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Ovarian cancer is among the most prevalent causes of mortality among women. Despite improvements in diagnostic methods, non-specific symptoms and delayed gynecological exams can lead to late-stage ovarian tumor discovery. In this study, the effect of an anti-cancer compound, 3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide (Compound 1), was examined. The impacts of cytotoxicity, apoptosis, and metabolomic changes in ovarian cancer cell lines SK-OV-3 and OVCAR-3, as well as glycosphingolipid (GSL) expression, on cancer stem cells (CSCs), marked as CD49f+, and non-CSCs (CD49f−) were explored. Treatment with Compound 1 reduced the percentage of CSCs compared to non-treated cells (p < 0.001). The functional impact of eight GSLs on CSCs and non-CSCs was examined using flow cytometry. The glycophenotype changed in both cell lines, with increases or decreases in its expression, after the treatment. These findings raise the possibility of specifically targeting CSCs in ovarian cancer therapy. Additionally, treatment with Compound 1 resulted in statistically meaningful increased apoptosis, including both early and late apoptosis (p < 0.001), suggesting a pivotal role in initiating programmed cell death by the apoptotic pathway. The analysis revealed that the metabolic activity of treated cancer cells was lower compared to those of the control group (p < 0.001).

New thieno[2,3-b]pyridine clubbed various thiazole ring systems were synthesized by the reaction of 2-(1-(3-amino-4,6-dimethylthieno[2,3-b]pyridin-2-yl)ethylidene)hydrazine-1-carbothioamide with chloroacetone, phenacyl chloride, and chloroacetic acid. The molecular modeling of the synthesized compounds using DFT/B3LYP methodology revealed that all have a low HOMO and LUMO energies, −4.85 - −5.52 and −2.79 - −3.62, respectively, where the compound 10 has the highest values. The targeting thienopyridine analogues with various thiazole moieties 3–10 was assessed in order to create new antimicrobial agents and compared with ampicillin, gentamicin and miconazole as reference antibacterial and antifungal drugs. Compounds 8–10 exhibited potent antimicrobial activity against Gram positive S. aureus, Gram Gram negative E. coli bacteria, and C. albicans (antifungal), with IC50 (18.9 ± 0.63––24.3 ± 0.74 µg/mL), (14.2 ± 0.41––19.5 ± 0.64 µg/mL), and (19.2 ± 0.58–––23.4 ± 0.65 µg/mL), respectively. Furthermore, Molecular docking stimulation on MOE program was applied to expect the effect and interactions of the newly thienopyridine analogues and E. coli DNA gyrase B as it expressed by PDB ID: 1AJ6.

Using sonication and mediated by piperazine, new arene-linked bis(thieno[2,3-b]pyridine) hybrids were efficiently prepared in this study. The target hybrids were prepared by reacting bis(α-haloketone) with two equivalents of the appropriate pyridine-2(1H)-thiones in the presence of 1.4 equivalents of piperazine. The reaction mixture was subjected to sonication at 60 °C for 30–40 min to produce the desired products in 88%–95% yields. When tested against six different ATCC bacterial strains, the new products demonstrated a wide range of antibacterial activity. The 4-(4-methoxyphenyl)-linked hybrids 1i and 1j, attached to 6-(4-methoxyphenyl) and 6-(p-tolyl) units, respectively, had the best efficacy against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa strains. Both hybrids showed more effective potency than the reference ciprofloxacin with MIC and MBC values in the ranges from 2.0 to 2.1, and 4.1 to 4.2 µM, respectively. Additionally, hybrids 1i and 1j demonstrated stronger efficacy than linezolid with MIC values ranging from 2.0 to 4.2 µM, and MBC values ranging from 8.2 to 8.5 µM, respectively, against the MRSA ATCC:33 591 and ATCC:43 300 strains. Furthermore, hybrids 1i and 1j showed inhibitory antibacterial biofilm activity comparable to the standard ciprofloxacin. They had IC50 values ranging from 3.8 to 4.6 µM against S. aureus, E. faecalis, E. coli, and P. aeruginosa strains. The cytotoxicity of hybrids 1i and 1j against the human breast epithelial cell line MCF-10A lends credence to both hybrids' potential as safe antibacterial agents. [ABSTRACT FROM AUTHOR]

New two series of thieno[2,3-b]pyridine-fused pyrimidinones 1 and 2 linked to thiazole or oxazole units were prepared utilizing a three-component tandem protocol. Therefore, a mixture of 1 equiv. of 3-aminothieno[2,3-b]pyridine-2-carboxylate was first microwave irradiated with 1.5 equiv. of dimethylformamide-dimethylacetal in toluene was at 110 °C for 15 min. Next, the crude enamine was dissolved in dioxane and 1 equiv. of the respective 4-arylazole-based amines was added. The mixture was microwaved at 100 °C for 20–30 min, resulting in a 74–89% yield of the target pyrimidinones. The new products showed a wide spectrum of antibacterial activity. In general, oxazole-linked pyrimidinones 2 exceeded their analogs 1 attached to thiazole units in antibacterial activity. Hybrids 2d, and 2e, with 4-(p-tolyl)oxazole and 4-(4-methoxyphenyl)oxazole units, demonstrated the best antibacterial potency among the new products with MIC/MBC values of 4.4/8.8 and 4.2/8.5 µM, respectively. According to SwissADME, all new pyrimidinones could be classified as drug-like. [ABSTRACT FROM AUTHOR]

Using ultrasound irradiation and the eco‐friendly piperazine, two series of (piperazine‐chromene)‐linked bis(thieno[2,3‐b]pyridine) hybrids attached to various arene or chromene units were efficiently prepared. Therefore, the target hybrids were prepared by reacting bis(pyridine‐2(1H)‐thione) with two equivalents of the appropriate α‐haloketones in the presence of 1.4 equivalents of piperazine. The reaction mixture was subjected to ultrasonic irradiations at 60 °C for 20–40 min to produce the desired products in 87–96 % yields. At concentrations of 15 and 25 μM, new hybrids were tested for anti‐acetylcholinesterase activity, as well as their ability to quench DPPH free radicals at a concentration of 25 μg/mL. Generally, the chromene unit attached to thienopyridine‐C2 has a significant effect on the inhibitory activity of the new hybrids. Moreover, the electronic properties of the substituent attached to the chromene‐C6 unit influence the inhibitory activity. The bis(thienopyridine) hybrid attached to 6‐methoxy‐2H‐chromen‐2‐one units demonstrated the best anti‐acetylcholinesterase activity at the previous concentrations, with inhibition percentages of 69.1 and 85.4. Additionally, with an inhibition percentage of 84.4, the previous hybrid demonstrated the most effective anti‐DPPH activity. [ABSTRACT FROM AUTHOR]

A new series of substituted ethyl 7-cyclopropyl-2-(2-aryloxo)-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylates 3a–e were prepared by utilizing ethyl 2-chloro-7-cyclopropyl-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (1) and replacing of the 2-chlorine with anions obtained from phenol (2a), salicylaldehyde derivatives 2b–d or thiophenol (2e), leading to the respective ethyl 7-cyclopropyl-2-(2-aryloxo)-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylates 3a–e. The new compounds were evaluated for their in vitro cytotoxicity towards sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. The screening revealed that compounds 3a, 3b, and 3e inhibited the growth of both cell lines. Compound 3b, with a phenol moiety, exhibited the highest growth inhibitory activity against CEM/ADR5000 and CCRF-CEM cells with IC50 values 4.486 ± 0.286 and 2.580 ± 0.550 µM, respectively. Collectively, the presented results demonstrate that the synthesized thieno[2,3-b]pyridines warrant further exploration for potential use as anti-cancer agents.

Methods for the preparation of new condensed derivatives of pyrido[3',2':4,5]thieno[3,2-d]pyrimidines based on 5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile were developed. Substitution reactions in the 3rd and 4th positions of 7,8-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-one were conducted. The neurotropic activity of 12 obtained compounds was studied in vivo in rats and mice. Eight compounds were found to have an anticonvulsant effect of antagonism with corazole. Four selected compounds had anxiolytic and behavior activating effects. Molecular docking of the synthesized compounds was performed to predict their interaction with the GABAA receptor. Five compounds were identified, the complexation of which with the GABAA receptor occurs in two places: the benzamidine site of subsite 1 and subsite 3 of the ECD interface, which indicates the inhibitory effect of the compounds on the target. [ABSTRACT FROM AUTHOR]

Ovarian cancer is among the most prevalent causes of mortality among women. Despite improvements in diagnostic methods, non-specific symptoms and delayed gynecological exams can lead to late-stage ovarian tumor discovery. In this study, the effect of an anti-cancer compound, 3-amino- N -(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3- b ]quinoline-2-carboxamide (Compound 1 ), was examined. The impacts of cytotoxicity, apoptosis, and metabolomic changes in ovarian cancer cell lines SK-OV-3 and OVCAR-3, as well as glycosphingolipid (GSL) expression, on cancer stem cells (CSCs), marked as CD49f + , and non-CSCs (CD49f - ) were explored. Treatment with Compound 1 reduced the percentage of CSCs compared to non-treated cells ( p < 0.001). The functional impact of eight GSLs on CSCs and non-CSCs was examined using flow cytometry. The glycophenotype changed in both cell lines, with increases or decreases in its expression, after the treatment. These findings raise the possibility of specifically targeting CSCs in ovarian cancer therapy. Additionally, treatment with Compound 1 resulted in statistically meaningful increased apoptosis, including both early and late apoptosis ( p < 0.001), suggesting a pivotal role in initiating programmed cell death by the apoptotic pathway. The analysis revealed that the metabolic activity of treated cancer cells was lower compared to those of the control group ( p < 0.001).

We describe herein an alternative method for the synthesis of 2‐aryl‐(3‐organochalcogenyl)thieno[2,3‐b]pyridines through the electrophilic cyclization of 3‐(arylethynyl)‐2‐(alkylthio)pyridines promoted by electrophilic species of organochalcogen compounds. These species were generated in situ by the oxidative cleavage of chalcogen‐chalcogen (Se, Te) bond of diorganyl dichalcogenides using Oxone® in ethanol as solvent in an open‐flask at 78 °C. The protocol allowed the synthesis of highly substituted thieno[2,3‐b]pyridines starting from several diorganyl dichalcogenides and 3‐(arylethynyl)‐2‐(alkylthio)pyridines, obtaining 21 new compounds in good to excellent yields (70–99%). Still, the method showed good efficiency on the gram‐scale synthesis. In addition, several synthetic transformations such as oxidation, selenylation and hydrogenation reactions were demonstrated. [ABSTRACT FROM AUTHOR]

A new series of substituted ethyl 7-cyclopropyl-2-(2-aryloxo)-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylates 3a–e were prepared by utilizing ethyl 2-chloro-7-cyclopropyl-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (1) and replacing of the 2-chlorine with anions obtained from phenol (2a), salicylaldehyde derivatives 2b–d or thiophenol (2e), leading to the respective ethyl 7-cyclopropyl-2-(2-aryloxo)-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylates 3a–e. The new compounds were evaluated for their in vitro cytotoxicity towards sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. The screening revealed that compounds 3a, 3b, and 3e inhibited the growth of both cell lines. Compound 3b, with a phenol moiety, exhibited the highest growth inhibitory activity against CEM/ADR5000 and CCRF-CEM cells with IC50 values 4.486 ± 0.286 and 2.580 ± 0.550 µM, respectively. Collectively, the presented results demonstrate that the synthesized thieno[2,3-b]pyridines warrant further exploration for potential use as anti-cancer agents. [ABSTRACT FROM AUTHOR]

Background: Heterocyclic compounds and their fused analogs, which contain pharmacophore fragments such as pyridine, thiophene and pyrimidine rings, are of great interest due to their broad spectrum of biological activity. Chemical compounds containing two or more pharmacophore groups due to additional interactions with active receptor centers usually enhance biological activity and can even lead to a new type of activity. The search for new effective neurotropic drugs in the series of derivatives of heterocycles containing pharmacophore groups in organic, bioorganic and medical chemistry is a serious problem. Methods: Modern methodology of drugs involves synthesis, physicochemical study, molecular modeling and selection of active compounds through virtual screening and experimental evaluation of the biological activity of new chimeric compounds with pharmacophore fragments. For the synthesis of new compounds, classical organic methods were used and developed. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. For docking analysis, various soft ware packages and methods were used. Results: As a result of multistep reactions, 11 new, tri- and tetracyclic heterocyclic systems were obtained. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures as well as some psychotropic effects. The biological assays evidenced that nine of the eleven studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of the compounds is low, and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity, it was found that the selected compounds have an activating behavior and anxiolytic effects on the “open field” and “elevated plus maze” (EPM) models. The data obtained indicate the anxiolytic (antianxiety) activity of the derivatives of tricyclic thieno[2,3-b]pyridines and tetracyclic pyridothieno[3,2-d]pyrimidin-8-ones, especially pronounced in compounds 3b–f and 4e. The studied compounds increase the latent time of first immobilization on the “forced swimming” (FS) model and exhibit antidepressant effects; compounds 3e and 3f especially exhibit these effects, similarly to diazepam. Docking studies revealed that compounds 3c and 4b bound tightly in the active site of γ-aminobutyric acid type A (GABAA) receptors with a value of the scoring function that estimates free energy of binding (∆G) at −10.0 ± 5 kcal/mol. Compound 4e showed the best affinity ((∆G) at −11.0 ± 0.54 kcal/mol) and seems to be an inhibitor of serotonin (SERT) transporter. Compounds 3c–f and 4e practically bound with the groove of T4L of 5HT_1A and blocked it completely, while the best affinity observed was in compound 3f ((∆G) at −9.3 ± 0.46 kcal/mol). Conclusions: The selected compounds have an anticonvulsant, activating behavior and anxiolytic effects and at the same time exhibit antidepressant effects.

New 4-acetyl-5-anilino-N-arylthiophene-2-carboxamide derivatives have been synthesized by reaction of 2-acetyl-3-oxo-N-phenylbutanethioamide with three different chloroacetamide reagents. The synthesized thiophenes have been used as precursors in preparation of various thiazole-thiophene hybrids via their condensation with thiosemicarbazide and following treatment of the corresponding thiosemicarbazone with chloroacetone and/or chloroacetic acid. The reaction of 4-acetyl-5-anilinothiophenes with DMF–DMA or malononitrile is the synthetic route to the targeted thieno[2,3-b]pyridine derivatives. Molecular structures of the synthesized compounds have been determined on the basis of IR, 1H and 13C NMR, and mass spectra. The synthesized thiophene-based compounds have been tested for in vitro cytotoxicity by the MTT assay using 5-flourouracil as a reference drug. Thiophene-2-carboxamide derivatives exhibit good inhibitory activity against four cell lines, especially those products that contain thiazolidinone ring or thiosemicarbazide moiety in their structures. [ABSTRACT FROM AUTHOR]

The growing risk of antimicrobial resistance besides the continuous increase in the number of cancer patients represents a great threat to global health, which requires intensified efforts to discover new bioactive compounds to use as antimicrobial and anticancer agents. Thus, a new set of pyridothienopyrimidine derivatives 2a,b–9a,b was synthesized via cyclization reactions of 3-amino-thieno[2,3-b]pyridine-2-carboxamides 1a,b with different reagents. All new compounds were evaluated against five bacterial and five fungal strains. Many of the target compounds showed significant antimicrobial activity. In addition, the new derivatives were further subjected to cytotoxicity evaluation against HepG-2 and MCF-7 cancer cell lines. The most potent cytotoxic candidates (3a, 4a, 5a, 6b, 8b and 9b) were examined as EGFR kinase inhibitors. Molecular docking study was also performed to explore the binding modes of these derivatives at the active site of EGFR-PK. Compounds 3a, 5a and 9b displayed broad spectrum antimicrobial activity with MIC ranges of 4–16 µg/mL and potent cytotoxic activity with IC50 ranges of 1.17–2.79 µM. In addition, they provided suppressing activity against EGFR with IC50 ranges of 7.27–17.29 nM, higher than that of erlotinib, IC50 = 27.01 nM.

The starting precursors 2-carbohydrazides, bearing thienopyridine moiety, were prepared using 2-thioxopyridine-3-carbonitriles as key synthons. Next, 2-carbohydrazides were reacted with a variety of 4-substituted benzylidinemalononitriles or 4-substituted benzaldehydes to afford a new series of the target hydrazones incorporating thienopyridine moiety. The elemental analyses and spectral data were used to demonstrate the structures of new hydrazones series. The in vitro antibacterial activities of the target hydrazones were evaluated against different strains of Gram-positive and Gram-negative bacteria. In comparison with chloramphenicol as a reference drug, hydrazones 13b, 13c and 13d, linked to p-Cl, p-Br and p-Me moiety, respectively, exhibited the strongest activities against all tested bacteria with MIC values in the range of 6.2–12.5 μg/mL. In addition, several new hydrazones were tested as in vitro cytotoxic agents against each of human breast carcinoma MCF-7 cell line, colon cancer Caco2 cell line and liver hepatocellular carcinoma HEPG2 cell line. The hydrazones 13b, 13c and 13d demonstrated the best cytotoxicity against the tested eukaryotic cells. Furthermore, both experimental and docking studies could predict the promising inhibitory activities of hydrazones 13c and 13d against COX-2 enzyme with IC50 of 0.110 and 0.104 µM, respectively, when compared with Celecoxib (IC50 of 0.115 µM). [ABSTRACT FROM AUTHOR]

In this research, we exploited derivatives of thieno[2,3-b]pyridine as dual inhibitors of the key enzymes in eicosanoid biosynthesis, cyclooxygenase (COX, subtypes 1 and 2) and 5-lipoxygensase (5-LOX). Testing these compounds in a rat paw oedema model revealed potency higher than ibuprofen. The most active compounds 7a, 7b, 8b, and 8c were screened against COX-1/2 and 5-LOX enzymes. Compound 7a was the most powerful inhibitor of 5-LOX with IC50 = 0.15 µM, while its p-chloro analogue 7b was more active against COX-2 (IC50 = 7.5 µM). The less desirable target COX-1 was inhibited more potently by 8c with IC50 = 7.7 µM. Surflex docking programme predicted that the more stable anti- conformer of compound (7a) formed a favourable complex with the active site of 5-LOX but not COX-1. This is in contrast to the binding mode of 8c, which resembles the syn-conformer of series 7 and binds favourably to COX-1.

Pyridine‐2(1H)‐thiones were used to prepare two novel series of nicotinonitriles and thieno[2,3‐b]pyridines using piperazine as an eco‐friendly catalyst and under ultrasonic irradiation. The in vitro antibacterial activities of both series were estimated against different Gram‐positive and negative bacterial strains. 2‐((4‐(Benzo[d][1,3]dioxol‐5‐yl)‐3‐cyano‐6‐(thiophen‐2‐yl)pyridin‐2‐yl)thio)acetamide (13 b) gave the least MIC/MBC values of 4.8/9.6, 4.8/9.6 and 9.6/19.7 μM against each of Staphylococcus aureus, Escherichia coli and Streptococcus mutans, respectively, when compared with Ciprofloxacin. Compound 13 b showed also the best biofilm inhibition activities with IC50 values in the range of 5.2‐7.3 μM against S. aureus, S. mutans and E. coli bacterial strains when compared with Ciprofloxacin. Moreover, the most potent antibacterial derivatives were subjected to further evaluation of their cytotoxic activity against HEPG2 and MCF‐7 cell lines as well as their capability to inhibit COX‐2 enzyme. 13 b exhibited the best cytotoxic activity against HEPG2 and MCF‐7 cell lines with IC50 of 23.9 and 29.8 μM, respectively, when compared with Doxorubicin. Also, 13 b revealed nearly inhibition activity equipotent to Celecoxib with IC50 of 0.12 μM. The in silico study was performed to predict the capability of the novel nicotinonitriles and thienopyridines as potent inhibitors of COX‐2 enzyme. [ABSTRACT FROM AUTHOR]

• In this study, two new thieno[2,3-b]pyridine derivatives were synthesized and characterized. • They were also found to be as potent against molecule p38 alpha MAP kinase. • The derivative with stronger biological activity is due to it is a stronger electrophile. In this study, two new thieno[2,3- b ]pyridine derivatives (2 and 3) have been synthesized and characterized by single X-ray diffraction. While compound 2 crystallizes in monoclinic space group P 2 1 / c, compound 3 crystallizes in triclinic space group P. These compounds were further subjected to molecular docking simulation with p38 alpha MAP kinase to understand the binding interaction mechanism, in addition to that ADMET analysis was also performed to explore the title compounds to characterize the future drug candidate. To rationalize their structure-activity relationship, a DFT study based on the B3LYP/6-311++G** theoretical level was also done in this study. [ABSTRACT FROM AUTHOR]

New thieno[2,3- b ]pyridine clubbed various thiazole ring systems were synthesized by the reaction of 2-(1-(3-amino-4,6-dimethylthieno[2,3- b ]pyridin-2-yl)ethylidene)hydrazine-1-carbothioamide with chloroacetone, phenacyl chloride, and chloroacetic acid. The molecular modeling of the synthesized compounds using DFT/B3LYP methodology revealed that all have a low HOMO and LUMO energies, −4.85 - −5.52 and −2.79 - −3.62, respectively, where the compound 10 has the highest values. The targeting thienopyridine analogues with various thiazole moieties 3–10 was assessed in order to create new antimicrobial agents and compared with ampicillin, gentamicin and miconazole as reference antibacterial and antifungal drugs. Compounds 8 – 10 exhibited potent antimicrobial activity against Gram positive S. aureus , Gram Gram negative E. coli bacteria , and C. albicans (antifungal), with IC 50 (18.9 ± 0.63––24.3 ± 0.74 µg/mL), (14.2 ± 0.41––19.5 ± 0.64 µg/mL), and (19.2 ± 0.58–––23.4 ± 0.65 µg/mL), respectively. Furthermore, Molecular docking stimulation on MOE program was applied to expect the effect and interactions of the newly thienopyridine analogues and E. coli DNA gyrase B as it expressed by PDB ID: 1AJ6. [ABSTRACT FROM AUTHOR]

The adhesion of cancer cells to vascular endothelium is a critical process in hematogenous metastasis and might be similar to the recruitment of leukocytes at the site of inflammation. It is mediated by E-selectin and its ligands, of which the most stereospecific is a glycoconjugate sialyl Lewis x (CD15s), which may be expressed as an oligosaccharide branch of the CD44 glycoprotein, as well as a self-contained glycosphingolipid. It is also known that increased sialylation of glycoconjugates is a feature of malignant cells. The aim of the study was to analyse the effect of a novel thieno[2,3-b]pyridine, compound 1, in MDA-MB-231 triple-negative breast cancer cells (TNBCs) upon CD15s and CD44 expression in different cell subpopulations using flow cytometry. CD15s expression was compared between mesenchymal-like cancer stem cells (CSC, CD44+CD24−), epithelial cells without CD44 (CD44−CD24+ and CD44−CD24−), and CD44+CD24+ cells that exhibit mesenchymal and epithelial features. In addition, expression of CD44 in CD15s+CSC and CD15s−CSC was determined. Compound 1 significantly decreased the percentage of CD15s+CSC, CD15s+CD44+CD24+, and CD15s+CD44− subpopulations, as well as the expression of CD15s in CD44+CD24+ and CD44− cells, and therefore shows potential as a treatment for TNBC.

The synthesis and structure-activity relationships of a novel series of 3-aminothieno[2,3- b ]pyridine-2-carboxamides were explored. Our efforts were focused on modifying the C-4 substituent of the thienopyridine ring to develop orally available bone anabolic agents. 4-Alkoxy derivatives were found to be novel ALPase enhancers without inhibitory effect on P450 activity. Among these derivatives, compound 6k was orally administered to ovariectomized rats, and it was found to significantly improve areal bone mineral density at a dose of 30 mg/kg/day. [ABSTRACT FROM AUTHOR]

Malaria causes hundreds of thousands of deaths every year, making it one of the most dangerous infectious diseases worldwide. Because the pathogens have developed resistance against most of the established anti-malarial drugs, new antiplasmodial agents are urgently needed. In analogy to similar antiplasmodial ketones, 4-arylthieno[2,3-b]pyridine-2-carboxamides were synthesized by Thorpe-Ziegler reactions. In contrast to the related ketones, these carboxamides are only weak inhibitors of the plasmodial enzyme PfGSK-3 but the compounds nevertheless show strong antiparasitic activity. The most potent representatives inhibit the pathogens with IC50 values in the two-digit nanomolar range and exhibit high selectivity indices (>100).

Formylated chlorothieno[2,3-b]pyridine derivatives were synthesized by reaction between N-protected 3-acetyl-2-aminothiophenes and Vilsmeier-Haack reagent under classical conditions. These products were not accessible without N-protection of the starting materials or by reaction between the reagent and 4-chlorothieno[2,3-b]pyridine under any conditions. The conditions of the reaction could be altered to produce unformylated derivatives in better yields than reaction with unprotected aminothiophene. [ABSTRACT FROM AUTHOR]

Three series of 5-bromo-thieno[2,3-b]pyridines bearing amide or benzoyl groups at position 2 were prepared as pim-1 inhibitors. All the prepared compounds were tested for their pim-1 enzyme inhibitory activity. Two compounds (3cand5b) showed moderate pim-1 inhibitory activity with IC50of 35.7 and 12.71 μM, respectively. Three other compounds (3d,3gand6d) showed poor pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on five cell lines [MCF7, HEPG2, HCT116, A549 and PC3]. Compound3gwas the most potent cytotoxic agent on almost all the cell lines tested. [ABSTRACT FROM PUBLISHER]

In the title molecule, C22H22N2O4S, the bicyclic core is slightly folded [1.9 (1)°], while pairwise intermolecular N—H...O hydrogen bonding forms dimers across centers of symmetry. The dihedral angle between the phenyl ring an the six-membered ring of the bicyclic core is 75.50 (4)°. The molecular conformation is stabilized by an intramolecular N—H...O hydrogen bond with graph-set motif S(6) and by a weak C—H...O contact, forming an S(7) motif. In the crystal, π–π interactions [centroid-to-centroid distance = 3.7484 (10) Å] between phenyl rings and two weak C—H...π interactions are also observed.

Some of synthetic bicyclic and polynuclear heterocyclic compounds based on pyridine scaffold were tested as in vitro , and these compounds found to exhibit interesting activities. Fused heterocycles containing sulfur such as thienopyridine, pyridothiazine, and some related fused heterocycles as new ring systems were achieved. Bicyclic thienopyridine 6 and pyrido[3,2- e][1,3]thiazin-4(3 H)-one 7 exhibited good antitumor activities compared with 5-fluorouracil. [ABSTRACT FROM AUTHOR]

Highlights: [•] Heterocyclization ring extension of androstenedione through ring E. [•] Fused pyran, pyrimidine and thiazole derivatives were produced. [•] Cytotoxicity of the newly synthesized products were measured against human cancer and normal cell lines. [Copyright &y& Elsevier]

Abstract: Current treatment for hepatitis C is barely satisfactory, there is an urgent need to develop novel agents for combating hepatitis C virus infection. This study discovered a new class of thieno[2,3-b]pyridine derivatives as HCV inhibitors. First, a hit compound characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. And then, structure activity relationship study of the hit compound led to the discovery of several potent compounds without obvious cytotoxicity in vitro (12c, EC50 =3.3μM, SI >30.3, 12b, EC50 =3.5μM, SI >28.6, 10l, EC50 =3.9μM, SI >25.6, 12o, EC50 =4.5μM, SI >22.2, respectively). Although the mechanism of them had not been clearly elucidated, our preliminary optimization of this class of compounds had provided us a start point to develop new anti-HCV agents. [Copyright &y& Elsevier]

Abstract: A cell-based assay was performed for the discovery of novel bone anabolic agents. Alkaline phosphatase (ALPase) activity of ST2 cells was utilized as an indicator of osteoblastic differentiation, and thienopyridine derivative 1 was identified as a hit compound. 3-Aminothieno[2,3-b]pyridine-2-carboxamide was confirmed to be a necessary core structure for the enhancement of ALPase activity, and then optimization of the C4-substituent on the thienopyridine ring was carried out. Introduction of cyclic amino groups to the C4-position of the thienopyridine ring improved the activity. Especially, N-phenyl-homopiperazine derivatives were found to be strong enhancers of ALPase among this new series. Furthermore, 3-amino-4-(4-phenyl-1,4-diazepan-1-yl)thieno[2,3-b]pyridine-2-carboxamide (15k) was orally administered to ovariectomized (OVX) rats over 6weeks for evaluating the effects on areal bone mineral density (aBMD), and statistically significant improvements in aBMD were observed from the dosage of 10mg/kg/day. [Copyright &y& Elsevier]

Background: Heterocyclic compounds and their fused analogs, which contain pharmacophore fragments such as pyridine, thiophene and pyrimidine rings, are of great interest due to their broad spectrum of biological activity. Chemical compounds containing two or more pharmacophore groups due to additional interactions with active receptor centers usually enhance biological activity and can even lead to a new type of activity. The search for new effective neurotropic drugs in the series of derivatives of heterocycles containing pharmacophore groups in organic, bioorganic and medical chemistry is a serious problem., Methods: Modern methodology of drugs involves synthesis, physicochemical study, molecular modeling and selection of active compounds through virtual screening and experimental evaluation of the biological activity of new chimeric compounds with pharmacophore fragments. For the synthesis of new compounds, classical organic methods were used and developed. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. For docking analysis, various soft ware packages and methods were used., Results: As a result of multistep reactions, 11 new, tri- and tetracyclic heterocyclic systems were obtained. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures as well as some psychotropic effects. The biological assays evidenced that nine of the eleven studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of the compounds is low, and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity, it was found that the selected compounds have an activating behavior and anxiolytic effects on the "open field" and "elevated plus maze" (EPM) models. The data obtained indicate the anxiolytic (antianxiety) activity of the derivatives of tricyclic thieno[2,3- b ]pyridines and tetracyclic pyridothieno[3,2- d ]pyrimidin-8-ones, especially pronounced in compounds 3b - f and 4e . The studied compounds increase the latent time of first immobilization on the "forced swimming" (FS) model and exhibit antidepressant effects; compounds 3e and 3f especially exhibit these effects, similarly to diazepam. Docking studies revealed that compounds 3c and 4b bound tightly in the active site of γ-aminobutyric acid type A (GABA A ) receptors with a value of the scoring function that estimates free energy of binding (∆G) at -10.0 ± 5 kcal/mol. Compound 4e showed the best affinity ((∆G) at -11.0 ± 0.54 kcal/mol) and seems to be an inhibitor of serotonin (SERT) transporter. Compounds 3c - f and 4e practically bound with the groove of T4L of 5HT&#95;1A and blocked it completely, while the best affinity observed was in compound 3f ((∆G) at -9.3 ± 0.46 kcal/mol)., Conclusions: The selected compounds have an anticonvulsant, activating behavior and anxiolytic effects and at the same time exhibit antidepressant effects.

4,4,4-Trifluoro-1-(thiophen-2-yl)butane-1,3-dione was reacted by grinding with cyanothioacetamide and cyanoacetamide under solvent-free conditions at 25 ±C to give pyridine-2(1H)thione/one derivatives in excellent yields. These compounds were further reacted by grinding with different halogenated reagents to give 2-S/O-alkyl pyridine derivatives. The latter compounds were utilized for the synthesis of thieno[2,3- b]pyridine, pyrazolopyridine, pyridothienopyrimidine and pyridothienooxazinone derivatives. [ABSTRACT FROM AUTHOR]

Abstract: Among the recently investigated targets for cancer therapy is the c-Src non-receptor tyrosine kinase. Indeed research around deregulated activity of this enzyme has proven its role in tumor progression, while the beneficial effects of c-Src inhibitors in several pathological models has also been demonstrated. We report here the preparation and pharmacological profile of a novel series of c-Src inhibitors that was elaborated around a 3-amino-thieno[2,3-b]pyridine discovered during an HTS campaign. c-Src enzyme inhibition and c-Src inhibition were investigated in a series of related compounds derived from the initial hit. Molecular modeling as well as X-ray studies on one active compound allowed us to hypothesize on ligand orientation and interactions within the ATP hydrophobic pocket. Design and synthesis of structural analogs then led to new ligands possessing quite efficient enzymatic and c-Src inhibition. The structure–activity elements disclosed in this study shed light on the role played by substituents on the thienopyridine ring as well as the impact of other aromatic moieties in the molecule when interacting with the enzyme. [Copyright &y& Elsevier]

Abstract: Several series of thieno[2-3-b]pyridine analogues were synthesized and screened for inhibitory activity against eukaryotic elongation factor-2 kinase (eEF2-K). Modifications around several regions of the lead molecules were made, with a ring fusion adjacent to the nitrogen on the thienopyridine core being critical for activity. The most active compound 34 shows an IC50 of 170nM against eEF2-K in vitro. [Copyright &y& Elsevier]

Pyridine-2(1H)-thione 5 was synthesized from the reaction of 3-[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-1-phenylpropenone (3) and cynothioacetamide (4). Compound 5 reacted with halogented compounds 6a-e to give 2-S-alkylpyridine derivatives 7a-e, which could be in turn cyclized into the corresponding thieno[2,3-b]-pyridine derivatives 8a-e. Compound 8a reacted with hydrazine hydrate to give 9. The latter compound reacted with acetic anhydride (10a), formic acid (10b), acetic acid, ethyl acetoacetate, and pentane-2,4-dione to give the corresponding pyrido[3',2':4,5]thieno-[3,2-d]pyrimidine 13a,b, pyrazolo[3',4':4,5]thieno[3,2-d]pyridine 14 and thieno[2,3-b]-pyridine derivatives 18 and 20, respectively. Alternatively, 8c reacted with 10a,b and nitrous acid to afford the corresponding pyrido[3',2':4,5]thieno[3,2-d]pyrimidine 24a,b and pyrido[3',2':4,5]thieno[3,2-d][1,2,3]triazine 26 derivatives, respectively. Finally compound 5 reacted with methyl iodide to give 2-methylthiopyridine derivative 27, which could be reacted with hydrazine hydrate to yield the corresponding pyrazolo[3,4-b]-pyridine derivative 29. [ABSTRACT FROM AUTHOR]

[Display omitted] The continuing investigation of SAR of 3-aminothieno[2,3- b ]pyridine-2-carboxamide derivatives has been described. In this study, C4-piperidine derivatives with polar functional groups were synthesized to develop orally available bone anabolic agents. The optimized compound 9o (DS96432529), which exhibited the best PK profile and high in vitro activity, showed the highest in vivo efficacy in this series. Moreover, significant synergistic effects were observed following co-administration of DS96432529 and alendronate or parathyroid hormone. The mechanism of action is most likely mediated through CDK8 inhibition. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the synthetic potentiality and chemical reactivity of 2-thioxo-1,2-dihydropyridine-3-carbonitrile derivative 1. This goal performed via its reaction with each of 1-chloroacetone and iodomethane to afford the corresponding 2-alkylthio derivatives 3 and 9, respectively. Compound 3 underwent intramolecular cyclization to afford the corresponding thieno[2,3-b]pyridine derivative 4 which in turn, reacted with dimethylformamide/dimethylacetal followed by hydrazine hydrate and nitrous acid to afford the corresponding pyridothienopyrimidine and pyridothienopyridazine derivatives 6 and 8, respectively. On the other hand, Compound 9 reacted with hydrazine hydrate to give 3-aminopyrazolo[3,4-b]pyridine derivative 10, which diazotized with nitrous acid to give the corresponding diazonium salt 11. Compound 11 coupled with several active -CH2-containing reagents to synthesize the corresponding pyridopyrazolo-triazines 15, 24, 29, and 31. The formulas of all newly synthesized heterocyclic compounds were elucidated by considering the data of IR, 1H NMR, Mass spectral data, as well as data from elemental analyses. [ABSTRACT FROM AUTHOR]

2-Thioxopyridine-3-carbonitrile derivatives 6a-c reacted with several halogen containing reagents 7a-d to afford the corresponding thieno[2,3-b]pyridine derivatives 9a-l, respectively. Thieno[2,3-b]pyridines 9c, g,k used for the preparation of their corresponding carbohydrazide derivatives 10a-c which in turn, used as good synthons for the synthesis of N-phenylmethylenethieno[2,3-b]pyridine-2-carbohydrazides 13a-c, pyrido[3',2':4,5]thieno[3,2-d]pyrimidinones 15a-c, 16a-c and 17 and 1,3,4-oxadiazole-2-thiols 20a-c and 21a-c via their reactions with benzaldehyde or benzylidenemalononitrile, triethylorthoformate and carbon disulfide followed by hydrazine hydrate respectively. Considering the data of IR, 1H NMR, mass spectra, and elemental analyses elucidated the chemical structures of the newly synthesized heterocyclic compounds. [ABSTRACT FROM AUTHOR]

Abstract: In the present investigation, two series of 2,5-disubstituted-3-imidazol-2-yl-pyrrolo[2,3-b]pyridines (2a–l) and thieno[2,3-b]pyridines (3a–l) were designed as analogs of BL 11282 (1). The in vitro glucose dependent insulinotropic activity of all the test compounds was evaluated using RIN5F cell based assay and all the test compounds showed glucose and concentration dependent insulin secretion. The in vivo antidiabetic activities of most potent compounds from each series (2c and 3c) were assessed in C57BL/6J mice. Compounds 2c and 3c showed dose dependent insulin secretion and significant glucose reduction in vivo. In general, compounds 2c and 3c were found to be equipotent at all the three different doses selected and with respect to BL 11282, both the test compounds were found to be more potent, at all the time points. [Copyright &y& Elsevier]

6-Amino-4-naphthyl-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitriles 3a, b were synthesized from the reaction of naphthaldehydes 1a, b and cyanothioacetamide (2). Compounds 3a, b were taken as starting materials for the synthesis of pyrazolo[3,4-b]pyridine 7a, b, and 8a, Pyrido-[2',3':3,4]pyrazolo[1,5-a]pyrimidine 9a, b; thieno[2,3-b]pyridine 16a-d, 18a, b, 21a-d, 24a, b, and 25a; and pyrido[3,2:4,5]thieno[3,2-d]pyrimidine 17a, b derivatives through their reactions with the corresponding reagents. All structures of the newly synthesized heterocyclic compounds were established on the basis of IR, 1H NMR, 13C NMR, mass spectra, and elemental analyses. [ABSTRACT FROM AUTHOR]

Abstract: Sulfonylureas stimulate insulin secretion independent of the blood glucose concentration and therefore cause hypoglycemia in type 2 diabetic patients. Over the last years, a number of aryl-imidazoline derivatives have been identified that stimulate insulin secretion in a glucose-dependent manner. In the present study, we have developed three series of substituted N-(thieno[2,3-b]pyridin-3-yl)-guanidine (2a–l), N-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3a–l), and N-(1H-indol-3-yl)-guanidine (4a–l) as new class of antidiabetic agents. In vitro glucose-dependent insulinotropic activity of test compounds 2a–l, 3a–l, and 4a–l was evaluated using RIN5F (Rat Insulinoma cell) based assay. All the test compounds showed concentration-dependent insulin secretion, only in presence of glucose load (16.7mmol). Some of the test compounds (2c, 3c, and 4c) from each series were found to be equipotent to BL 11282 (standard aryl-imidazoline), which indicated that the guanidine group acts as a bioisostere of imidazoline ring system. [Copyright &y& Elsevier]

Nicotinaldehyde 1 reacted with 2-cyanoethanethioamide 2to give 2-cyano-3-pyridin-3-ylprop-2-enethioamide 3, which reacted with a second mole of 2to give the corresponding 6′-amino-2′-thioxo-1′,2′-dihydro-3,4′-bipyridine-3′,5′-dicarbonitrile 6. The synthetic potentiality of compound 6 was investigated via its reaction with active halogen-containing reagents, e.g., chloroacetone, 2-chloro-3-oxobutanoate, 2-chloroacetamide, chloroaceto-nitrile, and ethyl chloroacetate, to afford the corresponding thieno[2,3-b]-pyridine derivatives. Structure elucidation of all newly synthesized heterocyclic compounds was based on the data of elemental analyses, and IR, 1H NMR, as well as mass spectra. Cytotoxicity, anti–HSV1, anti–HAV, and MBB activities were evaluated for all newly synthesized heterocyclic compounds. [ABSTRACT FROM AUTHOR]

2-cyanoethanthioamide 1 reacted with 1H-indole-3-carbaldehyde 2 to give the corresponding 2-cyano-3-(1H-indol-3-yl)prop-2-enethioamide 3 in a very good yield, which in turn reacted with 2,4-pentanedione 4 to give 5-acetyl-1,2-dihydro-4(1H-indol-3-yl)-6-methyl-2-thioxopyridine-3-carbonitrile. The synthetic potential of 5 was examined through its reaction with several active halogen-containing reagents, e.g., 1-chloropropan-2-one, chloroacetonitrile, 2-chloroacetamide, ethyl chloroacetate, chloroacetic acid, ethyl chloroformate, methyl iodide, and 2-bromo-1-arylethanones 13a–c to give the corresponding thieno[2,3-b]pyridine derivatives 15a–c. The data of elemental analysis as well as the data of IR (cm-1), 1H NMR (δ ppm), and mass spectra elucidated structures of all newly synthesized heterocyclic compounds. All newly synthesized heterocyclic compounds were evaluated as antimicrobial and GST enzyme activity and at the GSH enzyme level. [ABSTRACT FROM AUTHOR]

Abstract: In this work, we performed the design, synthesis, and the structure–activity relationship studies of 13 new derivatives of thieno[2,3-b]pyridine. These derivatives were prepared in high yields (96–70%) and their structures were elucidated by IR, 1H, 13C NMR, and MS. The biological results showed some derivatives as antiparasitic agents against Giardia lamblia. Computational analysis of HOMO and LUMO energy, HOMO orbital coefficient distribution, electrostatic potential map, dipole moment, and density HOMO was performed to gain insight into the SAR aspects. This study pointed the p-methoxy substituted derivative as a leading compound for the development of new microbicidal medicines based on thieno[2,3-b]pyridine analogs. [Copyright &y& Elsevier]

Bipyridine-3′0-carbonitrile derivatives 5 reacted with several halogen containing reagents, e.g., 1-chloroacetone, 3-chloropentan-2,4-dione, ethyl chloroacetate, ethyl 2-chloro-3-oxobutanoate, 2-chloroacetamide, chloroacetonitrile, and iodomethane to afford the corresponding thieno[2,3-b]-pyridine derivatives. Considering the data of IR, 1 H NMR, mass spectra and elemental analysis the chemical structures of the newly synthesized heterocyclic compounds elucidated. Cytotoxicity, anti-HSV1, (anti-Herpes Simplex virus type 1) anti-HAV (Hepatitis A virus), and MBB activity were evaluated for the newly synthesized heterocyclic compounds. [ABSTRACT FROM AUTHOR]

Condensation of propanal with cyanothioacetamide and morpholine gave 3-cyano-4-ethyl-5-methyl-6-morpholino-2-piperidone, the structure of which was studied by X-ray analysis. Reaction of propanal with cyanothioacetamides and cycloalkanone enamines gave 3-cyano-4-ethyl-2,5,6,7-tetrahydropyrindin-2(1H)-one and 3-cyano-4-ethyl-5,6-hexamethylenepyridine-2(1H)-thione. The latter was used for the preparation of substituted 2-benzyloxycarbonylmethylthiopyridine and 3-amino-2-benzyloxycarbonylthieno[2,3-b]pyridine. [ABSTRACT FROM AUTHOR]