76981-71-0Relevant academic research and scientific papers
Synthesis of thiophene derivatives: Substituent effect, antioxidant activity, cyclic voltammetry, molecular docking, DFT, and TD-DFT calculations
Colak, Naki,Ercag, Erol,Rajkumar, Parthasarathi,Serdaro?lu, Goncagül,Sugumar, Paramasivam,Uludag, Nesimi
, (2022/02/23)
The efficient pathway 6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate derivatives have been synthesized. Due to the promising biochemical reactivity, the bioactive agent synthesis in the frame of the thiophene moiety is one of the main objectives of the contemporary scientific disciplines. The structures of all the presently synthesized compounds were confirmed using spectroscopic methods (UV–vis, FT-IR, 1H NMR, 13C NMR). The cyclic voltammetry (CV) of three compounds (1-3) was performed using a bare ITO electrode and a Nafion modified ITO (Indium Tin Oxide) electrode. The antioxidant properties of these compounds were explored by the CUPRAC method and TEAC (Trolox equivalent total antioxidant capacity) coefficients revealed that the antioxidant capacity of the compounds was ranking as follows: compound 2 (C-2) > compound 3 (C-3) > compound 1 (C-1). The docking studies displayed that compound 1 was the most active compound against Escherichia coli thymidylate synthase (TS). The TD-DFT calculations displayed that two observed peaks on the UV–vis spectra of the thiophenes were related to the n→ π* and π→ π* transitions. Also, NBO (Natural Bond Orbital) analysis indicated that the resonance interactions (n→ π* and π→ π*) in the ground state of all compounds had an essential role in the decreasing of the stabilization energy. The antioxidant activity and molecular docking results were supported by the electrodonating power and hardness indexes in addition to the NBO results.
Design, Synthesis, and Structure-Activity Relationship of N-Aryl- N′-(thiophen-2-yl)thiourea Derivatives as Novel and Specific Human TLR1/2 Agonists for Potential Cancer Immunotherapy
Chen, Zhipeng,Zhang, Lina,Yang, Junjie,Zheng, Lu,Hu, Fanjie,Duan, Siqin,Nandakumar, Kutty Selva,Liu, Shuwen,Yin, Hang,Cheng, Kui
supporting information, p. 7371 - 7389 (2021/06/28)
The previous virtual screening of ten million compounds yielded two novel nonlipopeptide-like chemotypes as TLR2 agonists. Herein, we present the chemical optimization of our initial hit, 1-phenyl-3-(thiophen-2-yl)urea, which resulted in the identification of SMU-C80 (EC50 = 31.02 ± 1.01 nM) as a TLR2-specific agonist with a 370-fold improvement in bioactivity. Mechanistic studies revealed that SMU-C80, through TLR1/2, recruits the adaptor protein MyD88 and triggers the NF-κB pathway to release cytokines such as TNF-α and IL-1β from human, but not murine, cells. To the best of our knowledge, it is the first species-specific TLR1/2 agonist reported until now. Moreover, SMU-C80 increased the percentage of T, B, and NK cells ex vivo and activated the immune cells, which suppressed cancer cell growth in vitro. In summary, we obtained a highly efficient and specific human TLR1/2 agonist that acts through the MyD88 and NF-κB pathway, facilitating cytokine release and the simultaneous activation of immune cells that in turn affects the apoptosis of cancer cells.
Novel tetrahydrobenzo[b]thiophen-2-yl)urea derivatives as novel α-glucosidase inhibitors: Synthesis, kinetics study, molecular docking, and in vivo anti-hyperglycemic evaluation
Xie, Hong-Xu,Zhang, Juan,Li, Yue,Zhang, Jin-He,Liu, Shan-Kui,Zhang, Jie,Zheng, Hua,Hao, Gui-Zhou,Zhu, Kong-Kai,Jiang, Cheng-Shi
, (2021/08/19)
α-Glucosidase inhibitors, which can inhibit the digestion of carbohydrates into glucose, are one of important groups of anti-type 2 diabetic drugs. In the present study, we report our effort on the discovery and optimization of α-glucosidase inhibitors with tetrahydrobenzo[b]thiophen-2-yl)urea core. Screening of an in-house library revealed a moderated α-glucosidase inhibitors, 5a, and then the following structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased inhibitory activity against α-glucosidase than the parental compound 5a (IC50 of 26.71 ± 1.80 μM) and the positive control acarbose (IC50 of 258.53 ± 1.27 μM). Among them, compounds 8r (IC50 = 0.59 ± 0.02 μM) and 8s (IC50 = 0.65 ± 0.03 μM) were the most potent inhibitors, and showed selectivity over α-amylase. The direct binding of both compounds with α-glucosidase was confirmed by fluorescence quenching experiments. Kinetics study revealed that these compounds were non-competitive inhibitors, which was consistent with the molecular docking results that compounds 8r and 8s showed high preference to bind to the allosteric site instead of the active site of α-glucosidase. In addition, compounds 8r and 8s were not toxic (IC50 > 100 μM) towards LO2 and HepG2 cells. Finally, the in vivo anti-hyperglycaemic activity assay results indicated that compounds 8r could significantly decrease the level of plasma glucose and improve glucose tolerance in SD rats treated with sucrose. The present study provided the tetrahydrobenzo[b]thiophen-2-yl)urea chemotype for developing novel α-glucosidase inhibitors against type 2 diabetes.
Preparation method and application of tetrahydrobenzothiophene compound and pharmaceutical composition
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Paragraph 0196-0198; 0205-0207; 0214-0216; 0223-0225; ..., (2021/10/16)
The invention belongs to the field of medicines, and particularly relates to a tetrahydrobenzothiophene compound as well as a pharmaceutical composition and a preparation method and application thereof. The tetrahydrobenzothiophene compound is a compound I as shown I. In-flight R1 And R2 The C1 -4 is a saturated/unsaturated hydrocarbon group. - OCH3 , OCH2 CH3 Phenyl, substituted phenyl, NO2 One - COR of - OH - F, Cl - Br. I - H R1 AND R2 Or different. R3 It is-F. - Cl, Br, I, OH, Amino, C1 -4 saturated/unsaturated hydrocarbon group, OCH3 , OCH2 CH3 , H, Wherein one of them is, n ≥ 5, n Being an integer. The compound effectively inhibits salmonella by inhibiting the synthesis of ATP-dependent transporter in the lipopolysaccharide synthesis pathway. Aeruginosa, escherichia coli and staphylococcus aureus.
Synthesis and biological evaluation of new antitubulin agents containing 2-(30,40,50-trimethoxyanilino)-3,6-disubstituted-4,5,6,7-tetrahydrothieno[2,3-c]pyridine Scaffold
Balzarini, Jan,Brancale, Andrea,Cacciari, Barbara,Ferla, Salvatore,Finotti, Alessia,Gambari, Roberto,Hamel, Ernest,Liekens, Sandra,Manfredini, Stefano,Oliva, Paola,Prencipe, Filippo,Romagnoli, Romeo,Zurlo, Matteo
, (2020/04/17)
Two novel series of compounds based on the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 4,5,6,7-tetrahydrobenzo[b]thiophene molecular skeleton, characterized by the presence of a 30,40,50-trimethoxyanilino moiety and a cyano or an alkoxycarbonyl group at its 2- or 3-position, respectively, were designed, synthesized, and evaluated for antiproliferative activity on a panel of cancer cell lines and for selected highly active compounds, inhibition of tubulin polymerization, and cell cycle effects. We have identified the 2-(30,40,50-trimethoxyanilino)-3-cyano-6-methoxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivative 3a and its 6-ethoxycarbonyl homologue 3b as new antiproliferative agents that inhibit cancer cell growth with IC50 values ranging from 1.1 to 4.7 μM against a panel of three cancer cell lines. Their interaction with tubulin at micromolar levels leads to the accumulation of cells in the G2/M phase of the cell cycle and to an apoptotic cell death. The cell apoptosis study found that compounds 3a and 3b were very effective in the induction of apoptosis in a dose-dependent manner. These two derivatives did not induce cell death in normal human peripheral blood mononuclear cells, suggesting that they may be selective against cancer cells. Molecular docking studies confirmed that the inhibitory activity of these molecules on tubulin polymerization derived from binding to the colchicine site.
Synthesis and Evaluation of 2-Aminothiophene Derivatives as Staphylococcus aureus Efflux Pump Inhibitors
da Cruz, Rayssa M. D.,Zelli, Renaud,Benshain, Sarah,da Cruz, Ryldene M. D.,Siqueira-Júnior, José P.,Décout, Jean-Luc,Mingeot-Leclercq, Marie-Paule,Mendon?a-Junior, Francisco J. B.
, p. 716 - 725 (2020/04/09)
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.
5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives as inhibitors of full-length RORγt
Lao, Chuyu,Zhou, Xiaoqing,Chen, Huanpeng,Wei, Fengjiao,Huang, Zhaofeng,Bai, Chuan
, (2019/07/18)
Retinoid-related orphan receptor gamma-t (RORγt) belongs to the nuclear receptor superfamily that takes vital roles in the development and maturation of T-helper 17 cell (Th17) and lymph-node genesis. Because Th17 cells have been proved to be major effectors in human autoimmune and inflammatory diseases, the agonists and antagonists of RORγt have been discovered as promising leads for the therapeutics of these diseases. Most of the current studies of RORγt inhibitors have been focused on ligand binding domain (LBD) of RORγt because the structure and binding pockets of LBD have been elucidated and studied in detail. Recent research elucidated that the hinge domain (HD) of RORγt was significantly involved in the SUMOylation of RORγt and thus specifically affecting T cell development but not lymph-node genesis. These discoveries highlighted the potential of HD of RORγt as the target of RORγt inhibitors that could specifically inhibit Th17-related activities without affecting lymph-node genesis. In this study, we utilized a screening system with full-length RORγt including DBD, HD and LBD to evaluate the activities of a synthesized library of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives. We identified a potent lead compound (28) that effectively inhibited Th17 cell differentiation. Docking and structure–activity relationship (SAR) studies showed that compound 28 may not bind in the binding pocket as most of the known inhibitors, but may bind in the pocket closed to Gln223 and Leu244 in HD. Our studies showed evidence that the HD of RORγt could afford a binding pocket for Th17 specific inhibitors and this domain should be further studied to discover potent and specific RORγt inhibitors.
Identification of 4-methoxythieno[2,3-d]pyrimidines as FGFR1 inhibitors
Balanda, A. O.,Bdzhola, V. G.,Kotey, I. M.,Pletnova, L. V.,Protopopov, M. V.,Prykhod’ko, A. O.,Starosyla, S. A.,Yarmoluk, S. M.
, p. 152 - 162 (2020/06/02)
Aim. To identify novel FGFR1 inhibitors using virtual screening approach. Methods. We used methods of organic synthesis, molecular docking via the Autodock 4.2.6 program package and in vitro biochemical tests with γ-32P. Results. In vitro experiments showed that 9 of 23 tested compounds possess inhibitory activity against FGFR1 with IC50 values in the range from 0.9 to 5.6 μM. Conclusions. Nine FGFR1 inhibitors were developed. The mode of compounds binding with the ATP-acceptor site was determined using molecular docking methods and the dependence of the compounds’ activity on the substituents R1, R4 and R5 was evaluated.
An NMDAR positive and negative allosteric modulator series share a binding site and are interconverted by methyl groups
Perszyk, Riley,Katzman, Brooke M.,Kusumoto, Hirofumi,Kell, Steven A.,Epplin, Matthew P.,Tahirovic, Yesim A.,Moore, Rhonda L.,Menaldino, David,Burger, Pieter,Liotta, Dennis C.,Traynelis, Stephen F.
, (2018/08/28)
N-methyl-D-aspartate receptors (NMDARs) are an important receptor in the brain and have been implicated in multiple neurological disorders. Many non-selective NMDAR-targeting drugs are poorly tolerated, leading to efforts to target NMDAR subtyp
Structure-Based Virtual Screening, Compound Synthesis, and Bioassay for the Design of Chitinase Inhibitors
Dong, Yawen,Jiang, Xi,Liu, Tian,Ling, Yun,Yang, Qing,Zhang, Li,He, Xiongkui
, p. 3351 - 3357 (2018/04/11)
Chitinases play a vital part in the molting phase of insect pests. Inhibiting their activities by the use of drug-like small chemical molecules is thought to be an efficient strategy in pesticide design and development. On the basis of the crystal structure of OfChtI, a chitinase indispensable for the molting of the insect pest Ostrinia furnacalis (Asian corn borer), here we report a chemical fragment and five variant compounds as inhibitors of OfChtI obtained from a library of over 200?000 chemicals by a structure-based-virtual-screening approach. The compounds were synthesized with high atom economy and tested for their OfChtI-inhibitory activities in a bioassay. Compound 3 showed preferential inhibitory activity with a Ki value of 1.5 μΜ against OfChtI. Analysis of the structure-activity relationships of the compounds provided insight into their interactions with the enzyme active site, which may inform future work in improving the potencies of their inhibitory activities.
