2-substituted Derivatives Research Articles

Metal-Free Synthesis of 2-Substituted Quinazolines via Green Oxidation of o-Aminobenzylamines: Practical Construction of N-Containing Heterocycles Based on a Salicylic Acid-Catalyzed Oxidation System.

Conventional quinazoline synthesis methods involve a highly multistep reaction, and often require excess amounts of substrate to control the product selectivity, leading to significant resource wastage. Hence, in this study, from the viewpoint of green chemistry, we developed a novel metal-free synthetic method for 2-substituted quinazoline derivatives by the 4,6-dihydroxysalicylic acid-catalyzed oxidative condensation of o-aminobenzylamines and benzylamines using atmospheric oxygen. In this system, the use of a catalytic amount of BF3‧Et2O (10 mol%) as a Lewis acid successfully led to the efficient oxidative condensation and intramolecular cyclization of these amines, followed by aromatization to afford the corresponding 2-arylquinazolines in up to 81% yield with excellent atom economy and environmental factor. Furthermore, to expand this green oxidation method to gram-scale synthesis, we investigated the development of an oxidation process using salicylic acid itself as an organocatalyst, and established a method for the practical green synthesis of a series of nitrogen-containing heterocycles. We expect that the findings will contribute to the development of practical synthesis methods for pharmaceutical manufacturing and industrial applications, along with further advancements in green chemistry.

5-Substituted 3, 3′, 4′, 7-tetramethoxyflavonoids – A novel class of potent DNA triplex specific binding ligands

Herein, we present a class of potent triplex DNA binding ligands derived from the natural product quercetin, which is the first of its kind that has ever been reported in the literature. The binding of 5-substituted quercetin derivatives (3, 3′, 4′, 7-tetramethoxyflavonoids) to triplex and duplex DNA was investigated using several biophysical tools, including thermal denaturation monitored by UV, circular dichroism, differential scanning calorimetry, and isothermal titration calorimetry. Experimental data reveal that several 5-substituted 3, 3′, 4′, 7-tetramethoxyflavonoids have remarkable effects on binding to DNA triple helices, and they do not influence the double-helical DNA structures. A few derivatives such as compounds 5 and 7 have comparable (if not better) binding affinities to neomycin, a well-known DNA triplex binding ligand, under the same conditions. The amino-containing side chains at the 5-position of 3, 3′, 4′, 7-tetramethoxyflavonoids are crucial for the observed binding affinity and specificity.

Chiral Calcium Phosphate Catalyzed Enantioselective Synthesis of All-Carbon Quaternary Center by Friedel–Crafts Alkylation Reaction of Pyrroles and Trifluoromethylated Nitrostyrenes

AbstractA chiral calcium phosphate-catalyzed enantioselective Friedel–Crafts alkylation reaction of pyrroles and α-trifluoromethyl-β-nitrostyrenes has been developed. Pyrroles bearing an all-carbon quaternary center at 2-position were obtained with high to excellent enantioselectivity. Use of 4,7-dihydroindole as a nucleophile and subsequent oxidation resulted in the formation a 2-substituted indole derivative with excellent enantioselectivity. A 3,4-dihydropyrrolo[1,2-c]pyrimidine derivative was successfully synthesized by reduction followed by benzoylation of the product without loss of enantioselectivity. Application to a 1 mmol scale reaction was successfully achieved.

New Analogues of Uridine as Possible Anti-Viral Agents Specific to SARS-CoV-2

The development of specific drugs against SARS-CoV-2 infection is a major challenge facing global science and healthcare. Despite numerous attempts, there are still no truly effective drugs. Currently, the main approach in the creation of drugs against COVID-19 is repurposing, i.e., re-profiling existing drugs approved for medical use, for example, the use of a drug for the treatment of Ebola-Remdesivir, and the use of a drug for the treatment of influenza-Favipiravir. However, it is already obvious that these drugs are not specific enough nor effective enough. Another promising approach is the creation of new molecules, but it should be noted immediately that implementation requires much more time and costs. However, the search for new SARS-CoV-2 specific antiviral agents continues. The aim of our work was the creation of new 5-substituted uridine derivatives as potential inhibitors of coronavirus RNA-dependent RNA polymerase. The substances were obtained in high yields by the Suzuki-Miyaura reaction and characterized using modern physicochemical methods. However, testing of their antiviral activity against SARS-CoV-2 did not reveal a significant inhibitory effect.

Synthesis and DFT Investigation of New Low-Melting Supramolecular Schiff Base Ionic Liquid Crystals

Supramolecular, low-melting (near or below 0.0 °C) ionic liquid crystals with two rings of Schiff bases were prepared and studied. The Schiff bases were synthesized using 4-substituted aniline derivatives and 4-pyridine carbaldehyde and then mixed in equimolar amounts with linear 1-bromoalkanes of different chain lengths, namely C6, C8, and C14. The mesomorphic behavior and thermal properties of the compounds were determined by polarized optical microscopy (POM) and differential scanning calorimetry (DSC). Only the ionic liquids analogous with 1-bromotetradecane exhibit mesomorphic behavior. All, except the smectic A (SmA) monomorphic fluorine-substituted complex, show dimorphic enantiotropic mesophases, namely SmA followed by nematic (N) mesophases depending on the temperature rise. The DSC and POM results for the induced mesophases were then treated with density functional theory calculations (DFT). The results showed that both the polarity of the polar groups and the length of the alkyl groups strongly influence the mesomorphic properties of the ionic liquids.

Potential Anticancer Agents against Melanoma Cells Based on an As-Synthesized Thiosemicarbazide Derivative.

In this paper, thiosemicarbazide derivatives were synthesized as potential anticancer agents. X-ray investigations for 1-(2,4-dichlorophenoxy)acetyl-4-(2-fluorophenyl) thiosemicarbazide, 1-(2,4-dichlorophenoxy)acetyl-4-(4-metylothiophenyl)thiosemicarbazide and 1-(2,4-di chlorophenoxy)acetyl-4-(4-iodophenyl)thiosemicarbazide were carried out in order to confirm the synthesis pathways, identify their tautomeric forms, analyze the conformational preferences of molecules, and identify intra- and intermolecular interactions in the crystalline state. TLC and RP-HPLC analyses were used to determine lipophilicity. The lipophilicity analysis revealed that the 4-substituted halogen derivatives of thiosemicarbazides showed greater lipophilicity compared with 2-substituted derivatives. The optimal range of lipophilicity for biologically active compounds logkw is between 4.14 and 4.78. However, as the analysis showed, it is not a decisive parameter. The cytotoxicity of the new compounds was evaluated against both the G-361 and BJ cell lines. Cytotoxicity analyses and cell-cycle and cell apoptosis assays were performed. The MTT test demonstrated that three compounds were cytotoxic to melanoma cells and not toxic to normal fibroblasts in the concentration range used. The cell cycle analysis showed that the compounds had no significant effect on the cell cycle inhibition. An extensive gene expression analysis additionally revealed that all compounds tested downregulated the expression of dihydroorotate dehydrogenase (DHODH). DHODH is a mitochondrial enzyme involved in the de novo synthesis of pyrimidines. Due to the rapid rate of cancer cell proliferation and the increased demand for nucleotide synthesis, it has become a potential therapeutic target.

Investigation of Fe3O4@boehmite NPs as efficient and magnetically recoverable nanocatalyst in the homoselective synthesis of tetrazoles.

Magnetic boehmite nanoparticles (Fe3O4@boehmite NPs) were synthesized from a hybrid of boehmite and Fe3O4 nanoparticles. At first, boehmite nanoparticles (aluminum oxide hydroxide) were prepared via a simple procedure in water using commercially available materials such as sodium hydroxide and aluminum nitrate. Then, these nanoparticles were magnetized using Fe3O4 NPs in a basic solution of FeCl2·4H2O and FeCl3·6H2O. Fe3O4@boehmite NPs have advantages of both boehmite nanoparticles and Fe3O4 magnetic materials. Magnetic boehmite nanoparticles have been characterized by various techniques such as TEM, SEM, EDS, WDX, ICP, FT-IR, Raman, XRD and VSM. SEM and TEM images confirmed that particles size are less than 50 nm in diameter with a cubic orthorhombic structure. Then, Fe3O4@boehmite NPs were applied as a homoselective, highly efficient, cheap, biocompatibility, heterogeneous and magnetically recoverable nanocatalyst in the synthesis of 5-substituted 1H-tetrazole derivatives. Fe3O4@boehmite NPs can be recycled for several runs in the synthesis of tetrazoles. Also, all tetrazoles were isolated in high yields, which reveals high activity of Fe3O4@boehmite NPs in the synthesis of tetrazole derivatives. Fe3O4@boehmite NPs shows a good homoselectivity in synthesis of 5-substituted 1H-tetrazole derivatives.

Apoptosis induction in HeLa cervical cancer cell line by steroidal 16,17-seco-16,17a-dinitriles

Steroids are good candidates for drug development, thanks to their low general toxicity and possibility for structure modifications connected with change of their activity. Several 16,17-secoandrost-4-ene-16,17a-dinitrile compounds were synthesized and screened for anticancer effect previously, including 6-oxo and 6-hydroxyimino compounds. This research is continued with the attempts for different synthetic strategy and evaluation of anticancer effect mechanism. Synthesis of 3-hydroxyimino compounds was successful, but inseparable mix of isomers was excluded from biological tests. Tested secodinitriles expressed cytotoxic effect on HeLa cervix cancer cells as a model system, with submicromolar to molar IC50 values, where 6-substituted derivatives were more effective. After 72 h treatment with equitoxic concentrations equal IC50 values of test compounds the mechanism of this effect was studied using flow cytometry and specific fluorescent dyes. Modest change in both G0/G1 and G2/M resting phases and change in mitochondrial membrane potential were noticed, while the most pronounced effect was apoptosis induction. Total apoptosis was in range 50.72?58.31 % in all cell samples treated with secodinitriles, compared to 7.44 % in control samples. Total percent of dead cells, including both apoptotic and necrotic, ranged from 55.24 to 65.34 %, compared to 10.68 % in control. Selectivity towards cancer cells is very important feature of these compounds indicating their potential use as lead compounds in the drug development for the treatment of cancers of steroid hormone-dependent tissues.

1,7/8-Substituted isoquinoline derivatives: position isomerism caused by HIO3-induced dehydrogenation and solid-state fluorescence stimulus-responsive properties

1,7/8-Substituted isoquinolines with solid-state fluorescence stimulus-responsive properties are obtained from HIO3-induced dehydrogenation of 7,8-dihydroisoquinolines.

A Schiff base complex of lanthanum on modified MCM-41 as a reusable nanocatalyst in the homoselective synthesis of 5-substituted 1H-tetrazoles.

In this work, mesoporous MCM-41 was modified by a new Schiff-base formed from the condensation of triethylenetatramine and 5-bromosalicylaldehyde. Then, it was used for the stabilization of lanthanum metal (La-Schiff base@MCM-41) as a homoselective, reusable, efficient and biocompatible catalyst in the synthesis of 5-substituted 1H-tetrazole derivatives. The synthesized tetrazoles were characterized using 1H NMR and FT-IR spectroscopy and methods to measure their physical properties. La-Schiff base@MCM-41 was characterized by using various techniques such as ICP, CHN, XRD, TGA, BET, FT-IR spectroscopy, SEM, EDS and WDX. This catalyst has good stability and a heterogeneous nature, enabling it to be easily recovered and reused several times without significant loss in catalytic activity. This present strategy has important advantages such as utilizing PEG as a green solvent, short reaction times, excellent yields, easy recycling of the catalyst and pure separation of the products. The recovered La-Schiff base@MCM-41 catalyst was characterized by using FT-IR spectroscopy, SEM and AAS.

Synthesis and study of the effect of 3-substituted chromone derivatives on changes in the activity of mitochondrial complex III under experimental cerebral ischemia

Synthesis and study of the effect of 3-substituted chromone derivatives on changes in the activity of mitochondrial complex III under experimental cerebral ischemia

Synthesis of new 3-substituted quinolone derivatives with benzene sulfonamide group using hydrazine linker with their docking and antibacterial studies in vitro

Quinolones are among the prominent class of broad-spectrum antibiotics. In this work, a series of 1,4-dihydro-4-oxo-3-[3-{benzenesulfon}-2-hydrazino-1-oxo-]quinoline derivatives 6a-e were synthesized and tested for their antibacterial efficacy in vitro. Compounds 6a-e were characterized by NMR (1H,13C), HRMS and IR analysis. All these compounds confirmed bactericidal activity against tested bacterial strains. The MIC data have shown that compounds 6e (MIC = 7.5 mg/mL) displayed better activity against Staphylococcus aureus, Escherichia coli (ETEC) and Pseudomonas aeruginosa. Compounds 6b-e (MIC = 7.5 mg/mL) have similar activity as Norfloxacin against E. coli. Molecular docking studies was also conducted to explore binding interactions of our compounds at the active sites of the GyrB subunit of E. coli K-12.

Design and Synthesis of Novel Non-Peripheral Tetrasubstituted Phthalocyanines Bearing Dichlorophenylthio Groups and Comparison of Their Biological Properties with Peripheral Tetra Substituted Derivatives

Design and Synthesis of Novel Non-Peripheral Tetrasubstituted Phthalocyanines Bearing Dichlorophenylthio Groups and Comparison of Their Biological Properties with Peripheral Tetra Substituted Derivatives

Dual Gold/Silver Catalysis: Indolizines from 2-Substituted Pyridine Derivatives via a Tandem C(sp3)-H Alkynylation/Iminoauration.

A dual gold/silver-catalyzed cascade C(sp3)-H alkynylation/iminoauration of 2-substituted pyridines with hypervalent iodine(III) reagents for the synthesis of indolizines is described. This novel reaction involves the formation of an alkynyl Au(III) species, a dual gold/silver-catalyzed C(sp3)-H functionalization, and a subsequent iminoauration process. A number of indolizines bearing diverse functionalities were prepared in good to excellent yield. Furthermore, a gram-scale reaction was efficiently conducted.

Design, synthesis and biological evaluation of substituted 3-amino-N-(thiazol-2-yl)pyrazine-2-carboxamides as inhibitors of mycobacterial methionine aminopeptidase 1

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) is the number one cause of deaths due to a single infectious agent worldwide. The treatment of TB is lengthy and often complicated by the increasing drug resistance. New compounds with new mechanisms of action are therefore needed. We present the design, synthesis, and biological evaluation of pyrazine-based inhibitors of a prominent antimycobacterial drug target - mycobacterial methionine aminopeptidase 1 (MtMetAP1). The inhibitory activities of the presented compounds were evaluated against the MtMetAP1a isoform, and all derivatives were tested against a broad spectrum of myco(bacteria) and fungi. The cytotoxicity of the compounds was also investigated using Hep G2 cell lines.Overall, high inhibition of the isolated enzyme was observed for 3-substituted N-(thiazol-2-yl)pyrazine-2-carboxamides, particularly when the substituent was represented by 2-substituted benzamide. The extent of inhibition was strongly dependent on the used metal cofactor. The highest inhibition was seen in the presence of Ni2+. Several compounds also showed mediocre in vitro potency against Mtb (both Mtb H37Ra and H37Rv). Despite the structural similarities of bacterial and fungal MetAP1 to mycobacterial MtMetAP1, title compounds did not exert antibacterial nor antifungal activity. The reasons behind the higher activity of 2-substituted benzamido derivatives, as well as the correlation of enzyme inhibition with the in vitro growth inhibition activity is discussed.

New 4-thiazolidinone/quinoline-2-ones scaffold: Design, synthesis, docking studies and biological evaluation as potential urease inhibitors

• Synthesis of two series of 6-substituted 2-quinolone 4-thiazolidinone derivatives. • The structure of the target compounds was proved by different spectroscopic together with elemental analysis. • Some compounds showed outstanding urease inhibitory with approximately ~10–50 fold more potent than thiourea. • The binding interactions of these compounds were confirmed through molecular docking studies. • The correlation between the structure moieties and urease inhibition activity was discussed. Synthesis of two series of 6-substituted 2-quinolone 4-thiazolidinone derivatives 3a-i and 4a-c was achieved. The structure of the target compounds was proved by different spectroscopic including NMR, mass and IR spectra as well as elemental analysis. All the designed final compounds exhibited varied degrees of urease inhibitory activity with IC 50 values 0.46–27.1 μM compared with the standard thiourea having which exhibit IC 50 value of 21.9 ± 0.89 μM. Compounds 3b, 3d and 3e showed outstanding urease inhibitory potential with IC 50 values of 0.92±0.17, 0.74±0.14 and 0.46±0.04 μM, respectively, which is much better than the standard thiourea. The binding interactions of these compounds were confirmed through molecular docking studies; the most active compounds displayed complete overlay and a similar binding mode and pose with the reference. Both compound 3d with the standard ligand inside the urease proteins (ID: 4UBP)

Synthesis and photodynamic effect of 3-substituted methyl pyropheophorbide-a derivatives as novel photodynamic therapeutic agents for cancer treatment

The unique ability of chlorophyll derivatives to accumulate in tumor tissues and cause a photodynamic effect under laser radiation has been successfully used in photodynamic therapy (PDT). Previous research on modified peripheral substituents in chlorophyll showed that the presence and position of substituents in chlorin derivatives remarkably affect biological activities. Herein, we synthesized methyl pyropheophorbide-a (MPPa) derivatives, which are chlorophyll-a derivatives with heterocyclic aromatic substituents or pyrazole moieties on the peripheral positions. Then, we examined the PDT effects of these new derivatives in vitro and in vivo.

Ultrasound-assisted efficient and green synthesis of 2-substituted benzothiazoles under solvent-free condition using recyclable sulfated tungstate

Sulfated tungstate catalyzed an efficient and ecofriendly protocol has been described for the synthesis of 2-substituted benzothiazoles. The corresponding benzothiazoles were obtained using a condensation reaction of 2-aminothiophenol with various aldehydes under ultrasound irradiation at room temperature. Various functional groups on the 2-aminothiophenol as well as on the aldehydes were tolerated to provide 2-substituted benzothiazoles derivatives in excellent yields. The faster reaction rate, solvent-free or mild reaction conditions, wide functional group compatibility, excellent yields, easy work-up procedure, and excellent catalyst recyclability are the advantages of this protocol. These advantages make this process more practicable, cost-effective, and environmentally benign.

Design, Synthesis, and Antibacterial Evaluation of Novel Ocotillol Derivatives and Their Synergistic Effects with Conventional Antibiotics

The improper use of antibiotics has led to the development of bacterial resistance, resulting in fewer antibiotics for many bacterial infections. Especially, the drug resistance of hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) is distinctly serious. This research designed and synthesized two series of 3-substituted ocotillol derivatives in order to improve their anti-HA-MRSA potency and synergistic antibacterial activity. Among the synthesized compounds, 20–31 showed minimum inhibitory concentration (MIC) values of 1–64 µg/mL in vitro against HA-MRSA 18–19, 18–20, and S. aureus ATCC29213. Compound 21 showed the best antibacterial activity, with an MIC of 1 μg/mL and had synergistic inhibitory effects. The fractional inhibitory concentration index (FICI) value was 0.375, when combined with chloramphenicol (CHL) or kanamycin (KAN). The structure–activity relationships (SARs) of ocotillol-type derivatives were also summarized. Compound 21 has the potential to be developed as a novel antibacterial agent or potentiator against HA-MRSA.

New chromanone derivatives containing thiazoles: Synthesis and antitumor activity evaluation on A549 lung cancer cell line.

Novel 2-[2-(chroman-4-ylidene)hydrazinyl]-4/5-substituted thiazole derivatives (2a-i) were synthesized and investigated for their anticancer activity. Cytotoxic activity on A549 and NIH/3T3 cell lines was determined, most of the compounds exhibited high cytotoxic profile with selectivity. Selected compounds 2b, 2c, 2e, 2g, 2h, and 2i were tested to determine induction of apoptosis, mitochondrial membrane depolarization, and cell cycle arrest. The results showed that the compounds induced apoptosis intrinsically that they triggered loss of mitochondrial potential through increasing the accumulation of cells in G2/M. Besides, intrinsic apoptotic pathway was supported by down-regulation of anti-apoptotic protein Bcl-2 and up-regulation of proapoptotic protein Bax. Molecular docking study for compounds 2b, 2c, and 2g was promoted experimental outcomes.