A Quick Access to Structurally Diverse Triazoloquinazoline Heterocycles via the MIL-101(Cr)-Catalyzed One-Pot Multi-Component Reaction of a Series of Benzaldehydes, Dimedone, and 1H-1,2,4-Triazol-3-Amine Under Green Conditions.

A one-pot multicomponent reaction of a variety of benzaldehydes, dimedone, and 1H-1,2,4-triazol-3-amine for the efficient synthesis of quinazolinone derivatives under green conditions is reported. It was proved that MIL-101(Cr) could carry out successfully this multicomponent strategy to afford target products in high yields. The scope and limitation of this catalytic system concerning the aldehyde substrates were explored. Different aldehydes could be conveniently delivered to quinazolinones at room temperature with short reaction times in an atom-economy way. Notably, MIL-101(Cr) was also characterized by different analytic methods such as FT-IR, SEM, and EDX. The outstanding benefits of this methodology are the availability of substrates, using green conditions, excellent functional group compatibility, and reusability of catalysts, therefore providing easy access to a range of products of interest in organic and medicinal chemistry.

Synthesis of some new distyrylbenzene derivatives using immobilized Pd on an NHC-functionalized MIL-101(Cr) catalyst: photophysical property evaluation, DFT and TD-DFT calculations.

In this study the catalytic application of a heterogeneous Pd-catalyst system based on metal organic framework [Pd-NHC-MIL-101(Cr)] was investigated in the synthesis of distyrylbenzene derivatives using the Heck reaction. The Pd-NHC-MIL-101(Cr) catalyst showed high efficiency in the synthesis of these π-conjugated materials and products were obtained in high yields with low Pd-contamination based on ICP analysis. The photophysical behaviors for some of the synthesized distyrylbenzene derivatives were evaluated. The DFT and TD-DFT methods were employed to determine the optimized molecular geometry, band gap energy, and the electronic absorption and emission wavelengths of the new synthesized donor-π-acceptor (D-π-A) molecules in the gas phase and in various solvents using the chemical model B3LYP/6-31+G(d,p) level of theory.

Synthesis of new curcumin-based aminocarbonitrile derivatives incorporating 4H-pyran and 1,4-dihydropyridine heterocycles.

A multicomponent reaction containing curcumin, aldehydes, malononitrile and amine was developed for the one-pot synthesis of a novel library of 4H-pyran and 1,4-dihyropyridin heterocycles incorporating curcumin moiety. The products were obtained in the presence of p-toluenesulfonic acid as catalyst in ethanol as solvent in good to excellent yields.

Synthesis of new curcumin derivatives as influential antidiabetic α-glucosidase and α-amylase inhibitors with anti-oxidant activity.

In this study, a new class of curcumin derivatives was synthesized using a multicomponent reaction containing curcumin, aldehydes, and malononitrile. This new protocol afforded a novel class of 4H-pyran heterocycles incorporating curcumin moiety. The products were obtained in the presence of p-toluenesulfonic acid (PTSA) as a catalyst in ethanol solvent in good to excellent yields. The synthetic compounds indicated a notable inhibitory activity against α-glucosidase (α-Gls) and revealed a weak inhibitory property against α-amylase (α-Amy). Also, these synthetic compounds indicated significant antioxidant activity. The new curcumin derivatives were also discovered to display no significant effect against the growth of two bacterial microflora in the human intestine. A molecular docking study was done to realize the binding interaction of the synthetic curcumin derivatives with the α-Gls enzyme. The results of our study introduced new synthetic curcumin derivatives as potential antidiabetic drugs.

The synthesis and biological evaluation of nucleobases/tetrazole hybrid compounds: A new class of phosphodiesterase type 3 (PDE3) inhibitors.

Spired by the chemical structure of Cilostazol, a selective phosphodiesterase 3A (PDE3A) inhibitor, several novel hybrid compounds of nucleobases (uracil, 6-azauracil, 2-thiuracil, adenine, guanine, theophylline and theobromine) and tetrazole were designed and successfully synthesized and their inhibitory effects on PDE3A as well as their cytotoxicity on HeLa and MCF-7 cancerous cell lines were studied. Obtained results show the linear correlation between the inhibitory effect of synthesized compounds and their cytotoxicity. In some cases, the PDE3A inhibitory effects of synthesized compounds are higher than the Cilostazol. Besides, compared to a standard anticancer drug methotrexate, some of the synthesized compounds showed the higher cytotoxicity against the HeLa and MCF-7 cancerous cell lines.

The assessment of antidiabetic properties of novel synthetic curcumin analogues: α-amylase and α-glucosidase as the target enzymes.

Diabetes mellitus is a metabolic disorder characterized by high blood glucose levels and instability in carbohydrate metabolism. For treating diabetes, one important therapeutic approach is reducing the postprandial hyperglycemia which can be managed by delaying the absorption of glucose through inhibition of the carbohydrate-hydrolyzing enzymes, α-amylase (α-Amy) and α-glucosidase (α-Gls) in the digestive tract. In this work, a new class of curcumin derivatives incorporating pyrano[2,3-d]pyrimidine heterocycles was synthesized using a multicomponent reaction between curcumin, aldehydes, and barbituric acid. Using UV-Vis spectroscopic method, the synthetic compounds were assessed for their inhibitory properties against α-Amy and α-Gls enzymes. Also, the antioxidant potential of these compounds was measured spectroscopically and compared with Trolox which is known as a gold standard to measure antioxidant capacity. The results of present study suggest that the curcumin derivatives were able to efficiently inhibit both yeast and mammalian α-Gls. In comparison with the antidiabetic medicine acarbose, the synthetic curcumin derivatives were also capable to inhibit more effectively the yeast α-Gls. The partial inhibitory effects of these compounds against pancreatic α-Amy were also important in the terms of avoiding development of the possible gastrointestinal side effects. Moreover, some of the curcumin derivatives indicated stronger antioxidant activity than Trolox. Overall, these synthetic curcumin analogues might be considered as novel molecular templates for development of efficient antidiabetic compounds with promising inhibitory activities against α-Amy and α-Gls enzymes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-020-00685-z.

Microwave-accelerated diastereoselective catalyst-free one-pot four-component synthesis of 2-(N-carbamoylacetamide)-substituted 2,3-dihydrothiophenes in glycerol.

In the current study, glycerol was successfully employed as a nonvolatile, non-toxic, non-flammable, biodegradable, very cheap, easily accessible, and efficient reaction medium for the microwave-enhanced diastereoselective synthesis of 2-(N-carbamoylacetamide)-substituted 2,3-dihydrothiophenes via a catalyst-free one-pot four-component reaction. A versatile range of starting materials were used, and diverse products were obtained in good to excellent yields and very short reaction times. Moreover, the reaction medium was recovered and reused several times without any loss of the efficiency.

Highly Efficient, One Pot, Solvent and Catalyst, Free Synthesis of Novel Quinazoline Derivatives under Ultrasonic Irradiation and Their Vasorelaxant Activity Isolated Thoracic Aorta of Rat.

New quinazoline derivatives were prepared by one pot reaction of anthranilic acid, acetic anhydride and primary amines, under ultrasonic irradiation. As a result, Ultrasonic irradiation has led to affordable, clean synthesis of a variety of target compounds in much higher yields, than traditional methods. This method has numerous advantages: such as higher yields, shorter reactions time, and easier work-up. Several structural classes among these compounds were identified to have vasorelaxant activity. In this respect, all of the newly synthesized quinazolinone derivatives displayed vasorelaxant properties on the isolated thoracic rat aorta. The IC50 of compounds 2a (-6.00 ± 0.55), 2g (-7.31 ± 0.94), 2n (-7.15 ± 0.81) and 2p (-7.77 ± 0.31) was comparable to that seen in the Acetylcholine (-7.13 ± 0.14). The structures of the newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR, mass spectral studies, elemental analysis, and melting point.

Correction to "Synthesis and Antioxidant Activity Evaluation of Some Novel Aminocarbonitrile Derivatives Incorporating Carbohydrate Moieties".

[This corrects the article DOI: 10.1021/acsomega.8b01124.].

Amino acids and peptides as reactants in multicomponent reactions: modification of peptides with heterocycle backbones through combinatorial chemistry.

In this study, amino acids and peptides were used as reactants in a Hantzsch multicomponent reaction in order to synthesize new structurally diverse molecules containing these synthons. As well, an applicable strategy for modification of these natural molecules with heterocycle backbones such as pyrimidine, xanthene and acridine is introduced. Using this method, a set of new amino acid- and peptide-functionalized heterocycles were synthesized in good to excellent yields under mild conditions. Furthermore, carbohydrates were used as substrates in the synthesis of some derivatives. Overall, this methodology allows the possibility of synthesis of large numbers of natural product-based libraries, using amino acids, peptides and carbohydrates through combinatorial chemistry.

Metal-Organic Framework MIL-101(Cr) as an Efficient Heterogeneous Catalyst for Clean Synthesis of Benzoazoles.

A metal-organic framework [MIL-101(Cr)] was used as an efficient heterogeneous catalyst in the synthesis of benzoazoles (benzimidazole, benzothiazole, and benzoxazole), and quantitative conversion of products were obtained under optimized reaction conditions. The catalyst could be simply extracted from the reaction mixture, providing an efficient and clean synthetic methodology for the synthesis of benzoazoles. The MIL-101(Cr) catalyst could be reused without a remarkable decrease in its catalytic efficiency.

Synthesis and Antioxidant Activity Evaluation of Some Novel Aminocarbonitrile Derivatives Incorporating Carbohydrate Moieties.

In this study, a multicomponent reaction involving carbohydrates, ß-dicarbonyl compounds, and malononitrile was disclosed to synthesize a new class of polyhydroxy compounds incorporating pyrano[2,3-d]pyrimidine, pyrido[2,3-d]pyrimidine and chromene heterocycles under mild conditions. For the synthesis of this class of compounds, glucose, galactose, arabinose, maltose, and lactose were used as aldehyde component in the reaction with barbituric acid and malononitrile to produce pyrano[2,3-d]pyrimidine derivatives. By use of 1,3-cyclohexanedione instead of barbituric acid, chromene derivatives incorporating carbohydrate moieties were obtained. Also, the four-component condensation reaction between d-glucosamine, aldehyde, malononitrile, and barbituric acid was efficiently provided polyhydroxy-substituted pyrido[2,3-d]pyrimidine derivatives. This new combinatorial approach gave a range of carbohydrate-derived heterocycles in good to excellent yields with high potential biological applications. The antioxidant activities were evaluated using 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) antioxidant measuring system, and the data were expressed as Trolox equivalent antioxidant capacity. All of these compounds display significant antioxidant activity. The maximum and minimum antioxidant activities were observed for 4j and 6b, respectively. Our results indicated encouraging perspectives for the improvement and usage of this type of synthetic compounds, indicating significant levels of antioxidant activity.

Transition metal-free N-fluoroalkylation of amines using cyanurate activated fluoroalcohols.

A novel and highly efficient method for N-fluoroalkylation of amines using 2,4,6-tris(fluoroalkoxy)-1,3,5-triazines was developed. This simple approach allowed the N-fluoroalkylation of amines under fast, mild and efficient reaction conditions, without using a transition metal as a catalyst.

Protecting group-free radical decarboxylation of bile acids: Synthesis of novel steroidal substituted maleic anhydrides and maleimides and evaluation of their cytotoxicity on C6 rat glioma cells.

We report the first Barton radical decarboxylation of unprotected bile acids via in situ irradiation of their thiohydroxamic esters in the presence of citraconic anhydride and citracoimide, leading to the synthesis a series of steroidal maleic anhydrides and maleimides as novel hybrid bile acids. The cytotoxic activities were evaluated on C6 rat glioma cells.

L-cysteine functionalized magnetic nanoparticles (LCMNP): a novel magnetically separable organocatalyst for one-pot synthesis of 2-amino-4H-chromene-3-carbonitriles in water.

In this study, L-cysteine was chemically grafted to magnetic nanoparticles in order to prepare a reusable magnetic material incorporating an amino acid moiety. For this purpose, silica-coated magnetic nanoparticles (Fe3O4@SiO2) were reacted with trimethoxy(vinyl)silane to produce vinyl-functionalized magnetic nanoparticles (VMNP). Reaction of a VMNP substrate with L-cysteine in the presence of azobisisobutyronitrile (AIBN) resulted in the production of L-cysteine-functionalized magnetic nanoparticles (LCMNP). The LCMNP material was characterized using different microscopy and spectroscopy techniques such as FT-IR, XRD, TEM, SEM, EDX, VSM, and elemental analysis. Also, LCMNP was analyzed by thermogravimetric analysis (TGA) in order to determine its thermal behavior. The applicability of the LCMNP material was evaluated in a three-component coupling reaction between a nucleophile, salicylaldehyde and malononitrile as the catalyst for one-pot synthesis of 2-amino-4H-chromene-3-carbonitrile derivatives. The catalyst system showed high catalytic activity in this process and target products were obtained in high isolated yields in water as a green solvent. The LCMNP catalyst was reusable in this reaction at least 7 times with no significant decrease in its catalytic activity.

Synthesis of novel poly-hydroxyl functionalized acridine derivatives as inhibitors of α-Glucosidase and α-Amylase.

In this study a novel series of poly-hydroxyl functionalized acridine derivatives (L1-L9) was synthesized and their inhibitory activities against α-Glucosidase (α-Gls) and α-Amylase (α-Amy) were evaluated, spectroscopically. The synthetic compounds consist of three different substructures, including a 4-(4-aminophenoxy) phenyl group (R3), an acridine moiety (R2) and a poly-hydroxy chain (R1). The results indicate that among the synthetic compounds, L5 with a chromeno[3',4':5,6]pyrido[2,3-d]pyrimidine moiety demonstrates the highest inhibitory activity against both yeast and rat α-Gls enzymes. Also, L2 with the thioxo-pyrido[2,3-d:6,5-d'] dipyrimidine moiety plays an important role in the inhibition of yeast α-Gls. In addition, the results may suggest a significant role for the nature of sugar moiety of the synthetic compounds in their inhibitory action against α-Gls. Moreover, in comparison with Acarbose, which is a widely used anti-diabetic drug, these compounds show negligible inhibitory activity against pancreatic α-Amy, which is important in the term of their reduced susceptibility for possible development of the intestinal disturbance side effects. Results of this study may suggest these synthetic compounds as novel molecular templates for construction of potentially anti-diabetic drugs with the ability for more convenient management of postprandial hyperglycemia.

Novel curcumin-based pyrano[2,3-d]pyrimidine anti-oxidant inhibitors for α-amylase and α-glucosidase: Implications for their pleiotropic effects against diabetes complications.

Curcumin (bis-α,ß-unsaturated ß-diketone), the chief constituent of turmeric plant (Curcuma longa), plays significant role in prevention of various diseases including diabetes. The research objective in the current study was to synthesize novel anti-diabetic curcumin derivatives with inhibitory properties against α-amylase (α-Amy) and α-glucosidase (α-Gls), as these two carbohydrate-hydrolysing enzymes are known to be important molecular targets for attenuation of postprandial hyperglycemia. The curcumin-based pyrano[2,3-d]pyrimidine derivatives were synthesized in the presence of curcumin, barbituric acids and aldehydes, using a multi-component reaction (MCR). Also, their inhibitory properties against α-Amy and α-Gls were evaluated spectroscopically. The curcumin-derived compounds with two invariant substructures (curcumin-based subunit and barbituric acid moiety) and one variable aryl (Ar) group demonstrated inhibitory action against α-Amy and α-Gls. Moreover, the synthetic compounds revealed prominent antioxidant activities, when examined by a 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) decolorization assay system. Overall, these antioxidant inhibitors are potentially important anti-diabetic drugs, not only to restore euglysemic condition, but also to limit activity of the major reactive oxygen species (ROS) producing pathways in diabetic patients.

Carbohydrates as a reagent in multicomponent reactions: one-pot access to a new library of hydrophilic substituted pyrimidine-fused heterocycles.

In this study a multicomponent reaction involving carbohydrate derivatives as the main component in order to prepare a new library of polyhydroxy compounds incorporating pyrimidine-fused heterocycles (PFHs) is introduced. A set of polyhydroxy functionalized PFHs were synthesized using multicomponent reactions of sugar (glucose, galactose, arabinose and lactose), barbituric acid and amines. Also, the three-component condensation reaction between D-glucosamine, aldehyde, and barbituric acid efficiently provided polyhydroxy substituted PFH derivatives in a one-pot reaction under mild and green conditions. These new one-pot reactions gave a range of polyhydroxy substituted PFHs in good to excellent yield.

Synthesis of α-aminonitriles with benzimidazolic and theophyllinic backbones using the Strecker reaction.

An example of the application of the Strecker reaction in the synthesis of a new class of α-aminonitriles with benzimidazole and theophylline backbones has been developed. For the synthesis of these compounds, first 4-hydroxybenzaldehyde was reacted with 1,3- and 1,5-dibromides/epibromohydrin to produce the corresponding bromo-substituted aldehydes. Then, benzimidazole/theophylline was reacted with the latter to generate the related benzimidazolic/theophyllinic aldehydes. Finally, the Strecker reactions of the synthetic benzimidazolic and theophyllinic aldehydes with different amines afforded the target products.

Binding study of novel anti-diabetic pyrimidine fused heterocycles to ß-lactoglobulin as a carrier protein.

Bovine milk ß-lactoglobulin (ß-LG) demonstrates significant resistance against both gastric- and simulated duodenal digestions. Therefore, it seems a realistic protein candidate for safe delivery and protection of particularly pH sensitive drugs in stomach. Recently, pyrimidine fused heterocycles (PFHs) revealed inhibitory properties against α-glucosidase (α-Gls) which is an important target enzyme for those drugs playing significant role in treatment of type-II diabetes and HIV/AIDS infection. The delivery of these compounds to small intestine where the enzyme plays its biological function is of great importance. Therefore, in this work the interaction of PFH compounds with ß-LG, as a carrier protein has been investigated. Fluorescence, circular dichroism (CD) and UV-vis spectroscopic studies were used to examine the binding parameters and binding modes of the interaction. Moreover, the effects of PFH complexation on the secondary structures of ß-LG were studied. All of these compounds significantly quenched the fluorescence intensity of ß-LG due to a ground state complex formation. The binding and thermodynamic parameters were calculated. While hydrophobic interactions were proved to play significant role in the interaction of L1, L2 and L3, hydrogen bonding was shown to be important in the complexation of L4. The secondary structures of ß-LG were preserved upon interaction of these synthetic compounds. Based on the achieved results, these potentially therapeutic agents can significantly bind to ß-LG. Consequently, this protein might be useful for delivery of PFH compounds to small intestine where representing their potential ability to inhibit α-Gls and to reduce the postprandial hyperglycemia in diabetic patients.