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Click chemistry‐inspired design, synthesis, and molecular docking studies of biscoumarin derivatives using carbon‐based acid catalyst

Click chemistry‐inspired design, synthesis, and molecular docking studies of biscoumarin derivatives using carbon‐based acid catalyst

Abstract

A green and eco‐benign synthesis of biscoumarin derivatives using carbon sulfonic acid, a solid support catalyst has been described. The reaction involved a one‐pot two‐component reaction of 4‐hydroxycoumarin and aldehyde using carbon sulfonic acid involving Knoevenegal‐Michael condensation. A series of aromatic (bearing electron withdrawing and releasing group) and heteroaromatic aldehydes has been converted to biscoumarins with excellent isolated yields. The reaction is in compliance with green principles, that is, inexpensive catalyst, easy to prepare, nontoxic, easy handling, reusable up to five recycle runs, easy separation, short reaction time, no need of time consuming column purification, high yielding, and so on. The synthesized catalyst and biscoumarin derivatives were well characterized by spectral analysis. The molecular modeling studies showed that the designed molecular scaffolds (3a‐j) showed outstanding interaction with methylenetetrahydrofolate reductase (MTHFR) and cytochrome P450 3A4 (CYP3A4) proteins. It was noticed that 3f (−17.55 kJ/mol) and 3d (−26.23 kJ/mol) showed the highest docking score against CYP3A4 and MTHFR proteins, respectively.

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Organocatalyzed Kabbe condensation reaction for mild and expeditious synthesis of 2,2‐dialkyl and 2‐spiro‐4‐chromanones

Organocatalyzed Kabbe condensation reaction for mild and expeditious synthesis of 2,2‐dialkyl and 2‐spiro‐4‐chromanones

Abstract

An expeditious Kabbe condensation reaction for the synthesis of 2,2‐dialkyl and 2‐spiro‐chroman‐4(1H )‐ones has been developed using pyrrolidine‐butanoic acid in DMSO as bifunctional organocatalyst. Unlike existing methods, this reaction proceeds at room temperature with high yields, rendering it an attractive method to synthesize a vast variety of privileged 4‐chromones.

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Three‐component reaction for synthesis of 2‐amino‐6‐aryl‐5‐(phenylamino)‐3,7‐dihydro‐4H‐pyrrolo[2,3‐d]pyrimidin‐4‐one derivatives in water

Three‐component reaction for synthesis of 2‐amino‐6‐aryl‐5‐(phenylamino)‐3,7‐dihydro‐4H‐pyrrolo[2,3‐d]pyrimidin‐4‐one derivatives in water

Abstract

A new three‐component domino reaction for the synthesis of 2‐amino‐6‐aryl‐5‐(phenylamino)‐3,7‐dihydro‐4H ‐pyrrolo[2,3‐d ]pyrimidin‐4‐one derivatives 4 using acetic acid as catalyst has been established. The reaction was performed in aqueous media using readily available and inexpensive 2,6‐diaminopyrimidin‐4(3H )‐one 1 , 2,2‐dihydroxy‐1‐arylethan‐1‐one 2 and aniline 3 as substrates. The simple and efficient one‐pot three‐component approach, inexpensive catalyst, green reaction media, make the present methodology a good synthetic procedure.

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Fused bicyclic 1,2,4‐triazoles with one extra sulfur atom: Synthesis, properties, and biological activity

Fused bicyclic 1,2,4‐triazoles with one extra sulfur atom: Synthesis, properties, and biological activity

Abstract

Fused heterocyclic systems with 1,2,4‐triazole scaffold arouse great interest from researchers in the branch of heterocyclic and medical chemistry because of their wide biological activities as they are considered as fungicidal, antimicrobial, analgesic, bronchodilators, antioxidant, anti‐inflammatory agents, and they are G‐quadruple stabilizers; the molecular docking data for coumarin‐containing 1,2,4‐triazoles indicate their ability to act as a urease inhibitor. Therefore, the present review aims to investigate new trends in the chemistry of heterocycles incorporating thiazolo[3,2‐b][1,2,4]triazoles, thiazolo[2,3‐c][1,2,4]triazoles, thiazino[5,1‐b][1,2,4]triazoles, thiazino[3,4‐b][1,2,4]triazoles, triazolothiazepines, and their biological characteristics. The main sections discuss: (a) the synthetic routes to the production of substituted fused heterocyclic systems, which include condensation reactions, multiple bond annulation, and the reactions of electrophilic heterocyclization. (b) Description of chemical and biological characteristics of these fused heterocycles.

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Synthesis, biological evaluation, and docking study of a series of 1,4‐disubstituted 1,2,3‐triazole derivatives with an indole‐triazole‐peptide conjugate

Synthesis, biological evaluation, and docking study of a series of 1,4‐disubstituted 1,2,3‐triazole derivatives with an indole‐triazole‐peptide conjugate

Abstract

A series of new compounds containing an indole‐triazolepeptide conjugate were designed as potential agents possessing the dual anti‐bacterial and anticancer activities. Accordingly, 20 compounds were prepared via a multi‐step synthesis involving the copper‐catalyzed azide‐alkyne cycloaddition (CuAAC) as a key step in moderate to high yield. All the synthesized compounds were purified by chromatographic techniques and characterized by IR, 1H and 13C NMR and mass spectral data. The synthesized derivatives were screened for their antimicrobial activities against one gram‐positive (Staphylococcus aureus ) and three gram‐negative (Escherichia coli , Klebsiella pneumonia , and Proteus vulgaris ) bacteria using an agar‐well diffusion method. Most of the compounds showed moderate to reasonable antibacterial activities especially the compound 9e that showed good activities against all the strains. The potential of DNA gyrase inhibitory activity of this compound was assessed by using molecular docking studies in silico carried out using Autodock Vina software. The low ΔGbind value (−9.4 Kcal/mol) of compound 9e suggested its good interactions with the target protein in silico. The cytotoxic activities of some of the compounds synthesized were evaluated via a MTT assay using the human lung cancer cell line A549. Several compounds showed promising activities among which compound 9b , 9k, and 9e showed low IC50 values.

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Cytotoxicity, tyrosine kinase inhibition of novel pyran, pyridine, thiophene, and imidazole derivatives

Cytotoxicity, tyrosine kinase inhibition of novel pyran, pyridine, thiophene, and imidazole derivatives

Abstract

In this work, we are interested to use multicomponent reactions of cyclohexan‐1,3‐dione with different reagents for synthesizing new derivatives of pyran, pyridine, thiophene, and imidazole with antitumor activities. Twenty‐two newly synthesized derivatives were selected and tested for their anticancer potency. Several of these compounds exhibited quite interesting potencies toward three human tumor cell lines, namely NCI‐H460 (non‐small cell lung cancer), SF‐268 (CNS cancer), and MCF‐7 (breast adenocarcinoma), especially when compared to that of reference drugs, doxorubicin and 5‐Fu.Compounds 5b , 5c , 7b , 9b , 14a , 16c , 18a , 19c , 20b , and 22b , were found to be the most cytotoxic compounds toward the selected cell lines. On the other hand, 7b , 14a , 16c , 19c , and 22b revealed high inhibitions toward the tyrosine kinases. Active compounds against VEGFR‐2, 14a , 16c , and 19c, were docked inside VEGFR‐2enzyme to show the interaction between the tested compounds and the amino acids of the active site.

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Synthesis and in vitro anticancer activity of some novel cyclohepta[b]thiophene‐3‐carboxamides bearing pyrazole moiety

Synthesis and in vitro anticancer activity of some novel cyclohepta[b]thiophene‐3‐carboxamides bearing pyrazole moiety

Abstract

2‐Aminothiophene 3 was achieved through the one‐pot multicomponent reaction of cycloheptanone, cyanoacetamide, elemental sulfur, and morpholine in ethanol. Diazotization of 2‐aminothiophene 3 with NaNO2/HCl gave the corresponding diazonium salt 4 , that combined with the appropriate active methylene components; 5a , 5b , 7 , 11 , 13 , 16 , 18 , 21 , 9 , 19 , 22a , and 22b in pyridine (AcONa/EtOH) to form the corresponding hydrazones 6a , 6b , 8 , 10 , 14 , 15 , 17 , 20 , 23 , 24 , 25a , and 25b , respectively. Heating of compound 8 with malononitrile 9 in ethanol gave the thiazole 10 . Treatment of compound 10 , 25a , and 25b with hydrazine hydrate achieve the pyrazoles 12 , 27a , and 27b , respectively. Hydrazinolysis of compound 14 with hydrazine hydrate, followed by condensation of the obtained hydrazide 15 with acetylacetone 19 gave the pyrazole 20 . The recently orchestrated thiophenes were assessed for their cytotoxic action. The result revealed that compound 12 indicated comparable and better action towards HePG2, HCT‐116, MCF‐7, and PC3 cancer cell lines than Doxorubicin.

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Efficient one‐pot synthesis of novel 6′,9′‐dihydro‐2H,7′H‐spiro[pyrimidine‐5,8′‐[1,3]dioxolo[4,5‐f]quinoline]‐2,4,6(1H,3H)‐trione derivatives under mild and “green” reaction conditions

Efficient one‐pot synthesis of novel 6′,9′‐dihydro‐2H,7′H‐spiro[pyrimidine‐5,8′‐[1,3]dioxolo[4,5‐f]quinoline]‐2,4,6(1H,3H)‐trione derivatives under mild and “green” reaction conditions

Abstract

In this paper, an efficient method is introduced for the synthesis of 7′,9′‐disubstituted 6′,9′‐dihydro‐2H ,7′H ‐spiro[pyrimidine‐5,8′‐[1,3]dioxolo[4,5‐f ]quinoline]‐2,4,6(1H ,3H )‐trione derivatives under mild and “green” reaction conditions. The method is based on one‐pot multicomponent reaction of an aldehyde, barbituric acid, and benzo[d ][1,3]dioxol‐5‐amine in ethanol as a green and environmentally friendly solvent. The reaction has given the products in the highest isolated yield in the presence of acetic acid as catalyst under reflux conditions. Various aldehydes, bearing electron‐donating or ‐withdrawing functionalities have been used under the optimized conditions and successfully gave the desired products (13 examples) in high isolated yields.

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Synthesis of various fused heterocyclic rings from thiazolopyridine and their pharmacological and antimicrobial evaluations

Synthesis of various fused heterocyclic rings from thiazolopyridine and their pharmacological and antimicrobial evaluations

Abstract

Various fused‐heterocyclic‐derivatives containing thiazolopyridine moieties has been synthesized by allowing 5‐aminothiazolo[3,2‐a]pyridine derivative 1 to undergo annulations reactions with different reagents under different‐reaction conditions. The biological assessment of compounds 2 , 11 , 14 , 15 , and 19 showed remarkable antimicrobial activities. In addition, selected derivatives of the products were screened for their anticancer activities against two tumor cell lines using MTT assay and the results showed that some of these compounds have potent cytotoxic effect, as concluded from their IC50 values. Meanwhile, compounds 3a , 7 have exhibited very strong potency as anticancer candidates. Thiazolopyridine structures have been confirmed as a useful lead compounds for the development of new anticancer agents. Molecular docking showed that,‐some of the synthesized compounds more suitable inhibitor against‐ALR2 with farther alteration in future.

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Piperazine‐mediated tandem synthesis of bis(thieno[2,3‐b]pyridines): Versatile precursors for related fused [1,2,4]triazolo[4,3‐a]pyrimidines

Piperazine‐mediated tandem synthesis of bis(thieno[2,3‐b]pyridines): Versatile precursors for related fused [1,2,4]triazolo[4,3‐a]pyrimidines

Abstract

In this study, we discuss the utility of bis(cyanoacetamides) as versatile precursors to the piperazine‐mediated synthesis of a wide spectrum of bis(thieno[2,3‐b ]pyridine) derivatives, linked to aliphatic spacers via thioethers. The proposed tandem protocol involved the reaction of bis(cyanoacetamides) with two equivalents of the appropriate cinnamonitriles in dioxane in the presence of six equivalents of piperazine at reflux for 4 hours. Then, two equivalents of the appropriate halogen‐containing reagents were added and the reaction was heated at reflux for further 3 hours. The bis(thieno[2,3‐b ]pyridines) were taken as a key intermediates to new bis(4‐oxopyrido[3′,2′:4,5]thieno[3,2‐d ]pyrimidines). The above derivatives were reacted with the appropriate hydrazonyl chloride derivatives in dioxane in the presence of triethylamine to yield the corresponding bis([1,2,4]triazoles) with a related fused pyridothienopyrimidine moiety. The new structures were elucidated by IR, NMR spectral data, as well as elemental analyses.

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Synthesis and antioxidant activity study of carbothioamide and their corresponding thiazole derivatives

Synthesis and antioxidant activity study of carbothioamide and their corresponding thiazole derivatives

Abstract

A novel series of 5‐(p‐(prop‐2‐ynyloxy)phenyl)‐3‐aryl‐4,5‐dihydropyrazole‐1‐carbothioamides 2a‐f and functionalized 2‐(3‐(aryl)‐5‐(4‐(prop‐2‐ynyloxy)phenyl)‐4,5‐dihydropyrazol‐1‐yl)‐4‐(3‐arylsydnone‐4‐yl)thiazoles 4a‐l were synthesized. The newly synthesized compounds were elucidated by analytical and spectral analysis. From the single‐crystal X‐ray diffraction method, it was observed that 2d crystallizes in a monoclinic crystal system with P21/n space group. The compounds 2d crystallized with cell parameters a = 15.0614 (19) Å, b = 6.0805 (7) Å, c = 20.903 (7) Å, α = 114.136 (6)o, β = 110.709 (14) o, γ = 96.553 (5) o, V = 1790.6 (4) Å3, Z = 4. From the Hirshfeld surface computational method, the major intercontacts present in these molecules are H…H (31.6%), C…H (18.2%) and S…H (12.2%), respectively. The newly synthesized compounds were tested for their ability to bleach 2,2’‐diphenyl‐1‐picrylhydrazyl (DPPH) radical using DPPH scavenging assay. Among the synthesized compounds carbothioamide compounds 2c (90.7%) and 2b (89.8%) exhibited good DPPH scavenging activity compared to the rest of the compounds. Most of the synthesized carbothioamide molecules (2a‐f ) found to be potent compared to the thiazole derivatives (4a‐l ).

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Synthesis and biological evaluation of some heterocyclic scaffolds based on the multifunctional N‐(4‐acetylphenyl)‐2‐chloroacetamide

Synthesis and biological evaluation of some heterocyclic scaffolds based on the multifunctional N‐(4‐acetylphenyl)‐2‐chloroacetamide

Abstract

The chloroacetamide derivative, 1 , was used as a versatile precursor for the synthesis of various types of N ‐aryl‐2‐(benzothiazol‐2‐ylthio)acetamide derivatives. The reaction of 1 with 2‐mercaptobenzothiazole followed by condensation reaction of the produced sulfide with phenylhydrazine, 2‐cyanoacetohydrazide, and/or thiosemicarbazide furnished the conforming condensation products, 4 , 7 , and 10 , respectively. Treatment of the phenylhydrazone product, 4 , with Vilsmeier formylation reagent (POCl3/DMF) yielded the corresponding 4‐formylpyrazole derivative, 5 . The thiosemicarbazone product, 10 , was reacted with ethyl bromoacetate to furnish the thiazolin‐4‐one derivative, 11 . The substitution reactions of chloroacetamide derivative, 1 , with 2‐mercapto‐4,6‐dimethylnicotinonitrile and 6‐amino‐2‐mercaptopyrimidin‐4‐ol, were explored to identify the sulfide products, 14 and 17 . Cyclization of 14 into its corresponding thieno[2,3‐b ]pyridine compound, 15 , was performed using sodium ethoxide. The thiosemicarbazone, 10 , and sulfide derivative, 14 , were found to be the most potent antibacterial compounds against Escherichia coli and Staphylococcus aureus , exhibiting growth inhibitory activities of 80.8% and 91.7%, respectively. Moreover, the thiosemicarbazone, 10 , displayed the most significant antioxidant activity with inhibitory activity of 82.6%, which comes close to the antioxidant activity of L‐ascorbic acid.

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2H‐Indazolo[2,1‐b]phthalazine‐trione derivatives: Inhibition on some metabolic enzymes and molecular docking studies

2H‐Indazolo[2,1‐b]phthalazine‐trione derivatives: Inhibition on some metabolic enzymes and molecular docking studies

Abstract

In this study, substituted 2H‐indazolo[2,1‐b ]phthalazine‐1,6,11‐trione compounds (4a–d ) obtained via one‐pot three‐component condensation reaction of aromatic aldehydes, cyclic 1,3‐dione, and phthalhydrazide in ethanol catalyzed by Y(OTf)3 showed satisfactory inhibitory effects against some important enzymes. Also, these molecules had Ki values in the row of 185.92 ± 36.03‐294.82 ± 50.76 nM vs carbonic anhydrase I (CA I), 204.93 ± 46.90‐374.10 ± 83.63 nM against human CA II, 937.16 ± 205.82‐1021.83 ± 193.66 nM against α‐glycosidase (α‐Gly), respectively. For cholinesterase enzymes, the Ki values were found in the range of 47.26 ± 9.62‐72.05 ± 19.47 nM against acetylcholinesterase (AChE) and 65.03 ± 9.88‐102.83 ± 25.04 nM against butyrylcholinesterase (BChE), respectively. The inhibition effects of these compounds against enzymes whose name are AChE, BChE, α‐Gly, hCA I, and hCA II, were compared with control molecules like tacrine, acarbose, and acetazolamide.

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Exo/endo stereocontrolled synthesis of spiroindoloindolizidines by using classical and microwave conditions via the 1,3‐dipolar cycloaddition reaction

Exo/endo stereocontrolled synthesis of spiroindoloindolizidines by using classical and microwave conditions via the 1,3‐dipolar cycloaddition reaction

Abstract

Using both classical reflux and microwave‐mediated conditions, a series of new spiroindoloindolizidines was synthesized by multicomponent 1,3‐dipolar cycloaddition of azomethine ylides in unprecedented exo /endo stereocontrolled. Both conditions easily afforded two identical and separable exo /endo diastereomeric ratios of cycloadducts. However, the ratio of two diastereomeric products obtained from conventional conditions was reversed in all examined cases when the reactions were explored under microwave‐mediated conditions. As expected, utilizing the microwave‐assisted conditions produced higher yields and reaction rates compared to classical conditions. The structure and exact stereochemistry of synthesized cycloadducts were determined by applying various 2D‐NMR spectroscopic techniques and single‐crystal X‐ray diffraction. Finally, the mechanism of the reaction has been briefly investigated by using density functional theory (DFT) calculations.

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