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This study depicts the synthesis of a novel biocatalyst Cluster Fig Ash (CFA) from cluster fig. XRD, FT‐IR, EDX, TGA, BET and SEM techniques were used to characterize the synthesized CFA catalyst. The one‐pot multicomponent synthesis of pyrano[2,3‐c]pyrazoles derivatives under ambient conditions was utilised to test the catalytic activity of this synthesized CFA biocatalyst. It was found that an easy, reliable, and extremely efficient method has been proposed to synthesise pyrano[2,3‐c]pyrazoles derivatives using one‐pot, multicomponent reaction involving aldehyde, malononitrile, ethylacetoacetate, and Hydrazine monohydrate. [ABSTRACT FROM AUTHOR]

In this study, choline chloride/urea was used as a green deep eutectic solvent in the three-component reaction of hydrazine/phenylhydrazine, malononitrile, and aromatic aldehydes for synthesizing pyrazole derivatives, and in the four-component reaction of methyl/ethyl acetoacetate, hydrazine/phenylhydrazine, malononitrile, and aromatic aldehydes for synthesizing pyrano[2,3-c]pyrazole derivatives. Elemental analysis, ¹H, and 13C NMR spectroscopy were used to confirm the structure of the synthesized pyrazole and pyrano[2,3-c] pyrazole derivatives. The antimicrobial effects of the synthesized pyrazole and pyrano[2,3-c] pyrazole derivatives were investigated. In antimicrobial tests, instructions from clinical and laboratory standards institutes were used. Antimicrobial study was done on pathogenic gram-positive and gram-negative species, and specialized aquatic strains and fungal species. Using choline chloride/urea, novel pyrazole derivatives and pyrano[2,3-c]pyrazole derivatives were synthesized, and other derivatives were synthesized with higher efficiency in less time than some previously reported methods. MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) obtained for derivatives were higher than some antibiotic drugs. Synthesis and reports of new derivatives of pyrazole and pyrano[2,3-c]pyrazole, and investigation and reports of their antimicrobial properties on gram-positive, gram-negative, and specialized aquatic and fungal species are among the novel and important findings of this study. [ABSTRACT FROM AUTHOR]

In this study, choline chloride/urea was used as a green deep eutectic solvent in the three-component reaction of hydrazine/phenylhydrazine, malononitrile, and aromatic aldehydes for synthesizing pyrazole derivatives, and in the four-component reaction of methyl/ethyl acetoacetate, hydrazine/phenylhydrazine, malononitrile, and aromatic aldehydes for synthesizing pyrano[2,3-c]pyrazole derivatives. Elemental analysis, 1H, and 13C NMR spectroscopy were used to confirm the structure of the synthesized pyrazole and pyrano[2,3-c] pyrazole derivatives. The antimicrobial effects of the synthesized pyrazole and pyrano[2,3-c] pyrazole derivatives were investigated. In antimicrobial tests, instructions from clinical and laboratory standards institutes were used. Antimicrobial study was done on pathogenic gram-positive and gram-negative species, and specialized aquatic strains and fungal species. Using choline chloride/urea, novel pyrazole derivatives and pyrano[2,3-c]pyrazole derivatives were synthesized, and other derivatives were synthesized with higher efficiency in less time than some previously reported methods. MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) obtained for derivatives were higher than some antibiotic drugs. Synthesis and reports of new derivatives of pyrazole and pyrano[2,3-c]pyrazole, and investigation and reports of their antimicrobial properties on gram-positive, gram-negative, and specialized aquatic and fungal species are among the novel and important findings of this study.

A series of N-(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles was synthesised and screened for their potential to inhibit kinases and exhibit anticancer activity against primary patient-derived glioblastoma 2D cells and 3D neurospheres. A collection of 10 compounds was evaluated against glioma cell lines, with compound 4j exhibiting promising glioma growth inhibitory properties. Compound 4j was screened against 139 purified kinases and exhibited low micromolar activity against kinase AKT2/PKBβ. AKT signalling is one of the main oncogenic pathways in glioma and is often targeted for novel therapeutics. Indeed, AKT2 levels correlated with glioma malignancy and poorer patient survival. Compound 4j inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells and exhibited potent EC50 against glioblastoma cell lines. Although exhibiting potency against glioma cells, 4j exhibited significantly less cytotoxicity against non-cancerous cells even at fourfold–fivefold the concentration. Herein we establish a novel biochemical kinase inhibitory function for N-(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles and further report their anti-glioma activity in vitro for the first time.KEY MESSAGEAnti-glioma pyrano[2,3-c]pyrazole 4j inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells. 4j also displayed PKBβ/AKT2 inhibitory activity. 4j is nontoxic towards non-cancerous cells.

The SARS-CoV-2 pandemic at the end of 2019 had major worldwide health and economic consequences. Until effective vaccination approaches were created, the healthcare sectors endured a shortage of operative treatments that might prevent the infection’s spread. As a result, academia and the pharmaceutical industry prioritized the development of SARS-CoV2 antiviral medication. Pyranopyrazoles have been shown to play a prominent function in pharmaceutical chemistry and drug sighting because of their significant bioactive properties. We provide herein a novel sequence of pyranopyrazoles and their annulated systems whose antiviral efficacy and cytotoxicity were explored versus human coronavirus 229E (HCoV-229E) Vero-E6 cell lines as a model for the Coronaviridae family. Fifteen synthetic congeners pointed out miscellaneous antiviral efficacies against HCoV-229E with variable inhibition degrees. Compound 18 showed a high selectivity index (SI = 12.6) that established spectacular inhibitory capacity against human coronavirus 229E. Compounds 6, 7, and 14 exposed moderate efficacies. Compounds 6, 7, 14, and 18 exhibited substantial antiviral action through the replication phase with reduction percentages extending from 53.6%, 60.7%, and 55% to 82.2%, correspondingly. Likewise, when assessed to the positive control tipranavir (88.6%), the inhibitory efficiency of compounds 6, 7, 14, and 18 versus the SARS-CoV2 Mpro provided high percentages of 80.4%, 73.1%, 81.4% and up to 84.5%, respectively. In silico studies were performed to investigate further the biological activity and the target compounds’ physical and chemical features, including molecular dynamic (MD) simulations, protein–ligand docking, ADME studies, and density functional theory (DFT) calculations. These inquiries demonstrated that this series of metabolically stable pyranopyrazoles and their annulated systems are effective human coronavirus inhibitors that inhibit the viral Mpro protein and may have emerged as a novel COVID-19 curative option.

A series of N-(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles was synthesised and screened for their potential to inhibit kinases and exhibit anticancer activity against primary patient-derived glioblastoma 2D cells and 3D neurospheres. A collection of 10 compounds was evaluated against glioma cell lines, with compound 4j exhibiting promising glioma growth inhibitory properties. Compound 4j was screened against 139 purified kinases and exhibited low micromolar activity against kinase AKT2/PKBβ. AKT signalling is one of the main oncogenic pathways in glioma and is often targeted for novel therapeutics. Indeed, AKT2 levels correlated with glioma malignancy and poorer patient survival. Compound 4j inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells and exhibited potent EC50 against glioblastoma cell lines. Although exhibiting potency against glioma cells, 4j exhibited significantly less cytotoxicity against non-cancerous cells even at fourfold–fivefold the concentration. Herein we establish a novel biochemical kinase inhibitory function for N-(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles and further report their anti-glioma activity in vitro for the first time. Anti-glioma pyrano[2,3-c]pyrazole 4j inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells. 4j also displayed PKBβ/AKT2 inhibitory activity. 4j is nontoxic towards non-cancerous cells. [ABSTRACT FROM AUTHOR]

An efficient, ZnO-NiO-Fe3O4 nano-composite catalyzed method has been developed for the ultrasonic irradiation synthesis of some 6-amino-3-methyl-4-aryl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile heterocycles in good to excellent yields. ZnO-NiO-Fe3O4 nanocomposite was characterized by XRD, FE-SEM, EDS, and DLS techniques. According to the XRD analysis, the sample consisted of three different phases: ZnO (hexagonal), NiO (cubic), and Fe3O4 (cubic). The average particle size of the sample is 68 nm. Supplemental data for this article is available online at [ABSTRACT FROM AUTHOR]

The SCMNPs@BPy-SO3H catalyst was prepared and characterized using Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetric Analysis (TGA), Vibrating Sample Magnetometry (VSM), Energy Dispersive X-ray Spectroscopy (EDX), X-ray Diffraction (XRD), and Scanning Electron Microscopy (SEM). Afterwards, its capability was efficiently used to promote the one-pot, three-component synthesis of pyrano[2,3-c]pyrazole and 2-amino-3-cyano-pyrano[3,2-c]chromen-5(4H)-one derivatives. The strategy resulted in the desired products with excellent yields and short reaction times. The SCMNPs@BPy-SO3H catalyst was readily recovered using a permanent magnetic field and it was reused in six runs with a slight decrease in catalytic activity. Copyright © 2020 BCREC Group. [ABSTRACT FROM AUTHOR]

Widespread resistance of Plasmodium falciparum to current artemisinin-based combination therapies necessitate the discovery of new medicines. Pharmacophoric hybridization has become an alternative for drug resistance that lowers the risk of drug–drug adverse interactions. In this study, we synthesized a new series of hybrids by covalently linking the scaffolds of pyrano[2,3-c]pyrazole with 4-aminoquinoline via an ethyl linker. All synthesized hybrid molecules were evaluated through in vitro screenings against chloroquine-resistant (K1) and -sensitive (3D7) P. falciparum strains, respectively. Data from in vitro assessments showed that hybrid 4b displayed significant antiplasmodial activities against the 3D7 strain (EC50 = 0.0130 ± 0.0002 μM) and the K1 strain (EC50 = 0.02 ± 0.01 μM), with low cytotoxic effect against Vero mammalian cells. The high selectivity index value on the 3D7 strain (SI > 1000) and the K1 strain (SI > 800) and the low resistance index value from compound 4b suggested that the pharmacological effects of this compound were due to selective inhibition on the 3D7 and K1 strains. Molecular docking analysis also showed that 4b recorded the highest binding energy on P. falciparum lactate dehydrogenase. Thus, P. falciparum lactate dehydrogenase is considered a potential molecular target for the synthesized compound.

A simple and efficient protocol is developed for the synthesis of dihydropyrano[2,3-c]pyrazole derivatives by a one pot, four component reaction of ethylacetoacetate, hydrazine hydrate, malanonitrile and various aldehydes in the presence of a catalytic amount of DABCO in aqueous medium. This method provides several advantages such as high yield, shorter reaction time, mild reaction condition, operational simplicity, easy work-up procedure with environment friendly nature and purification of products by non-chromatographic methods has been developed.

We describe a one-pot four component synthesis of pyrano[2,3-c]pyrazoles from hydrazine hydrate or phenyl hydrazine, ethyl acetoacetate, an aldehyde, and malononitrile in the presence of catalytic amounts of a caffeine as a green catalyst in water at 50 ºC. The present protocol offers the advantages of a clean reaction, a short reaction time, a high product yield, and an environmentally-friendly, easily-purified, and economically-available catalyst.

In this study, choline chloride/urea was used as a green deep eutectic solvent in the three-component reaction of hydrazine/phenylhydrazine, malononitrile, and aromatic aldehydes for synthesizing pyrazole derivatives, and in the four-component reaction of methyl/ethyl acetoacetate, hydrazine/phenylhydrazine, malononitrile, and aromatic aldehydes for synthesizing pyrano[2,3-c]pyrazole derivatives. Elemental analysis, 1 H, and 13 C NMR spectroscopy were used to confirm the structure of the synthesized pyrazole and pyrano[2,3-c] pyrazole derivatives. The antimicrobial effects of the synthesized pyrazole and pyrano[2,3-c] pyrazole derivatives were investigated. In antimicrobial tests, instructions from clinical and laboratory standards institutes were used. Antimicrobial study was done on pathogenic gram-positive and gram-negative species, and specialized aquatic strains and fungal species. Using choline chloride/urea, novel pyrazole derivatives and pyrano[2,3-c]pyrazole derivatives were synthesized, and other derivatives were synthesized with higher efficiency in less time than some previously reported methods. MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) obtained for derivatives were higher than some antibiotic drugs. Synthesis and reports of new derivatives of pyrazole and pyrano[2,3-c]pyrazole, and investigation and reports of their antimicrobial properties on gram-positive, gram-negative, and specialized aquatic and fungal species are among the novel and important findings of this study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Habeeb Naser, Thoulfikar A. Alamir, Al-Shukarji, Ahmed, Qassem, Kamal, Almeleebia, Alwaily, Hasan Kadhum, Alawadi and Alsalamy.)

The SARS-CoV-2 pandemic at the end of 2019 had major worldwide health and economic consequences. Until effective vaccination approaches were created, the healthcare sectors endured a shortage of operative treatments that might prevent the infection's spread. As a result, academia and the pharmaceutical industry prioritized the development of SARS-CoV2 antiviral medication. Pyranopyrazoles have been shown to play a prominent function in pharmaceutical chemistry and drug sighting because of their significant bioactive properties. We provide herein a novel sequence of pyranopyrazoles and their annulated systems whose antiviral efficacy and cytotoxicity were explored versus human coronavirus 229E (HCoV-229E) Vero-E6 cell lines as a model for the Coronaviridae family. Fifteen synthetic congeners pointed out miscellaneous antiviral efficacies against HCoV-229E with variable inhibition degrees. Compound 18 showed a high selectivity index (SI = 12.6) that established spectacular inhibitory capacity against human coronavirus 229E. Compounds 6 , 7 , and 14 exposed moderate efficacies. Compounds 6 , 7 , 14 , and 18 exhibited substantial antiviral action through the replication phase with reduction percentages extending from 53.6%, 60.7%, and 55% to 82.2%, correspondingly. Likewise, when assessed to the positive control tipranavir (88.6%), the inhibitory efficiency of compounds 6 , 7 , 14 , and 18 versus the SARS-CoV2 Mpro provided high percentages of 80.4%, 73.1%, 81.4% and up to 84.5%, respectively. In silico studies were performed to investigate further the biological activity and the target compounds' physical and chemical features, including molecular dynamic (MD) simulations, protein-ligand docking, ADME studies, and density functional theory (DFT) calculations. These inquiries demonstrated that this series of metabolically stable pyranopyrazoles and their annulated systems are effective human coronavirus inhibitors that inhibit the viral M pro protein and may have emerged as a novel COVID-19 curative option.

The application of yttrium iron garnet (YIG) superparamagnetic nanoparticles as a new recyclable and highly efficient heterogeneous magnetic catalyst for one-pot synthesis of pyrano[2,3-c]pyrazole derivatives under solvent-free conditions, as well as etherification and esterification reactions are described. The advantages of the proposed method include the lack of organic solvents, clean reaction, rapid removal of the catalyst, short reaction times, excellent yields, and recyclability of the catalyst. [ABSTRACT FROM AUTHOR]

In search of new generation of triazole based antifungal agents, synthesis of series of new 1,2,3-triazolyl pyrano[2,3-c]pyrazoles under ultrasonic irradiation using NaHCO3 has been reported. The bioevaluation results indicate that, the compounds 7c, 7d, 7e, 7f, and 7i displayed excellent antifungal activity with lower MIC ≤ 25 µg/mL. Most of the compounds from the series showed potent antioxidant activity with a lower IC50 value in the range 09.39 ± 0.42–14.97 ± 0.24 µg/mL, in comparison to butylated hydroxyl toluene (BHT). Molecular docking studies against potential target sterol 14α-demethylase (CYP51) was also performed and showed excellent binding affinity with the target enzyme. Moreover, in silico ADME study shows that the derivatives could serve as drug like molecules for further drug development in clinical research. [ABSTRACT FROM AUTHOR]

Abstract In the present study, a series of novel and biologically potent 6-amino-1-(2,4-dinitrophenyl)-4-phenyl-1,4-dihydropyrano [2,3-c]pyrazole-5-carbonitrile derivatives (5a-5u) have been synthesized through multicomponent reaction between various substituted aromatic aldehyde derivative (4a - 4u), 2, 4-dinitrophenyl hydrazine (1), ethyl acetoacetate (2) and malononitrile (3) in the presence of SnCl 2 as a prompt catalyst using both microwave irradiation method as well as conventional method. The structure of synthesized compounds were confirmed by various spectroscopic methods such as 1H NMR, 13C NMR, IR, Mass analysis and elemental analysis. All the synthesized compounds were subjected in vitro antibacterial, anti-tuberculosis screening and cytotoxicity MTT assay. In vitro biological study revealed that the synthesized compound 5a, 7a and 8a are showing good anti-bacterial and anti-tuberculosis activity. The in silico study of ADME pharmacokinetic properties were also predicted for synthesized compounds for checking their bioavailability. Furthermore, molecular docking study of synthesized compounds with enoyl-ACP reductase (oxidoreductase) was carry out to find out the binding affinity of compounds. Docking study demonstrated that compound 7b and 7a possessed superior binding affinity with target enzyme by strong hydrogen bonding. We have also carried out molecular dynamics simulation to check the stability of docked complex, conformational changes and primary molecular interaction. Graphical abstract Image 1 Highlights • Synthesis, characterization of targeted compounds. • Potent activity against TB H 37 Rv. • Molecular docking and Dynamics study. [ABSTRACT FROM AUTHOR]

3-Methyl-1H-pyrazol-5(4H)-one (1) was used as a template to develop new anticancer compounds and investigate their SAR. The ring modification of compound 1 occurred through its reaction with aromatic aldehydes and different reagents to afford the corresponding 6-oxopyrano[2,3-c]pyrazoles4a-c and their amino analogues 6-aminopyrano[2,3-c]pyrazoles6a-c, 8; the pyrazolopyrano[2,3-b]pyridines 10a-c and the chromenopyrano[2,3-c]pyrzolones13, 14. The reaction of compound 1 with thiourea and appropriate aromatic aldehydes afforded the pyrazolo[3,4-d]pyrimidine derivatives 17a-c. On the other hand, the pyrazolo[3,4-d]thiazole derivatives 22a-d were obtained via the reaction of 1 with sulpher and aryl isothiocyanates in presence of triethylamine. The reaction of compound 1 with phenylisothiocyanate followed by treatment with the a-halocarbonyl compounds 24a-c afforded the thiazole derivatives 25a-c. The synthesized products were evaluated for their cytotoxicity against cancer and normal cell lines. Most compounds showed significant anticancer activity without affecting the normal fibroblast cells. The toxicity of the mostpontent cytotoxic compounds was measured using Brine-Shrimp Lethality Assay.

A simple, green and efficient protocol for the one-pot four-component synthesis of pyrano[2,3-c]pyrazole derivatives produced from reaction between aryl aldehydes, ethyl acetoacetate, malononitrile and hydrazine hydrate in the presence of nano magnetic piperidinium benzene-1,3-disulfonate was synthesized in water at 60 °C. The Fe3O4@SiO2 nanoparticle-supported IL was designed and synthesized. The present process offers advantages such as clean reaction, short reaction time, good to excellent yield, easy purification and easy recoverable catalyst. [ABSTRACT FROM AUTHOR]

Abstract: A simple and efficient synthesis of 6‐amino‐5‐cyano‐4‐aryl‐1,4‐dihydropyrano[2, 3‐c]pyrazoles and 2‐amino‐3‐cyano‐4‐aryl‐7,7‐dimethyl‐5,6,7,8‐tetrahydrobenzo[b]pyrans has been developed that involves a four‐component reaction of aromatic aldehydes, malononitrile, hydrazine hydrate or phenyl hydrazine and 1,3‐dicarbonyl compounds using glycerol as both solvent and catalyst at ambient temperature. Several advantages have been achieved such as high yields, facile conducting reactants or working up products, high Eco Scale, atom economy and the absence of toxic or hazardous catalysts or solvents. [ABSTRACT FROM AUTHOR]

Synthesis of pyrimido[1,2-a]benzimidazole and pyrano[2,3-c]pyrazole derivatives were achieved using polyethylene glycol (PEG-400) as promoting reaction medium in water under catalyst-free conditions at reflux and room temperature, respectively. The structure of pyrimido[1,2-a]benzimidazole was confirmed using1H NMR,13C NMR, DEPT, and HMBC experiments. The promising points for the present methodology are efficiency, generality, high yield, short reaction time, cleaner reaction profile, ease of product isolation, simplicity, potential of recycling reaction medium, and finally agreement with green chemistry protocols. [ABSTRACT FROM PUBLISHER]

Pyrrolo[3,4-c]pyrazole-4,6(1H,5H)-dione, pyrano[2,3-c]pyrazole-5-carbonitrile, pyrano[2,3-d]4-imidazolines, pyrido[2,1-b]benzimidazole, pyrido[2,1-b][1,3]benzoxazole, pyrido[2,1-b][1,3]benzothiazole and pyrido[2,1-b]quinazoline were synthesised from antipyrine derivatives with appropriate reagents such as maleimides, malononitrile, ethyl cyanoacetate, benzimidazole-2-acetonitrile, benzothiazole-2-acetonitrile, benzoxazol-2-acetonitrile, benzoylacetonitrile and other reagents. The newly synthesised compounds were established by elemental analysis, spectral data, and alternative synthetic routes whenever possible.

• A series of new pyrano[2,3- c ]pyrazole and pyrazolo[4′,3′:5,6]pyrano[2,3- d ]pyrimidine derivatives were synthesized using facile green approach in excellent yields. • Compound M2 was isolated as an un expected novel compound. • The antimicrobial, antioxidant, and anti-cancer activities of the titled compounds were evaluated in vitro and most of the compounds manifested auspicious biological outcomes. • Compound M21 was the most promising anti-bacterial agent with potential binding affinity against the penicillin-binding protein. • Compound M5 was the most cytotoxic compound with potential binding affinity against CDK2 proteins. An eco-friendly approach was conducted for synthesizing pyrano[2,3- c ]pyrazoles M1 - M25 via a one-pot reaction of hydrazine hydrate 99%, ethyl acetoacetate or diethyl malonate, carbonyl group source, and active methylene compounds. Besides, pyrazolo[4′,3′:5,6]pyrano[2,3- d ]pyrimidines M26 - M31 was synthesized via intramolecular cyclization of M10 and M13. Thereafter, the antimicrobial, antioxidant, and anti-cancer activities of the titled compounds were evaluated utilizing an array of techniques. Fortunately, the vast majority of the compounds exhibited promising biological activities. Over and above, in silico study was employed to determine the expected mode of action of the synthesized compounds. M21 was the most promising anti-bacterial agent, while M5 was the most cytotoxic compound. Finally, DFT theoretical calculations were used to study the stability and structural parameters of the newly synthesized compounds. DFT calculations showed the energy gaps between the HOMO-LUMO with all the investigated compounds in a range of 4.04–5.66 eV allowing for easy exchange of electrons and the reactivity. [Display omitted] [ABSTRACT FROM AUTHOR]

A new, efficient, and environmentally benign protocol for the one-pot, four-component synthesis of dihydropyrano[2,3-c]pyrazoles by condensation of ethylacetoacetate, hydrazine hydrate, aromatic aldehyde, and malononitrile catalyzed by 3-methyl-1-sulfonic acid imidazolium chloride ([Msim]Cl) as an ecofriendly catalyst with high catalytic activity and reusability at 30°C under solvent-free conditions is reported. The reactions proceed to be completed within 5-15 min in 87-97% yield. [ABSTRACT FROM AUTHOR]

3-Methyl-1H-pyrazol-5(4H)-one (1) was used as a template to develop new anticancer compounds and investigate their SAR. The ring modification of compound 1 occurred through its reaction with aromatic aldehydes and various reagents to afford the corresponding 6-oxopyrano[2,3-c]pyrazoles 4a-c and their amino analogues 6-aminopyrano[2,3-c]pyrazoles 6a-c,8; the pyrazolopyrano[2,3-b]pyridines 10a-c and the chromenopyrano[2,3-c]pyrazolones 13,14. The reaction of 1 with thiourea and appropriate aromatic aldehydes afforded the pyrazolo[3,4-d]pyrimidine derivatives 17a-c. On the other hand, the pyrazolo[3,4-d]thiazole derivatives 22a-d were obtained via the reaction of 1 with sulfur and aryl isothiocyanates in the presence of triethylamine. The reaction of 1 with phenylisothiocyanate followed by treatment with the α-halocarbonyl compounds 24a-c afforded the thiazole derivatives 25a-c. The synthesized products were evaluated for their cytotoxicity against cancer and normal cell lines. Most compounds showed significant anticancer activity without affecting the normal fibroblast cells. The toxicity of the most pontent cytotoxic compounds was measured using Brine-Shrimp Lethality Assay. [ABSTRACT FROM AUTHOR]

• Wang-OSO 3 H was effective for the synthesis of pyrano[2,3- c ]pyrazole derivatives. • This sonochemical approach proceeded in pure water and catalyst was recyclable. • In silico / in vitro evaluation against SIRT1 identified 5i and 5l as promising hits. • in silico study indicated importance of H-bonding with ILE347 and ASP348. • Acceptable ADME properties were predicted for compound 5i and 5l. The pyrano[2,3- c ]pyrazole framework was explored for the design and synthesis of compounds as potential inhibitors of SIRT1. The feasibility of this strategy was reasoned by the unique structural features of this scaffold and the reported cytotoxicity of compounds containing this framework. The sonochemical synthesis of target compounds was accomplished by using the Wang resin (Wang-OSO 3 H) as a recoverable catalyst under eco-friendly conditions. Thus, the desired 4-substituted 6-amino-3-methyl-1,4-dihydropyrano[2,3- c ]pyrazole-5-carbonitrile derivatives were prepared via a 4-component reaction of β -ketoester, hydrazine, aldehyde and malononitrile in pure water in good yields. The recyclability of the catalyst was demonstrated successfully. All the synthesized compounds were initially assessed in silico against the targeted protein i.e. hSIRT1 that indicated compound 5i and 5l along with several other compounds as possible inhibitors. Both of these compounds participated in two vital H-bond interactions with the residue GLN345 and ASN346 in silico that was reflected in their estimated total energy. In vitro assessment of these pyrano[2,3- c ]pyrazoles against SIRT1 revealed encouraging inhibitory activities (> 50% inhibition) that was in agreement with the results of docking studies. Indeed, 5i and 5l were identified as the most active compounds in this series. The Structure-Activity-Relationship (SAR) study suggested important role of the C-4 aryl substituent along with the N-1 phenyl ring of the pyrano[2,3- c ]pyrazole moiety in the SIRT1 inhibitory activities of this class of compounds. Thus, a OH or Cl group at the p -position of the C-4 benzene ring together with the N-1 phenyl moiety appeared to be beneficial for activity. Overall, the initial design and then sonochemical synthesis followed by in silico as well as in vitro studies allowed identification of pyrano[2,3- c ]pyrazole based small molecules as potential inhibitors of SIRT1. [Display omitted] The design and sonochemical synthesis followed by in silico as well as in vitro studies allowed identification of pyrano[2,3- c ]pyrazole based small molecules as potential inhibitors of SIRT1 [ABSTRACT FROM AUTHOR]

• Synthesis of dihydropyrano[2,3-c]pyrazoles in high yields and short reaction times. • IRMOF-3/GO/CuFe 2 O 4 nanocomposite is introduced as a new and superior catalyst. • IRMOF-3/GO/CuFe 2 O 4 was identified using different spectroscopic analysis. • The heterogeneous catalyst can be easily recycled with a slightly decrease in its activity. In the present study, we reported a facile and cost-effective method for synthesizing magnetic copper ferrite nanoparticles supported on IRMOF-3/GO [IRMOF-3/GO/CuFe 2 O 4 ]. The prepared IRMOF-3/GO/CuFe 2 O 4 was completely characterized by various spectroscopic techniques such as Brunauer-Emmett-Teller (BET), scanning electron microscopy (SEM), X-ray diffraction (XRD), infrared spectroscopy (IR), thermogravimetric (TGA), energy-dispersive X-ray spectroscopy, and elemental meapping. The synthesized nanocatalyst demonstrated high catalytic activity in the synthesis of dihydropyrano[2,3-c]pyrazoles via a one-pot reaction of hydrazine hydrate, acetylene ester, aryl aldehydes, and malononitrile exposed to ultrasound irradiations. In comparison to formerly reported approaches, this protocol has various advantages including wide substrate compatibility, short reaction times, excellent yields, little catalyst loading, good reusability, and high efficiency. The catalyst was separated by simple filtration and after several rounds of reuse and recovery, the amount of activity in this catalytic system remained nearly constant. [ABSTRACT FROM AUTHOR]

An efficient, high-yielding, and rapid protocol has been developed for the synthesis of diversity-oriented 6-amino-2,4-dihydropyrano[2,3-c]pyrazol-5-carbonitriles derivatives via a four-component, one-pot cyclocondensation reaction of ethyl acetoacetate, hydrazine hydrate, aldehydes, and malononitrile using silica-supported tetramethylguanidine as a heterogeneous catalyst for the first time. The protocol proves to be efficient and environmentally benign in terms of very easy workup, good yields, and ease of recovery of catalyst. In addition, the present method is superior in terms of green media, the amount of catalyst, and reaction time. [ABSTRACT FROM PUBLISHER]

Abstract: We developed an efficient and simple one-pot synthesis of functionalized multi-substituted 2,4-dihydro-pyrano[2,3-c]pyrazole dicarboxylates from β-ketoesters, hydrazine, dimethyl acetylenedicarboxylate and malononitrile in EtOH. This four-component one-pot reaction carried out in the presence of DABCO catalyst showed advantages over a one-pot three-component method in its simple procedure, high yield and low toxicity. [Copyright &y& Elsevier]

Abstract: Cocamidopropyl betaine (CAPB) as a biodegradable surfactant produces a new worm-like micellar medium for rapid synthesis of dihydropyrano[2,3-c]pyrazoles via a four-component reaction of aldehydes, ethyl acetoacetate, malononitrile, and hydrazine hydrate at 50–60°C. This zwitterionic surfactant was superior to anionic, cationic, and nonionic alternatives for accessing high yields of pure products without the use of any organic solvent. While the reaction medium was reusable, simple isolation of products, mild reaction conditions, low loading of CAPB for critical micelle concentration and short reaction times are additional advantages of this green procedure. [Copyright &y& Elsevier]

Highlights: [•] Dihydro-pyrano[2,3-c]pyrazoles were synthesized with aromatic aldehydes obtained from lignin. [•] The synthesis of dihydro-pyrano[2,3-c]pyrazoles was carried out with microwave-assisted technology. [•] The syringyl substituted compounds exhibited very potent antioxidant activity. [•] Those compounds possessed low cytotoxicity. [•] Their structure–activity relationship (SAR) was studied. [•] It provided an effective approach for value-added application of lignin. [ABSTRACT FROM AUTHOR]

This review highlights the methods used for the synthesis of enaminonitriles of pyrano[2,3-c]pyrazole compounds. Their reactivity and synthetic importance were investigated. In this context, recent progress in the synthesis and use of enaminonitriles of pyrano[2,3-c]pyrazole as precursors for heterocyclic compounds is reviewed. The synthetic routes for preparation of enaminonitriles are based on multicomponent reactions including three- or four-component reactions. Enaminonitriles can be used as building blocks for carbocyclic five-, six-, and seven-membered heterocycles as well as fused heterocyclic compounds. The bibliography includes 94 references. [ABSTRACT FROM AUTHOR]

Highlights: [•] First four-component biocatalytic reaction in organic synthesis. [•] First lipase catalyzed synthesis of biologically important dihydropyrano[2,3-c]pyrazole core. [•] First catalytic application of lipase from Aspergillus niger in a multicomponent reaction. [•] Catalytic efficiency, recyclability, and effect of solvents were thoroughly studied. [•] Easy access of dihydropyrano[2,3-c]pyrazoles from less reactive aliphatic aldehydes and ketones. [Copyright &y& Elsevier]

Nano magnetic complex lanthanum strontium magnesium oxide LaSrMnO (LSMO) has been explored as an efficient and recyclable catalyst to effect the one-pot three-component condensation reactions between aromatic aldehydes, malononitrile and 5,5-dimethyl-cyclohexane-1,3-dione, or 3-methyl-1-phenyl-2-pyrazolin-5-one in EtOH under ultrasound irradiation conditions. 2-Amino-5-oxo-5,6,7,8-tetrahydro-4 H-chromenes and 1,4-dihydropyrano[2,3-c]pyrazol-5-yl cyanides were respectively synthesized from these reactions in high yields. This nano-catalyst can be easily recovered via magnetic concentration and reused without any significant drop in its catalytic activity. Graphical abstract: Magnetic LaSrMnO nanoparticles have been explored to efficiently catalyze the one-pot condensation of aromatic aldehydes, malononitrile and 5,5-dimethyl-cyclohexane-1,3-dione, or 3-methyl-1-phenyl-2-pyrazolin-5-one in EtOH under ultrasound-irradiation conditions. As a result, 2-Amino-5-oxo-5,6,7,8-tetrahydro-4 H-chromenes and 1,4-dihydropyrano[2,3-c]pyrazol-5-yl cyanides were produced respectively in excellent yields. High efficiency, easy workup, high yields, use of cost-effective and non toxic catalyst are the main merits of this method. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

One pot solvent-free synthetic method is developed for the synthesis of novel pyrano[2,3-c]pyrazole analogs. Cytotoxicity experiments conducted against a pair of cancerous, non-cancerous lung cell lines, and a cervical cell line is described. These compounds are selectively toxic against cancer cells and not normal cells. Molecular mechanism is established for the mode of DNA binding of these compounds using electrochemical and proton NMR methods. [ABSTRACT FROM AUTHOR]

Abstract: A green and efficient one-pot, four-component synthesis of methyl 6-amino-5-cyano-4-aryl-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylates in water is described. The method is catalyst-free, atom-economical, and does not involve tedious work-up or purification affording the target compounds in good yields. [Copyright &y& Elsevier]

A series of substituted pyrano[2,3-c]pyrazole derivatives were synthesized by a one-pot reaction of methyl 4-methyl-3-oxovalerate, phenylhydrazine, aromatic aldehyde, and malononitrile in ethanol with catalysis by triethylamine. The title compounds were obtained in good to excellent yields. A possible mechanism for this reaction was proposed. [ABSTRACT FROM PUBLISHER]

Abstract: The enantioselective tandem Michael addition–cyclization reaction between 3-methyl-2-pyrazolin-5-one and benzylidenemalononitriles was studied with modularly designed organocatalysts (MDOs) to yield 6-amino-5-cyanodihydropyrano[2,3-c]pyrazoles in high yields and moderate to good enantioselectivities. Most importantly, a new catalytic mode of the MDOs was established. Instead of being used as a nucleophile to form an enamine intermediate, the reaction center modules (amino acids) of the MDOs are now used as a Lewis base in this base-catalyzed reaction. Since there are more reactions catalyzed by Lewis bases than by the enamine mechanism, this finding greatly expands the scope of the MDOs in organic reactions. On the other hand, because the stereocontrolling modules (cinchona alkaloid derivatives) themselves may be used as Lewis base catalysts, this new method may also be viewed as an expeditious way for the modification of the reaction center of the cinchona alkaloid catalysts. [Copyright &y& Elsevier]

Abstract: A tetrabutylammonium hydrogen sulfate (TBA-HS) mediated procedure for one pot synthesis of novel benzopyran-annulated pyrano[2,3-c]pyrazoles via domino/Knoevenagel-hetero-Diels–Alder reaction has been demonstrated. [Copyright &y& Elsevier]

Abstract: Pyrrolo[3,4-c]pyrazole-4,6(1H,5H)-dione, pyrano[2,3-c]pyrazole-5-carbonitrile, pyrano[2,3-d]4-imidazolines, pyrido[2,1-b]benzimidazole, pyrido[2,1-b][1,3]benzoxazole, pyrido[2,1-b][1,3]benzothiazole and pyrido[2,1-b]quinazoline were synthesised from antipyrine derivatives with appropriate reagents such as maleimides, malononitrile, ethyl cyanoacetate, benzimidazole-2-acetonitrile, benzothiazole-2-acetonitrile, benzoxazol-2-acetonitrile, benzoylacetonitrile and other reagents. The newly synthesised compounds were established by elemental analysis, spectral data, and alternative synthetic routes whenever possible. [Copyright &y& Elsevier]

A simple and clean method tor producing 6-amino-4-aryl-5-cyano-3-methyl-1-pheny1-1,4-dihydropyrano[2,3-c]pyrazole from aromatic aldehyde, malono-nitrile and 3-methyl-1-phenyl-2-pyrazolin-5 one catalyzed by hexadecyltrimethylammonium bromide (HTMAB) in water is described. This method provides several advantages such as mild reaction conditions, simple workup procedure, and being environmentally friendly. [ABSTRACT FROM AUTHOR]

The diazolones 1a–c were reacted with triethylorthoformate and hippuric acid derivatives 3 to afford the novel pyrano[2,3-c]pyrazole derivatives 4. The latter undergoes ring cleavage by reaction with acetic acid-ammonium acetate and was transformed into the corresponding pyrazolo[3,4-b]pyridine derivatives 6. The reaction of 2-cyanomethyl-benzimidazole 7 with triethylorthoformate and hippuric acid derivatives 3 to give the pyrido[1,2-a]-benzimidazoles 10 has also been discussed. [ABSTRACT FROM AUTHOR]

Widespread resistance of Plasmodium falciparum to current artemisinin-based combination therapies necessitate the discovery of new medicines. Pharmacophoric hybridization has become an alternative for drug resistance that lowers the risk of drug–drug adverse interactions. In this study, we synthesized a new series of hybrids by covalently linking the scaffolds of pyrano[2,3-c]pyrazole with 4-aminoquinoline via an ethyl linker. All synthesized hybrid molecules were evaluated through in vitro screenings against chloroquine-resistant (K1) and -sensitive (3D7) P. falciparum strains, respectively. Data from in vitro assessments showed that hybrid 4b displayed significant antiplasmodial activities against the 3D7 strain (EC50 = 0.0130 ± 0.0002 μM) and the K1 strain (EC50 = 0.02 ± 0.01 μM), with low cytotoxic effect against Vero mammalian cells. The high selectivity index value on the 3D7 strain (SI > 1000) and the K1 strain (SI > 800) and the low resistance index value from compound 4b suggested that the pharmacological effects of this compound were due to selective inhibition on the 3D7 and K1 strains. Molecular docking analysis also showed that 4b recorded the highest binding energy on P. falciparum lactate dehydrogenase. Thus, P. falciparum lactate dehydrogenase is considered a potential molecular target for the synthesized compound. [ABSTRACT FROM AUTHOR]

[Display omitted] • An efficient, and environmentally friendly protocol has been developed for the synthesis of pyrano[2,3- c ]pyrazole. • The synthesis compounds were characterized using spectroscopic methods and DFT calculations. • The newly synthesized compounds were screened for their anti-inflammatory and antioxidant activity. Pyranopyrazole and its derivatives are classified to be a pharmacologically significant active scaffold for almost all modes of biological activities. In this work, An efficient, green, and facile three-component reaction for preparing pyrano[2,3- c ]pyrazole derivatives via the condensation reaction of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, ethyl acetoacetate, and malononitrile in the presence of ZnO Nanoparticle. The products are produced with high yields and in shorter reaction times. It also is mild, safe, green, and environmentally friendly. The geometric parameters such as dipole moment, bond length, dihedral angles, total energy, heat of formation, atomic charges and energies at a highly accurate for prepared compounds were computed by Denisty Functional Theory along with the B3LYP functional. The newly synthesized compounds were screened for their anti-inflammatory and antioxidant activity. Some of the tested compounds displayed promising activities. The newly prepared compounds were found to be potent towards the antioxidant activity. Results indicated that compounds 11 and 12 exhibited significant (p ≥ 0.05) in vitro total antioxidant activity as 44.93 ± 0.15 and 39.60 ± 0.10 U/ML, respectively higher than standard ascorbic acid (29.40 ± 0.62). [ABSTRACT FROM AUTHOR]

The reaction of acetoacetanilide ( 1) with the α-cyanocinnamonitrile derivatives 2 yielded the Michael adducts 4 which could be converted into the pyrano[2,3-c] pyrazole derivatives 5 via their reaction with hydrazine hydrate. Cyclisation of 4 afforded the cyanoaminopyrans 9 which could in turn be converted into the corresponding pyridine derivatives 10. The pyranopyrazoles 9 reacted with different activated nitrile derivatives ( 3a-c) to give the pyrano[2,3-c]pyridine derivatives 13, 16 and 19 respectively. The biological activity of the synthesised heterocyclic derivatives was investigated and discussed. [ABSTRACT FROM AUTHOR]

• A novel composite including graphene oxide nano-sheets and zinc oxide nanoparticles. • High catalytic activity of Fe 3 O 4 /GO@melamine-ZnO in multicomponent synthesis reactions. • Excellent intercalation of ZnO nanoparticles between 2D nano-sheets. • Well functionalization of graphene oxide nano-sheets with melamine as cross-linkers. • Super capacitive behavior of Fe 3 O 4 /GO@melamine-ZnO nanocomposite. Herein, an efficient versatile nanocomposite constructed of melamine-functionalized graphene oxide nano-sheets (GO@melamine), iron oxide nanoparticles (Fe 3 O 4 NPs), and zinc oxide (ZnO NPs) is presented. Moreover, two different applications have been studied for the prepared Fe 3 O 4 /GO@melamine-ZnO nanocomposite: First, as a heterogeneous catalyst for synthesis of pyrano[2,3-c]pyrazole derivatives in short reaction time (10 min) with high yields (96 %), second, as a substantial electrical supercapacitor with typical capacitive behavior, high resistance, and excellent electrode stability. From the catalytic aspect, high effectiveness, convenient isolation, and significant reusability could be referred as the distinguished properties for the produced nanocomposite. Turn-over number (TON) and turn-over frequency (TOF) values for the presented catalytic system have been estimated 17.2 × 106 and 1.71 × 106 min−1, respectively, which revealed high catalytic performance of this catalytic system. From electrochemical aspect, economic benefits for fabrication of the introduced nanocomposite containing low-cost materials, make it as a suitable electrical supercapacitor for industrial applications. [ABSTRACT FROM AUTHOR]