2-aminothiophene Derivatives Research Articles

Synthesis and biological studies of 2-aminothiophene derivatives as positive allosteric modulators of glucagon-like peptide 1 receptor

As a step toward the development of novel small-molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes, obesity, and heart diseases, we discovered a novel 2-amino-thiophene (2-AT) based lead compound bearing an ethyl 3-carboxylate appendage. In this work, we report the syntheses and biological studies of more than forty 2-AT analogs, that have revealed a 2-aminothiophene-3-arylketone analogue 7 (MW 299) showing approximately a 2-fold increase in insulin secretion at 5 μM when combined with the GLP-1 peptide at 10 nM. In vivo studies using CD1 mice at a dose of 10 mg/kg, clearly demonstrated that the blood plasma glucose level was lowered by 50% after 60 min. Co-treatment of 7 with sitagliptin, an inhibitor of GLP-1 degrading enzyme Dipeptidyl Peptidase IV, further confirmed 7 to be an effective PAM of GLP-1R. The small molecular weight and demonstrated allosteric modulating properties of these compound series, show the potential of these scaffolds for future drug development.

Fe3O4 nanoparticles impregnated eggshell as an efficient biocatalyst for eco-friendly synthesis of 2-amino thiophene derivatives

In this study, a biodegradable and eco-friendly biocatalyst (eggshell/Fe3O4) was synthesized utilizing eggshell impregnated with Fe3O4 nanoparticles. The characterization of prepared catalyst was carried out by Fourier transform infrared radiation (FT-IR), scanning electron microscopy (SEM), X-ray Diffraction (XRD), energy-dispersive X-ray (EDX), thermal gravimetric analysis-differential thermogravimetry (TGA-DTG), vibrating sample magnometer (VSM), and atomic force microscopy (AFM). The eggshell/Fe3O4 biocatalyst was served in multi-component reactions (MCRs) for the synthesis of 2-amino thiophene derivatives from variety aromatic aldehydes, malononitrile, ethyl acetoacetate, and sulfur (S8). To achieve optimal reaction conditions, a thorough examination was conducted on key factors, such as the solvent type, reaction time and temperature, and the ratio of eggshell to Fe3O4. The findings suggest that high yield product can be obtained at microwave temperature (MW) in EtOH solvent within 10 min. Additionally, the eggshell/Fe3O4 biocatalyst exhibited high catalytic activity, which was sustained over the five cycles, without any significant decline in its performance.

New Approaches for the Synthesis N-alkylated Benzo[b]thiophene Derivatives together with their Antiproliferative and Molecular Docking Studies.

2-Amino thiophene derivatives are important compounds not only for their uses in many heterocyclic reactions but also due to their wide range of pharmaceutical and biological activities. The aim of this work was to explore a number of new heterocyclic derivatives, studying their inhibitions toward cancer cell lines and studying their structure activity relation ship. Alkylation of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was achieved through its reaction with chloroacetone and 2-bromo-1-(4-aryl)ethanone derivatives to give compounds 3 and 11a-c. The produced compoumds were subjected to further heterocylization reactions and cytotoxic evaluation against the three cancer cell lines MCF-7, NCI-H460 and SF-268, together with the normal cell line WI 38. Further evaluations were obtained through studying their inhibitions against cancer cell lines classified according to the disease. Anticancer screening against hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines for all compounds together with the molecular docking of 12c, 12d, 12e and 12f were studied. Anti-proliferative evaluations and inhibitions for all of the synthesized compounds showed that many compounds exhibited high inhibitions. Toward the three cancer cell lines, compounds 3, 5a, 7a, 9a, 9b, 11b, 12b, 12d, 12e, 12f, 14c, 14e, 14f, 15e, 15f, 16e, 16f, 17c, 18b, 22a and 22c were the most cytotoxic compounds. The high activities of some compounds were attributed to the presence of the electronegative CN and or Cl groups within the molecule. Most of the tested compounds exhibited inhibitions higher than the reference doxorubicin toward hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines. The score of binding energy of compounds 12c, 12d, 12e and 12f was close to the reference Foretinib which appeared through the molecular docking results of such compounds.

DFT and experimental study on the spectral and nonlinear optical properties of a highly conjugated imine

In this study, (2-((1E,2E)-3-phenylallylidene) amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile) [referred from here onwards as HCIM that is a highly conjugated imine] was synthesized via a condensation reaction between cinnamaldehyde and a 2-aminothiophene derivative, and subjected to computational and experimental approaches. At first, the IR, UV–Vis spectral, and HOMO–LUMO analysis of the synthesized compound were carried out by density functional theory (DFT) at B3LYP/6-311++G(d,p) level. Secondly, experimental study on the nonlinear optical (NLO) properties (third order optical coefficients) of compound HCIM in methanol was conducted by Z-can technique. The IR results indicated that the computational and experimental of vibrational frequencies were in good agreement with each other. The calculated HOMO-LUMO gap (HLG) in gas phase and methanol is 3.14 and 3.085 eV, respectively, and this parameter was used to interpret Z-scan data’s. The values of calculated absorption spectra of the compound HCIM in gas phase were close to them in solution phase (methanol). Also, the experimental results showed that the main origin of NLO refraction is thermal lensing effect and positive nonlinear absorption is due to electrostriction effect. Electrostriction is a characteristic of organic molecules with low HOMO-LUMO energy gap about 3.1 eV, that exhibits high electrical polarizability. Finally, the results suggest that compound HCIM is advantageous for NLO applications.

Synthesis of 2-Aminofurans and 2-Aminothiophenes through Elemental Sulfur-Promoted Switchable Redox Condensation Reaction of Enaminones with Methylene Nitriles.

Herein, we report an elemental sulfur-promoted switchable redox condensation reaction that can selectively prepare 2-aminofurans and 2-aminothiophenes from the corresponding enaminones and methylene nitriles, respectively. Mechanistic studies demonstrated that the enaminones, as dual nucleophiles, reacted with nitrile acetate to produce 2-aminofurans via 3,5-annulation under promotion by elemental sulfur. These reactions used readily available starting materials, transition metal-free, eco-friendly procedures, gram-scale syntheses, and wide functional group tolerance. The methodology may be useful for the construction of 2-aminofuran and 2-aminothiophene derivatives with potential biological activity.

Synthesis, structural evaluation, antioxidant, DNA cleavage, anticancer activities and molecular docking study of metal complexes of 2-amino thiophene derivative

Novel heterocyclic ligand of 2-amino thiophene derivative and metal complexes with manganese, cobalt, nickel, copper and zinc bivalent ions were prepared. Compounds were analyzed through elemental analysis, molar conductance, magnetic moment, FT-IR, UV–Visible, NMR (1H and 13C), EPR and XRD. The above spectroscopic data confirmed that ligand coordinated to metal through enolate oxygen, nitrogen of azomethine and carbonyl group. EPR data confirmed the geometry of copper complex and evidenced that the metal–ligand bonds are reasonable covalent character. The XRD analysis explained the crystalline character of compounds and fluorescence spectroscopy showed considerable fluorescent properties. In view of biological activities, the antioxidant properties of samples were assayed by scavenging activity of DPPH radical and results to prove greater activity of all the compounds except Cu(II) complex. DNA cleavage ability of compounds was evaluated using gel electrophoresis method. It revealed that the compounds effectively cleaved the pUC18 plasmid DNA. The anticancer studies of all the compounds were screened against cell lines MCF-7 Human Breast Cancer cells and K-562 Human Leukemia cells using SRB assay. The IC50 values suggested that synthesized compounds are more active towards above cancer cell lines compared with Adriamycin. Highly potent compounds in anticancer activity were studied by molecular docking against receptor CDK2.

2-Aminothiophene derivatives as a new class of positive allosteric modulators of glucagon-like peptide 1 receptor.

We report the discovery of two new 2-aminothiophene based small molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes. One of the chemotypes, (S-1), has a molecular weight of 239 g/mol, the smallest molecule among all reported GLP-1R PAMs. When combined with GLP-1 peptide, S-1 increased the GLP-1R activity in a dose-dependent manner in a cell-based assay. When combined with the peptide agonist of vasoactive intestinal polypeptide receptor 1 (VIPR1), S-1 showed no specific activity on VIPR1, another class B GPCR present in the same HEK293-CREB cell line. Insulin secretion studies found S-1 combined with GLP-1 increased insulin secretion by 1.5-fold at 5μM. In a mechanistic study, evidence is provided that the synergistic effect of S-1 with GLP-1may be partly due to the enhanced impact on CREB based phosphorylation. Given the favorable profile of these chemotypes, the work reported herein suggests that 2-aminothiophene derivatives are a new and promising class of GLP-1R PAMs.

Chitosan-Based Films with 2-Aminothiophene Derivative: Formulation, Characterization and Potential Antifungal Activity.

In this study, films of chitosan and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (6CN), a 2-aminothiophene derivative with great pharmacological potential, were prepared as a system for a topical formulation. 6CN-chitosan films were characterized by physicochemical analyses, such as Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction (XRD), and scanning electronic microscopy (SEM). Additionally, the antifungal potential of the films was evaluated in vitro against three species of Candida (C. albicans, C. tropicalis, and C. parapsilosis). The results of the FTIR and thermal analysis showed the incorporation of 6CN in the polymer matrix. In the diffractogram, the 6CN-chitosan films exhibited diffraction halos that were characteristic of amorphous structures, while the micrographs showed that 6CN particles were dispersed in the chitosan matrix, exhibiting pores and cracks on the film surface. In addition, the results of antifungal investigation demonstrated that 6CN-chitosan films were effective against Candida species showing potential for application as a new antifungal drug.

Synthesis, Characterization, Crystal Structure, Hirshfeld Surface, Electronic Excitation, Molecular Docking, and DFT Studies on 2-Amino Thiophene Derivative

Ethyl-2-amino-5,6,7,8-tetrahydro-4H-cyclo-hepta[b]thiophene-3-carboxylate (EACHT) has been synthesized, characterized via single-crystal X-ray diffraction at 293 K and investigated quantum chemically by DFT approach, surface analysis by Hirshfeld and spectrochemically by NMR (1H-NMR and 13C-NMR), FTIR, and UV–Visible. The compound crystallizes in monoclinic crystal system with P21/c space group with Z = 4, with following unit cell dimensions: a = 9.5956 (3) Å, b = 9.5607 (4) Å, c = 13.7226 (7) Å. To get the optimized structure which is base for all the other calculations (vibrational frequency, NBO, natural hybrid orbital, nonlinear optical, frontier molecular orbital, etc.), B3LYP method with 6-311++G(d,p) basis set was used. Complete potential energy distribution assignments were done successfully by VEDA. 1H-NMR and 13C-NMR shifts were estimated by GIAO method and results were compared with experimental spectra. TDDFT method and PCM solvent model was utilized for electronic property analysis such as UV–Vis (in gas phase, ethanol, and DMSO) and compared with the experimental UV–Vis spectra. The HOMO and LUMO energy results emphasize adequate charge transfer was happened within the molecule. NBO analysis MEP surface analysis electron localization function Diagram and Fukui function analysis were done. Hole and Electron density distribution maps were drawn in two different excited states of higher oscillatory strength with DMSO, MeOH as solvents. Docking with seven different receptors, and drug likeness was also carried out.

Design, synthesis and antimicrobial activity of novel 2-aminothiophene containing cyclic and heterocyclic moieties

One of the major challenges in the community and healthcare was an impedance of pathogenic bacteria to antibiotics. This work developed 2-aminothiophene derivatives as novel antimicrobial agents. Various 2-aminothiophene derivatives (3a–f, 5a–c, 6a, b, 7, 8a, b and 9) with cyclic and heterocyclic moieties at 5-position were synthesized, and characterized using NMR, IR, and mass spectroscopic techniques. The newly synthesized compounds were evaluated for their antimicrobial activity against bacteria S. pneumoniae, B. subtilis, P. aeruginosa, E. coli, and fungi A. fumigatus, S. mracemosum, G. candidum, C. albicans. Compound 3a with OH group at para position of phenyl ring exhibited significant antibacterial activity stronger than that of the drug standards Ampicillin and Gentamicin. Compound 6b possess pyrazole ring and compound 9 bearing pyridine ring showed promising antifungal activity compare to the standard drug Amphotericin B. The remaining compounds exhibited good to moderate inhibitory activities. In summary, the results suggest that the compounds from 2-aminothiophene derivatives can be used as antimicrobial agents.

Design, Synthesis and Antifungal Activity of New Schiff Bases Bearing 2-Aminothiophene Derivatives Obtained by Molecular Simplification

Seventeen Schiff bases bearing 2-aminothiophene derivatives were designed and synthesized using molecular simplification. The resulting compounds (4a-4q) were evaluated for their in vitro antifungal activity against dermatophytes. Prediction of their druglikeness and pharmacokinetic properties, establishment of their structure-activity relationships (SAR), and cytotoxic evaluation of the most active compounds were performed. Using an eco-friendly procedure, microwave assisted synthesis resulted in compounds in good yields (35-85%). Compounds 4a-4q presented good druglikeness and pharmacokinetic profiles and no cytotoxicity for any cell line tested up to 100 μM. The compounds presenting the best antifungal profiles were 4e, 4f, 4g, 4k, 4l, 4m, 4o and 4p with more than one minimum inhibitory concentration (MIC) value occurring between 16‑64 μg mL-1, thus, in some cases better than the reference drug (fluconazole). SAR testing indicated that the presence of halogens and nitro substituents increases antifungal activity. Taken together, the results demonstrate that 2-aminothiophene derivatives are promising lead compounds for the development of antifungal drugs.

Microwave-Assisted Synthesis of 2-Aminothiophene Derivatives via Improved Gewald Reactions

Microwave-Assisted Synthesis of 2-Aminothiophene Derivatives via Improved Gewald Reactions

Synthesis and Evaluation of 2-Aminothiophene Derivatives as Staphylococcus aureus Efflux Pump Inhibitors.

2-aminothiophene derivatives (2AT) in which the thiophene ring is fused with a cycloalkyl or a N-acylated piperidine ring by positions 5 and 6 and carrying a 3-carbethoxy group were synthesized and their bacterial growth and enzyme inhibitory effects against efflux proteins of Staphylococcus aureus leading to resistance to fluoroquinolones and erythromycin (ERY) were investigated. Compounds that most effectively decreases the minimum inhibitory concentrations (MICs) of ciprofloxacin (CIP) were assayed for their dose and time effects on the accumulation and efflux of ethidium bromide (EtBr) in the SA-1 strain. None of the compounds displayed antibacterial activity however, three derivatives carrying 2-amino, 2-aminoacetyl and 2-aminotrifluoroacetyl group enhanced the activity of CIP and ERY by 8- and 16-fold, respectively, and were able to restore the sensitivity of resistant strains, acting as typical efflux pump inhibitors (EPIs). The 2-aminoacetyl and 2-aminotrifluoroacetyl derivatives and two other piperidinyl 2-aminotrifluoroacetyl derivatives increased EtBr accumulation in a dose- and time-dependent manner, and one of them was also able to inhibit the EtBr efflux. Taken together, these results represent an important advance in the development of new EPIs, and demonstrate that 2AT represent a good scaffold for developing new antibiotic adjuvants.

Gewald synthesis, antitumor profile and molecular modeling of novel 5-acetyl-4-((4-acetylphenyl)amino)-2-aminothiophene-3-carbonitrile scaffolds

Novel targets of 2-aminothiophene derivatives (2–9) were synthesized based upon preparation of the newly 5-acetyl-4-((4-acetylphenyl)amino)-2-aminothiophene-3-carbonitrile (2) using Gewald methodology. Several functional chemical reactions were performed depending on the reactivity of the substituents attached to the thiophene nucleus towards various nucleophiles. The chemical structures of the synthesized compounds were elucidated by various spectral analyses. Molecular modeling studies displayed the geometrical structures for the investigated compounds and exhibited that the sulfur and carbon atoms at positions 2 and 4 have positive charges while those at 3 and 5 positions have negative charges which found to be more reactive. The potential biological activities of the investigated compounds were examined as antitumor agents against two human tumor cell lines namely; hepatocellular carcinoma (HEPG-2) and mammary gland breast cancer (MCF-7). All the compounds were found to inhibit the growth of both human tumor cell lines with variable degrees comparing with the reference control drug (Doxorubicin). The practical findings were in a good agreement with modeling study.

Synthesis and biological evaluation of novel hybrid compounds derived from gallic acid and the 2-aminothiophene derivatives

Gallic acid (GA) and its benzamide derivatives have a wide variety of biological activities, such as antimicrobial, antioxidant, anticancer. In this study, we have reported the synthesis of some new hybrid compounds comprised of the 2-aminothiophene and GA moieties and evaluation of their cytotoxic activities against HeLa (cervical cancer), HCT116 (human colon cancer), and FT (fibroblast) cell lines as well as antimicrobial activities against some Gram-positive and Gram-negative bacteria. The reaction of some 2-aminothiophene derivatives (previously prepared from the Gewald reaction) with galloyl chloride having the acetylated hydroxyl groups and the subsequent deprotection of the hydroxyl groups gave the desired hybrid compounds. Then, the antimicrobial activity of the compounds was evaluated using disc diffusion and minimum inhibitory concentration assays. Finally, the MTT assay was carried out to evaluate the cytotoxicity of the synthesized compounds on the mentioned cell lines. The structure of the synthesized compounds was elucidated by conventional spectroscopic methods such as NMR, FT-IR, and UV–Vis spectroscopy. All compounds prevented the growth of Staphylococcus coagulase more than the positive control of chloramphenicol, and one compound was more sensitive to the growth of Klebsiella pneumonia compared to the standard antibiotic. All compounds showed acceptable activity against cancer cells. The highest activity was observed against HeLa with an IC50 value of 3.2 μg/mL for compound 3d and against HCT116 with IC50 of 59.4 μg/mL for 3b. The high anticancer activity of compound 3d against HeLa allows us to consider it as a good lead compound for the development of new potent anticancer agents for the treatment of cervical cancer.

Synthesis of 2-Aminothiophene Derivatives Catalyzed by Amano Lipase M from Mucor javanicus

Synthesis of 2-Aminothiophene Derivatives Catalyzed by Amano Lipase M from <i>Mucor javanicus</i>

Evaluation of the antiproliferative activity of 2-amino thiophene derivatives against human cancer cells lines.

In spite of great progress in understanding cancer biology, current therapeutic procedures remain unsatisfactory. Chemotherapy is often followed by secondary effects with cellular toxicity negatively affecting the results. The discovery and development of new safe and efficient antitumor agents is necessary. Derivatives of 2-amino thiophene have been a topic of constant investigation due to their versatile synthetic applicability and broad spectrum of biological applications; among which are antifungal and antiproliferative activity shown in prior studies of our group. In the current study, compounds 6CN09, 6CN10, 6CN12, 6CN14, 7CN09 and 7CN11 were analyzed as to antiproliferative effect in human cells of cervical adenocarcinoma (HeLa), human pancreatic adenocarcinoma (PANC-1) and mice fibroblasts (3T3), which were exposed to the compounds in concentrations of 5, 10, 25 and 50μM during 24 and 48h. They were submitted to MTT assay. In order to elucidate the action mechanism of antitumor thiophene derivatives flow cytometry was performed to evaluate cell death and cell cycle analysis. The results showed that thiophene derivatives demonstrated great antiproliferative potential in the HeLa and PANC-1 cell lines when compared with the control, and the percentage of cell proliferation inhibition approximated or was higher than the standard drug used; doxorubicin (Dox). In highlight were the derivatives 6CN14 and 7CN09 that showed greater efficiency in the antiproliferative evaluation. Further, all compounds had a protective effect on the non-tumor 3T3 cell line. The flow cytometry analysis showed few cells in apoptosis in both the HeLa and PANC-1 lines, although the compounds interfered with the progression of the cell cycle, and avoided cell growth and multiplication in the HeLa tumor line. These thiophene derivatives demonstrated cytostatic and antiproliferative effects and may be considered as promising molecular candidates for anticancer drugs.

A green chemical approach: a straightforward one-pot synthesis of 2-aminothiophene derivatives via Gewald reaction in deep eutectic solvents

The synergic effect of choline chloride/urea as a deep eutectic solvent was investigated in the synthesis of 2-aminothiophene derivatives via a three-component cyclocondensation of a ketone or an aldehyde with activated nitriles and elemental sulfur catalyzed by NaOH as cheap and highly accessible base. The advantages of this catalytic protocol are eco-friendly, easy to set up, reusability, and a simple separation and purification of products without using chromatography in high yields at short times.

Improvement of Solubility and Antifungal Activity of a New Aminothiophene Derivative by Complexation with 2-Hydroxypropyl-β-cyclodextrin

This study aimed to prepare a complex of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and 6CN10, a poorly water soluble 2-aminothiophene derivative with antifungal properties, by freeze-drying technique. The complex was characterized by thermal analysis, infrared/Raman spectroscopy, X-ray diffraction and scanning electron microscopy. In addition, we used the data of the phase solubility study, 1H, and 2D NMR spectroscopy and molecular modeling in order to investigate the interactions between 6CN10 and HP-β-CD. The apparent solubility of 6CN10 with HP-β-CD increased more than 29 fold. The phase solubility assay in water at 25 oC showed an AP-type curve, with an apparent stability constant K1:1 and K1:2 of 96 and 0.1989 M-1, respectively. The results of IR, NMR and docking indicate that 6CN10 is able to form complexes with HP-β-CD (1:1 and 1:2 stoichiometric ratios), generating the formation of inclusion and preferably, non-inclusion complexes. The antifungal activity against Cryptococcus neoformans demonstrated the superior performance of the complex (46.66 µg mL-1) when compared with the free drug (166.66-333.33 µg mL-1). The present study provides useful information for the potential application of complexation with low soluble compounds and about the type of complex formation between 6CN10 and HP-β-CD.

Regioselective metal-free one-pot synthesis of functionalized 2-aminothiophene derivatives.

A facile metal-free synthesis of 2-aminothiophene derivatives by the reaction of 2-ynals with thioamides in alcohols has been developed. This transformation allows the assembly of 2-aminothienyl ether derivatives via a well-designed aldol condensation/regioselective intramolecular cyclization/conjugate addition cascade reaction and provides a straightforward synthetic protocol for constructing 2,3,5-trisubstituted 2-aminothiophenes.