Series Of Thieno Research Articles

Synthesis and biological evaluation of novel thienopyrimidine derivatives as diacylglycerol acyltransferase 1 (DGAT-1) inhibitors

A novel series of thieno[3,2-d]pyrimidine derivatives were synthesised and their inhibitory effects against diacylglycerol acyltransferase 1 (DGAT-1) were assessed. cis-Isomer 17a showed potent and selective inhibitory activity against DGAT-1 in SF9 cells. In addition, 17a had an acceptable pharmacokinetic profile and accumulated mainly in the small intestine and liver. Oral administration of 17a led to a significant reduction in plasma triacylglycerol level during an oral lipid tolerance test (OLTT) in murine and canine models. Taken together, 17a is a high-quality candidate that deserves further investigation.

6-Cinnamoyl-4-arylaminothienopyrimidines as highly potent cytotoxic agents: Design, synthesis and structure-activity relationship studies

In this paper, we described the synthesis and cytotoxic activities of two new series of thieno[2,3-d]pyrimidine and thieno[3,2-d] pyrimidine derivatives. Most of the synthesized compounds had significant antiproliferative activities against PC3, MDA-MB-231, A549, and HeLa cell lines in comparison to the reference drug, erlotinib. Compounds N-(4-((3,5-dichlorophenyl)amino)thieno[2,3-d]pyrimidin-6-yl)cinnamamide 8e and (E)-N-(4-((3,4-dichlorophenyl)amino)thieno[2,3-d]pyrimidin-6-yl)-3-(4-methoxyphenyl)acrylamide 8g with IC50 values of 4 nM and 33 nM, respectively, against HeLa cell line were chosen for further studies. The apoptosis induced activity and cell cycle arrest were determined and the results provided evidence that these compounds induced cell death via apoptosis and arrested cell growth in sub-G1 phase. In addition, western blot analysis manifested the promising result of suppressing the EGFR signaling pathway (p-EGFR/p-ERK1/2). The docking studies appreciated the considerable potency of compound 8e based on hydrogen and covalent binding interactions. Eventually, in silico pharmacokinetic prediction indicated the acceptable bioavailability of all final compounds.

Design, synthesis, and biological evaluation of thieno[3,2-d]pyrimidine derivatives as potential simplified phosphatidylinositol 3-kinase alpha inhibitors.

A series of thieno[3,2-d]pyrimidine derivatives as phosphatidylinositol 3-kinase (PI3K) inhibitors was designed using the combination strategy. The synthesis and biological evaluation of the derivatives demonstrated their potent inhibition of PI3K, culminating in the discovery of 7 and 21. Determination of a co-crystal structure of 7 complexed with PI3Kα provided the structural basis for the high enzymatic activity. Furthermore, cellular investigation of compounds 7 and 21 revealed that they efficiently suppressed cancer cell lines proliferation through inhibition of intracellular PI3K/AKT/mammalian target of rapamycin pathway. The results provided potent simplified inhibitors of PI3K with a promising overall profile and a chemical series for further optimization to progress into vivo experiments.

Metal-Free Dehydrogenative Double C–H Sulfuration To Access Thieno[2,3-b]indoles Using Elemental Sulfur

We report a base-promoted metal-free approach for the synthesis of thieno[2,3-b]indole derivatives. This method combined four C-H σ-bond cleavage reactions of two different kinds of C-H bonds and two C-S σ-bond formation processes. A series of thieno[2,3-b]indoles were obtained starting from 3-benzylindole derivatives with good yields and high regioselectivity, with the elemental sulfur serving as a cheap and readily available sulfur source. Good efficiency could be maintained even when the reaction was performed on a gram scale. A plausible mechanism was proposed on the basis of mechanistic studies.

Efficient Synthesis and Biological Evaluation of 2,4‐Diaminothieno[2,3‐d]pyrimidine Derivative

AbstractCancer is a main reason for human morbidity and mortality globally. Screening and identifying new anticancer chemical substances is considered as a valid treatment for carcinoma. In our study on synthesis and search towards the development of potential anticancer agents, a series of thieno[2,3‐d]pyrimidine derivatives were prepared from the functionalized iminophosphorane via aza‐Wittig reaction. Their structures were confirmed by 1H NMR, 13C NMR, MS and elemental analysis. The in vitro antitumor activities of compounds were analyzed with CCK8 standard method. It revealed these thieno[2,3‐d]pyrimidine derivatives were exhibited cytotoxicity against HepG2, HEp‐2, and MCF‐7 cell lines. The most potent compounds, 5 h and 5 j, were efficacious against HEp‐2 cells with IC50 1.8μmol/L and 0.8μmol/L, respectively. Meanwhile, 5 a, 5 d and 5 h showed broad spectrum of cytotoxicity for HepG2, Hep2 and MCF‐7 three different cell lines with IC50 range of 1.8‐87.5μmol/L. Furthermore, we demonstrated that cytotoxicity of 5 j was due to the activation of caspase‐9 involved apoptotic pathway, which is death receptor independent.

Synthesis, reactions, and biological study of some new thienopyrimidine derivatives as antimicrobial and anti‐inflammatory agents

Pyrimidine and thienopyrimidine derivatives play a very important role in organic chemistry because of their wide applications as bioactive compounds with multiple biological activities. However, a literature survey revealed that the merger of different groups in the thieno[2,3‐d]pyrimidine heterocyclic ring enhances its antibacterial, antifungal and anti‐inflammatory activities. This encouraged us to prepare a new series of thieno[2,3‐d]pyrimidine heterocyclic compounds and to test them as antimicrobial and anti‐inflammatory agents. These compounds have shown remarkable activity toward fungi, bacteria, and inflammation. Thus, these compounds have been prepared by the chloroacylation of 5‐amino‐4‐phenyl‐2‐(p‐tolylamino)thieno[2,3‐d] pyrimidine‐6‐carboxamide (4) using chloroacetyl chloride under neat condition to afford the target compound (6), which was used as precursor for the synthesis of a number of bioactive compounds. Thus reaction of the chloromethylpyrimidine derivative (6) with triphenylphosphine in dry benzene gave the corresponding ((4‐oxo‐9‐phenyl‐7‐(p‐tolylamino)‐3,4‐dihydropyrimido[4′,5′:4,5]thieno[2,3‐d]pyrimidin‐2‐yl)methyl) triphenylphosphonium chloride (7). Compounds 8a–8c and 9a–9c were obtained by the reaction of 7 with some selected aromatic aldehydes and ketones in methanol and sodium methoxide under Wittig reaction condition. The structures of the all new synthesized compounds were established on the basis of their analytical and spectral data (IR, 1H NMR, 13C NMR, and MS).

Synthesis, Antimicrobial, and Anticancer Activities of a New Series of Thieno[2,3‐d] Pyrimidine Derivatives

A new series from thieno[2,3‐d] pyrimidine derivatives have been synthesized based on 2‐(ethylmercapto)‐4‐mercapto‐6‐phenyl‐5‐pyrimidine carbonitrile, these compounds used in the synthesis of many pyrimidothienopyrimidine derivatives and triazolo[1″,5″:1″,6″]pyrimido[4′,5′:4,5]thieno[2,3‐d] pyrimidine derivatives. The chemical composition of these compounds was confirmed by 1H NMR, 13C NMR, and MS techniques. Some of the synthesized compounds were screened for their antimicrobial and anticancer agent. Compound (9b) showed strong effect on Aspergillus Fumigatus (RCMB 2568), Candida albicans (RCMB 05036), Saphylococcus aureus (RCMB 010010), Bacillis subtilis (RCMB 010067), Salmonella sp. (RCMB 010043), and Escherichia coli (RCMB 010052). Compounds (2) and (5a–k) were evaluated for their IC50 values against two cancer cell lines (MCF‐7 and HeLa cells) in the presence of Paclitaxel as reference material. Compound (5g) showed the highest cytotoxicity against MCF‐7 (IC50 values about 18.87 ± 0.2 μg/mL) cells compared with Paclitaxel (IC50 values about 40.37 ± 1.7 μg/mL). Also, compound (5d) showed the highest cytotoxicity against HeLa (IC50 values about 40.74 ± 1.7 μg/mL) cells compared with Paclitaxel (IC50 values about 45.78 ± 0.8 μg/mL).

Synthesis, cytotoxic evaluation and target identification of thieno[2,3-d]pyrimidine derivatives with a dithiocarbamate side chain at C2 position

Two series of thieno[2,3-d]pyrimidine derivatives bearing a dithiocarbamate side chain at the C2 position were synthesized and evaluated for cytotoxic activity in human lung cancer A549 and colon cancer HCT-116 cell lines. Compound 3n exhibited the most cytotoxic effect on A549 cells with an IC50 value of 4.87 μM, inducing a cell cycle arrest at G2/M phase and activating the spindle assembly checkpoint (SAC). To identify the target protein(s) of 3n, we incorporated biotin with 3n through a three-carbon chain and an amide bond to synthesize probe 10. The targeted proteins were pulled down from the A549 total cell lysate by biotin-streptavidin affinity purification and analyzed by mass spectrometry. Tubulin was the only protein identified, which is related to the SAC and directly binds to probe 10 both in vivo and in vitro. Furthermore, compound 3n inhibited tubulin polymerization in vitro in a dose-dependent manner, competed with taxol in binding to tubulin, exerting cytotoxic activity toward taxol-resistant A549 cells. These results demonstrate that thieno[2,3-d]pyrimidine derivative 3n exhibits cytotoxicity in cancer cells by targeting tubulin to activate the SAC and potentially acts as a therapeutic lead compound for taxol-resistant cancers.

Design, synthesis, neuroprotective, antibacterial activities and docking studies of novel thieno[2,3-d]pyrimidine-alkyne Mannich base and oxadiazole hybrids

A series of thieno[2,3-d]pyrimidine alkyne Mannich base derivatives (7a-e, 8a-e) and thieno[2,3-d]pyrimidine 1,3,4-oxadiazole derivatives (9a-e, 10a-e) have been synthesized and evaluated for their neuroprotective and neurotoxicity activities where 9a, 10d displayed good neuroprotection 10.6 and 11.88 µg/mL respectively against the H2O2 induced cell death at the EC50 values and 9b, 9d showed respective toxic effects on PC12 cells at CC50 86.12 and 94.16 µg/mL. Compounds 9a, 9e, 10a and 10b showed strong antibacterial activity against two gram positive (S. aureus, B. subtilis) and two gram-negative strains (E. coli, P. aeruginosa) and showed good binding affinities with C(30) carotenoid dehydrosqualene synthase, Gyrase A and LpxC. This is the first report for the demonstration of thieno[2,3-d] pyrimidine derivatives as promising neuroprotective agents against H2O2 induced neurotoxicity on PC12 cells.

A Convenient One‐Pot Synthesis of Thieno[2′,3′:4,5]Pyrimido[1,2‐b]‐[1,2,4,5]Tetrazines

A novel series of thieno[2′,3′:4,5]pyrimido[1,2‐b][1,2,4,5]tetrazin‐6‐one derivatives 14 were prepared from the reaction of 3‐amino‐2‐thioxo‐1,2,3,5,6,7‐hexahydro‐4H‐cyclopenta[4,5]thieno[2,3‐d]pyrimidin‐4‐one 3 or its methylthio 4 with hydrazonoyl chlorides 9. The mechanism of the studied reactions has been discussed and further evidence for the assigned structure of the products is based on alternative synthesis. A single crystal X‐ray analysis of compound 14e has been carried out.

Effects of varying the lengths of the donor units in π-extended thienothiophene isoindigo-based polymer semiconductors

A series of thieno[3,2-b]thiophene isoindigo polymers is synthesized with five different donors that show the versatility of the new acceptor moiety.

Receptor-guided 3D-QSAR studies, molecular dynamics simulation and free energy calculations of Btk kinase inhibitors

BackgroundBruton tyrosine kinase (Btk) plays an important role in B-cell development, differentiation, and signaling. It is also found be in involved in male immunodeficiency disease such as X-linked agammaglobulinemia (XLA). Btk is considered as a potential therapeutic target for treating autoimmune diseases and hematological malignancies.ResultsIn this work, a combined molecular modeling study was performed on a series of thieno [3,2-c] pyridine-4-amine derivatives as Btk inhibitors. Receptor-guided COMFA (q2 = 0.574, NOC = 3, r2 = 0.924) and COMSIA (q2 = 0.646, NOC = 6, r2 = 0.971) models were generated based on the docked conformation of the most active compound 26. All the developed models were tested for robustness using various validation techniques. Furthermore, a 5-ns molecular dynamics (MD) simulation and binding free energy calculations were carried out to determine the binding modes of the inhibitors and to identify crucial interacting residues. The rationality and stability of molecular docking and 3D-QSAR results were validated by MD simulation. The binding free energies calculated by the MM/PBSA method showed the importance of the van der Waals interaction.ConclusionsA good correlation between the MD results, docking studies, and the contour map analysis were observed. The study has identified the key amino acid residues in Btk binding pocket. The results from this study can provide some insights into the development of potent, novel Btk inhibitors.

Structural modifications at the 6-position of thieno[2,3-d]pyrimidines and their effects on potency at FLT3 for treatment of acute myeloid leukemia

Fms-like tyrosine kinase 3 (FLT3) is a well-known and important target for the treatment of acute myeloid leukemia (AML). A series of thieno[2,3-d]pyrimidine derivatives from a modification at the 6-position were synthesized to identify effective FLT3 inhibitors. Although compounds 1 and 2 emerged as promising FLT3 inhibitors among the synthesized compounds, both compounds exhibited poor metabolic stability in human and rat liver microsomes. Hence, further optimization was required for the discovery of FLT3 inhibitors, with a focus on improving metabolic stability. Compound 16d, which had structural modifications of the methyl group at the 5-position and the 4-(2-methylaminoethoxy) phenyl group at the 6-position, exhibited good inhibitory activity against FLT3 and showed effective antiproliferative activity against four leukemia cell lines, including MV4-11. Moreover, compound 16d displayed enhanced metabolic stability. The results of this study indicated that 16d could be a promising compound for further optimization and development as a potent FLT3 inhibitor.

Synthesis and antitumor activity of α-aminophosphonate derivatives containing thieno[2,3-d]pyrimidines

Abstract Two series of thieno[2,3-d]pyrimidine derivatives were designed and synthesized, in which bioactive α -aminophosphonate subunits were introduced at the N3 position through an N N bond connection. The in vitro cytotoxic activity of the novel compounds was tested against human esophageal carcinoma cells (EC109), human hepatocarcinoma cells (HepG2), human gastric carcinoma cells (MGC-803), respectively, by the MTT method. The evaluation results revealed that compounds 6mb , 6mf , 6mg , 6nd and 6nh exerted the most potent inhibition against HepG2, MGC-803 and EC109 cells, respectively. In particular, compound 6mg presented excellent inhibitory effect against HepG2 (91.2%) and MGC-803 (94.4%) cells.

Synthesis and biological evaluation of novel thieno[2,3-d]pyrimidine-based FLT3 inhibitors as anti-leukemic agents

The most common mutations in acute myeloid leukemia (AML) are those that cause the activation of FMS-like tyrosine kinase 3 (FLT3). Therefore, FLT3 is regarded as a potential target for the treatment of AML. A novel series of thieno[2,3-d]pyrimidine-based analogs was designed and synthesized as FLT3 inhibitors. All synthesized compounds were assayed for the tyrosine kinase activity of FLT3 and growth inhibitory activity in four human leukemia cell lines (THP1, MV4-11, K562, and HL-60). Among these compounds, compound 17a, which possesses relatively short and simple substituents at the C6 position of thieno[2,3-d]pyrimidine, emerged as the most promising anti-leukemic agent. Compound 17a exhibited potent inhibition of FLT3-positive leukemic cell growth and of the FLT3 D835Y kinase; such inhibition is required for the successful treatment of AML. The data supports the further investigation of this class of compounds as potential anti-leukemic agents.

Design, synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety as potent antitumor agents

Two series of thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety were designed, synthesized and evaluated for their biological activity. The preliminary investigation showed that most compounds displayed good to excellent potency against four tested cancer cell lines as compared with GDC-0941 and sorafenib. In particular, the most promising compound 29a showed the most potent antitumor activities with IC50 values of 0.081 μM, 0.058 μM, 0.18 μM, and 0.23 μM against H460, HT-29, MKN-45 and MDA-MB-231 cell lines, respectively. The SAR analyses indicated that compounds with mono-halogen groups at 4-position on the terminal phenyl ring were more active than those with double-halogen groups or methyl groups. In addition, the introduction of chlorine atoms into 6,7-position of thieno[3,2-d]pyrimidine moiety led to a slight decline, but more selective activity against H460 and HT-29 cell lines.

Substituent dependent tunable fluorescence in thieno[3,2-c]pyrans

A series of thieno[3,2-c]pyrans were designed and synthesized by l-proline catalyzed reaction which exhibits substituent dependent fluorescence.

Synthesis and anticancer activities of thieno[3,2-d]pyrimidines as novel HDAC inhibitors

A series of thieno[3,2-d]pyrimidines bearing a hydroxamic acid moiety as novel HDAC inhibitors were designed and synthesized. The structures of the new synthesized compounds were confirmed using IR, 1H, 13C NMR spectrum. Compounds 11–13 showed potent inhibitory activities against HDACs with IC50 values at 0.38, 0.49 and 0.61μM. Most of target compounds displayed strong anti-proliferative activity by a MTT assay on three human cancer cell lines including HCT-116, MCF-7 and HeLa. Compound 11, having potent inhibitory activities against HDACs, induced apoptosis and G2/M cell cycle arrest in HCT-116 cell line.

Synthesis and characterisation of thieno[3,2-b]thiophene-based linear shaped liquid crystals

A series of thieno[3,2-b]thiophene-based liquid crystalline molecules has been synthesised. To investigate the effects of alkyl substituent groups and structure of mesogenic cores, eight kinds of thieno[3,2-b]thiophene-based molecules containing different alkyl substituent groups and mesogenic cores have been synthesised. These molecules were characterised by differential scanning calorimetry, polarising optical microscopy, ultraviolet–visible absorption spectroscopy, fluorescence spectroscopy, cyclic voltammetry and polarised fluorescence spectroscopy. The results indicated that the thieno[3,2-b]thiophene-based donor-acceptor-donor (D-A-D) type molecules showed the presence of a smectic A phase. Changes in the length of alkyl substituents and mesogenic cores affected the phase transitions, optical and electrochemical properties of the molecules.

Synthesis and Antimicrobial Activity of Some New Thieno[2,3-b]thiophene Derivatives

A series of thieno[2,3-b]thiophene moiety-containing bis-cyanopyrazoles 5a–c, bis-aminopyrazole 9 and bis-pyridazine derivatives 11 were synthesized and evaluated in vitro for their antimicrobial potential. The antimicrobial activity of some selected products was evaluated and showed good results. 5,5'-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(3-acetyl-1-(4-chlorophenyl)-1H-pyrazole-4-carbonitrile) (5d) was found to be more potent than the standard drug amphotericin B against Geotricum candidum and equipotent to amphotericin Bagainst Syncephalastrum racemosum. In addition, it was found to be equipotent to the standard drug Penicillin G against Staphylococcus aureus. Moreover, it was more potent than the standard drug streptomycin against Pseudomonas aeruginosa and Escherichia coli.