 5-(1H-benzo[d][1,2,3]triazol-1-yl)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, thiosemicabazide and various substituted phenacyl bromides. The newly synthesized benzotriazole-pyrazole clubbed thiazole hybrids were characterized by FT-IR, 1H NMR, 13C NMR and HRMS methods. The synthesized compounds were screened for antibacterial activity against E. coli, B. subtilis, B. megaterium, and S. aureus and antifungal activity against A. niger, A. oryzae, Rhizophus spp., and C. albicans. All thiazole derivatives exhibited potent antibacterial and antifungal action against all tested strains. Besides, % radical scavenging activity was also evaluated and results showed good antioxidant potential of the synthesized compounds. The cytotoxicity study revealed that synthesized compounds has no to less toxicity as compared to standard Triton X-100.

A rapid synthesis of quinoxalines by using Al2O3–ZrO2 as heterogeneous catalyst

In this study, we present a highly efficient and environmentally benign protocol for synthesizing biologically important quinoxaline derivatives. The synthesis involves the reaction of 1,2-diamines with substituted phenacyl bromides or benzil, taking place at room temperature in N,N-dimethylformamide (DMF) solvent. The reaction is facilitated by a bifunctional heterogeneous catalyst composed of Al2O3–ZrO2 binary metal oxide. Our method offers numerous advantages, including excellent product yield, renewable catalytic conditions, minimal catalyst usage, safer chemistry, short reaction time, and a simple work-up procedure. To determine the chemical structure of the synthesized derivatives, we employed characterization techniques such as nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). Additionally, the Al2O3–ZrO2 catalyst was characterized using X-ray diffraction (XRD), scanning electron microscopy with energy-dispersive X-ray analysis (SEM-EDAX), and thermogravimetric analysis (TGA).

Polyethylene glycol mediated, novel, one-pot three-component synthesis of benzimidazolyl-thiazoles as potent α-glucosidase inhibitors: Design, synthesis, molecular modelling, ADME studies

Polyethylene glycol promoted, novel, one-pot, three-component synthesis of benzimidazole based thaizole derivatives (4a-s) has been synthesized via a multi-component approach by using 5-amino-2-mercaptobenzimidazole, phenyl isothiocyanates, and substituted phenacyl bromides using PEG-400 as a recyclable and greener solvent in a shorter reaction time without any by-products. All the synthesized compounds (4a-s) were well characterized by analytical and spectroscopic techniques. Furthermore, some of the synthesized compounds were evaluated for their in-vitro α-amylase inhibition activity using Acarbose as a standard positive control. Among the tested scaffolds, compound 4d, 4c, 4 h, 4j and 4b have shown significant inhibitory activity against α-amylase enzyme with IC50 values 12.02 ± 0.56; 12.25± 0.28; 12.74 ± 0.45; 17.83 ± 0.21 and 19.10 ± 0.88 μg/mL respectively. Also we insight in to the molecular docking studies, based on the binding results, compounds 4c and 4d to have shown stable binding patterns to the human pancreatic α–amylase with montbretin A (PDBID: 4W93). The structure-activity relationship (SAR) studies of all the title scaffolds were also established. The α- amylase inhibition, molecular docking studies, molecular dynamic simulations, and drug-likeness properties (Lipinski parameters and in-silico ADME properties) of the title compounds were suggested that these are promising anti-diabetic active skeletons.

Design, synthesis and in vitro antitubercular evaluation of novel 7-methoxy pyrrolo[1,2-a]quinoline analogues as CYP 121 inhibitors

A novel series of pyrrolo[1,2-a]quinoline analogues (4a-n) was designed via a heterocyclic fusion approach for their antitubercular evaluation. The targeted compounds were synthesized by reacting 6-methoxy quinoline with different substituted phenacyl bromides, to get quinolinium ylide intermediates (2a-i), which have further undergone [3+2] cycloaddition with electron-deficient acetylenes to furnish novel 7-methoxy pyrrolo[1,2-a]quinoline derivatives (4a-n). All these newly synthesized intermediate products and final compounds have been characterized by spectroscopic techniques such as 1H NMR, 13C NMR, HRMS, and FT-IR. The intermediate ylides and final pyrrolo[1,2-a]quinoline analogues were evaluated for their antitubercular potential against the Mtb H37Rv strain (ATCC 27294). All the tested compounds exhibited antitubercular activity with the MIC99 in the range of 25–50 µM (10.4–25.7 µg/mL), compared to the standard drug Isoniazid (0.195 µM=0.026 µg/mL). An in silico molecular docking study revealed the strong binding affinity of target compounds with the enzyme Mtb CYP 121. The pharmacokinetic properties and toxicity predictions indicate overall drug-likeness for synthesized compounds. In this study, the compounds 4i, 4j, and 4k displayed considerable anti-TB activity against Mtb H37Rv with MIC99 values of 25 µM (10.43, 10.54, and 11.65 µg/mL respectively). CC50 of the test compounds were determined by cell viability assay using THP-1 macrophages. The compounds having methoxy and halogen substitution at the para position of the benzoyl fragment of designed molecules exhibited the best activity among the series.

Synthesis and Biological Screening of New 2-(5-Aryl-1-phenyl-1H-pyrazol-3-yl)-4-aryl Thiazole Derivatives as Potential Antimicrobial Agents.

A new series of 2-(5-aryl-1-phenyl-1H-pyrazol-3-yl)-4-aryl thiazoles (10a-ab) have been synthesized by a cyclocondensation reaction of 5-aryl-1-phenyl-1H-pyrazole-3-carbothioamide (7a-d) with substituted phenacyl bromide (8a-f). The structure of newly synthesized 2-(5-aryl-1-phenyl-1H-pyrazol-3-yl)-4-aryl thiazole (10a-ab) derivatives was characterized by spectroscopic analysis. The compounds 10a-ab were evaluated for in vitro antibacterial activity against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), Bacillus subtilis (NCIM 2063), Staphylococcus aureus (NCIM 2178), and in vitro antifungal activity against Aspergillus niger (ATCC 504) and Candida albicans (NCIM 3100). Among the twenty-eight pyrazolyl-thiazole derivatives, six compounds, 10g, 10h, 10i, 10j, 10o, and 10t, showed good activity against P. mirabilis; four compounds 10q, 10u, 10y, and 10z showed good activity against S. aureus; and twenty-four derivatives showed good antifungal activity against A. niger. Compounds 10g, 10q, 10r, 10s, and 10ab showed comparable activity with respect to the reference drug Ravuconazole. Thus, the significant antimicrobial activity of 2-(5-aryl-1-phenyl-1H-pyrazol-3-yl)-4-aryl thiazole (10a-ab) derivatives prompted that these scaffolds could assist in the development of lead compounds to treat microbial infections.

Para-Substituted Thiosemicarbazones as Cholinesterase Inhibitors: Synthesis, In Vitro Biological Evaluation, and In Silico Study.

The current research reports the synthesis of 14 para-substituted thiosemicarbazone derivatives in good to excellent yields using standard procedures. Initially, 4-ethoxybenzaldehyde (1) and 4-nitrobenzaldehyde (2) were refluxed with thiosemicarbazide in the presence of acetic acid in ethanol for 4-5 h. Then, various substituted phenacyl bromides were treated with the desired thiosemicarbazones (3 and 4) in the presence of triethylamine in ethanol with constant stirring for 5-6 h. The resulting derivatives were confirmed through electron impact mass spectrometry and 1H NMR spectroscopy and evaluated for anticholinesterase inhibitory activity. Among the series, four compounds, 19, 17, 7, and 6, showed potent inhibitory activity against the acetylcholinesterase (AChE) enzyme, having IC50 values of 110.19 ± 2.32, 114.57 ± 0.15, 140.52 ± 0.11, and 160.04 ± 0.02 μM, respectively, compared with standard galantamine (IC50 = 104.5 ± 1.20 μM). Similarly, compounds 19 (IC50 = 145.11 ± 1.03 μM), 9 (IC50 = 147.20 ± 0.09 μM), 17 (IC50 = 150.36 ± 0.18 μM), and 6 (IC50 = 190.21 ± 0.13 μM) were the most excellent inhibitors of butyrylcholinesterase (BChE) when compared with the standard drug galantamine (IC50 = 156.8 ± 1.50 μM). In silico studies were accomplished on the produced derivatives in order to explain the binding interface of compounds with the active sites of AChE and BChE enzymes.

Synthesis of 1,2,3‐Triazole‐Containing 2,3‐Dihydrofuran Derivatives, Evaluation of Anticancer Activity and Molecular Docking Studies

AbstractA simple and convenient one‐pot three‐component method to synthesize 1,2,3‐triazole‐based 2,3‐dihydrofuran derivatives from the condensation of 5,5‐dimethylcyclohexane‐1,3‐dione, substituted phenacyl bromide, triethylamine and 1,2,3‐triazole based benzaldehyde using a mixture of CH3CN/water as a reaction medium is described. The current protocol delivers numerous advantages such as good yield, short reaction time, easy work‐up and simplicity in the procedure as it uses a green method and an eco‐friendly catalyst. The target compounds are screened for their in‐vitro anticancer activity and most of the compounds are found to exhibit promising activity compared to standard drug Doxorubicin. Molecular docking studies performed on caspase‐3 and COVID‐19 main protease revealed well defined binding interactions and docking scores.

New class of fused [3,2-b][1,2,4]triazolothiazoles for targeting glioma in vitro

Glioma is aggressive malignant tumor with limited therapeutic interventions. Herein we report the synthesis of fused bicyclic 1,2,4-triazolothiazoles by a one-pot multi-component approach and their activity against C6 rat and LN18 human glioma cell lines. The target compounds 2-(6-phenylthiazolo[3,2–b][1,2,4]triazol-2-yl) isoindoline-1,3-diones and (E)-1-phenyl-N-(6-phenylthiazolo[3,2–b][1,2,4]triazol-2-yl) methanimines were obtained by the reaction of 5-amino-4H-1,2,4-triazole-3-thiol with substituted phenacyl bromide, phthalic anhydride, and different aromatic aldehydes in EtOH/HCl under reflux conditions. In C6 rat glioma cell lines, compounds 4g and 6i showed good cytotoxic activity with IC50 values of 8.09 and 8.74 μM, respectively, resulting in G1 and G2-M phase arrest of the cell cycle and activation of apoptosis by modulating phosphorylation of ERK and AKT pathway.

Choline Chloride-Based Deep Eutectic Solvents as Green Effective Medium for Quaternization Reactions.

The Menshutkin reaction represents the alkylation of tertiary amines by alkyl halide where the reactants are neutral and the products, quaternary ammonium salts, are two ions with opposite signs. The most commonly used organic solvents in quaternization reactions are volatile organic solvents (VOSs), namely acetone, anhydrous benzene, dry dichloromethane (DCM), dimethylformamide (DMF) and acetonitrile (ACN). The purpose of this work was to examine eutectic solvents as a "greener" alternative to conventional solvents so that quaternization reactions take place in accordance with the principles of green chemistry. Herein, sixteen eutectic solvents were used as replacements for volatile organic ones in quaternization reactions of isonicotinamide with substituted phenacyl bromides. The reactions were carried out at 80 °C by three synthetic approaches: conventional (4-6 h), microwave (20 min) and ultrasound (3 h). Microwave-assisted organic reactions produced the highest yields, where in several reactions, the yield was almost quantitative. The most suitable eutectic solvents were based on choline chloride (ChCl) as the hydrogen bond acceptor (HBA) and glycerol, oxalic or levulinic acid as hydrogen bond donors (HBDs). The benefits of these three deep eutectic solvents (DESs) as a medium for quaternization reactions are the simplicity of their preparation for large-scale production, with inexpensive, available and nontoxic starting materials, as well as their biodegradability.

Phenyl pyrrolo [1,2-a] quinolines- finding of a key by-product during quinolinium salt preparation

A key by-product, 2-phenylpyrrolo [1,2-a] quinoline, is isolated and characterized during the preparation of bioactive Pyridinium and quinolinium salts at ambient temperature. This protocol turned out to be an efficient approach for the one-pot synthesis of a series of 2-phenylpyrrolo [1,2-a] quinoline derivatives from 2-methyl quinoline and substituted phenacyl bromides. This method implicates a transition metal-based catalyst and base-free, environment-friendly solvent-free reaction conditions. All the newly synthesized derivatives have been characterized by 1H-NMR, 13C-NMR, and HRMS.

New benzoxazole-based sulphonamide hybrids analogs as potent inhibitors of α-amylase and α-glucosidase: Synthesis and in vitro evaluation along with in silico study

The development of drugs resistance in diabetes mellitus is a growing clinical problem, creates many challenges for patient. To overcome these problems, there is a serious deficiency of anti-diabetic agents, may be synthesized that inhibit alpha amylase and alpha glucosidase activity. Here, we have design and synthesized benzoxazole based sulphonamide derivatives and evaluated for their anti-diabetic activity. Twenty-two benzoxazole based sulphonamide derivatives were synthesized by reacting 2-aminophenol with carbon disulphide in the presence of base (Et3N) to obtained 2-marcapto benzoxazole which was further dissolved in ethanol by slow addition of different substituted phenacyl bromide in the presence of triethylamine, afforded varied S-substituted benzoxazole products. These products were dissolved in ethanol and hydrazine hydrate was added an excess in the presence of acetic acid to gives Schiff base. This Schiff base products were further dissolved in THF along with different substituted benzene sulphonyl chloride followed by addition of few drops of Et3N, yielded benzoxazole based sulphonamide derivatives (1–22). Moreover, SAR was established for the synthesized compounds and molecular docking studies were conducted for the potent moieties in order to explore the binding modalities of analogs. Among the tested series few analogues were found few folds better potential than standard drug but analog 1 (IC50 = 1.10 ± 0.20 µM, 1.20 ± 0.30 µM), showed promising anti-diabetic activity against α-amylase and α-glucosidase (11.12 ± 0.15 µM and 11.29 ± 0.07 µM respectively).

Discovery of new fenamate-based derivatives as anticancer agents and potent VEGFR-2 inhibitors

VEGFR-2 is a critical target for the treatment of solid tumors. This work represents synthetic approaches to a new class of fenamate-based derivatives with essential pharmacophoric properties comparable to VEGFR-2 inhibitors. The reaction of tolfenamic acid hydrazide with substituted phenacyl bromide, and phenylisothiocynate derivatives produced novel tolfenamic acid (TA) derivatives (compounds 4 and 5). The target molecules were validated using spectroscopic techniques such as FT-IR and 1HNMR. Docking tests were performed to determine how the synthesized chemicals bind to the putative molecular target, VEGFR-2. The docking results demonstrated that the synthesized compounds could bind VEGFR-2 correctly. Finally, computational physicochemical analysis of the most active candidates revealed that they have favorable assets and reasonable drug-likeness reports.

Evaluation of synthetic 2-aryl quinoxaline derivatives as α-amylase, α-glucosidase, acetylcholinesterase, and butyrylcholinesterase inhibitors

Variety of 2-aryl quinoxaline derivatives 1–23 were synthesized in good yields, by reacting 1,2-phenylenediamine with varyingly substituted phenacyl bromides in the presence of pyridine catalyst. All molecules 1–23 were characterized by spectroscopic techniques and evaluated for their diverse biological potential against α-amylase (α-AMY), α-glucosidase (α-GLU), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes. Synthetic derivatives possess enhanced inhibitory potential against all enzymes at nanomolar concentrations. In particular, compound 14 was found much superior with IC50 = 294.35, 198.21, 17.04, and 21.46 nM against α-AMY, α-GLU, AChE, and BChE, respectively, as compared to standard inhibitors. Furthermore, selected potent compounds, including 3, 4, 8, 14, 15, 17, and 18, were subjected to molecular docking studies to decipher the binding energies and interactions of ligands (synthetic molecules) with all four target enzymes.

A Facile One-Pot, Three-Component Synthesis of a New Series of Thiazolyl Pyrazoles: Anticancer Evaluation, ADME and Molecular Docking Studies

A series of thiazolyl pyrazoles (4a–f, 6a–f, and 8a–b) were synthesized by a conventional method using thiosemicarbazide, substituted phenacyl bromides, or substituted 3-(2-bromoacetyl) coumarins, 1-Boc-3-cyano-4-pyrrolidone, or 1-Boc-3-cyano-4-piperidone. All synthesized compounds' structures were confirmed by spectral (1H- and 13C-NMR, FTIR, Mass) and analytical data. The target compounds were screened for their in vitro anticancer activity. The results found that the compound 8a and 8b has shown significant antiproliferative activity against HeLa, A549, and MDA-MB-231 cancer lines. Furthermore, in silico ADME profiles were also predicted to set effective lead candidates for future anticancer drug discovery initiatives. The synthesized thiazolyl pyrazoles derivatives were further subjected to docking simulations, and the results were in agreement with the in vitro results.

Convenient multicomponent synthesis of furo[3,2-c]coumarins in the promoting medium DIPEAc and assessment of their therapeutic potential through in silico pharmacophore based target screening

A one-pot three-component approach for the synthesis of dihydrofuro[3,2-c]coumarins was developed via the reaction of aryl/hetryl aldehydes, substituted phenacyl bromides and 4-hydroxycoumarin using N,N-diisopropyl ethyl ammonium acetate as the promoting medium.

Eco-friendly Synthesis of Some New Benzylidene-iminothiazolyl-pyrazol-3-ol Derivatives via One-Pot Multicomponent Reaction and Evaluation of Antioxidant Activities

In present work, one-pot multicomponent reaction (MCR) route for the synthesis of benzylideneiminothiazolyl- pyrazol-3-ol derivatives (5a-p) by reacting ethyl cyanoacetate (1), substituted benzaldehyde (2a-c), thiosemicarbazide (3) and substituted phenacyl bromide (4a-g). This reaction proceeds by using bleaching earth clay (BEC) (pH 12.5) in PEG-400 as a green reaction media. All the synthesized compounds were characterized by IR, 1H NMR, 13C NMR and mass spectral data. The pharmacological investigation of the synthesized compounds suggest that most of them showed good antioxidant activity.

Synthesis and antibacterial activity of 3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a] azepin-1-ium bromides and aryl-(4-R1-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-1-ylmethyl)-amines

The aim of this work is to develop methods of synthesis of 3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-1-ium bromides and aryl-(4-R1-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-1-ylmethyl)-amines and to study their antimicrobial activity against strains of gram-positive and gram-negative bacteria as well as yeast fungi.
 Materials and methods. 1Н NMR spectra were recorded on Bruker 400 spectrometer operating at frequency of 400 MHz. Antimicrobial activity of the compounds synthesized was evaluated by their minimum inhibitory concentration (MIC) values.
 Results and discussion. The interaction of 3-arylaminomethyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepines with substituted phenacyl bromides produced novel 3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-1-ium bromides. The latter when refluxed in 10 % solution of NaOH gave aryl-(4-R1-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-1-ylmethyl)-amines. The study of antimicrobial activity of the compounds obtained allowed to find derivatives which are active against С. albicans and S. aureus strains. Among the compounds tested 3-[(41-bromophenylamino)-methyl]-1-[2-(4-methoxyphenyl)-2-oxoethyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-1-ium bromide 5cd appeared to be more active than the reference drug Cefixime and displayed close antimicrobial activity as the antibiotic Linezolid.
 Conclusions. It was found out that derivatives of 3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-1-ium bromides display broad spectrum of antimicrobial activity and are able to inhibit growth of both bacteria and fungi. S. aureus and C. albicans turned out to be the most sensitive strains to the compounds tested, MIC was in the range of 6.2-25.0 mg/mL. Gram-negative strains of microorganisms were less sensitive to the compounds evaluated and 5fа was the most active derivative displaying antimicrobial activity at the concentration of 50.0 mg/mL. Antimicrobial activity of triazoloazepinium bromide derivatives was similar to that one of Linezolid and Fluconazole reference drugs and more pronounced than the activity of Cefixime.
 Hence, the data gathered evidence the feasibility of further study of the antimicrobial properties of the most active compounds in in vivo experiments aiming at assessment of the prospects for the creation of new effective and safe antimicrobial drugs based on them