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A series of novel thienopyridines and pyridothienoquinolines (3a,b–14) was synthesized, starting with 2-thioxo-1,2-dihydropyridine-3-carbonitriles 1a and 1b. All compounds were evaluated for their in vitro antimicrobial activity against six bacterial strains. Compounds 3a,b, 4a, 5b, 6a,b, 7a, 9b, 12b, and 14 showed significant growth inhibition activity against both Gram-positive and Gram-negative bacteria compared with the reference drug. The most active compounds (4a, 7a, 9b, and 12b) against Staphylococcus aureus were also tested for their in vitro inhibitory action on methicillin-resistant Staphylococcus aureus (MRSA). The tested compounds showed promising inhibition activity, with the performance of 12b being equal to gentamicin and that of 7a exceeding it. Moreover, the most promising compounds were also screened for their Escherichia coli DNA gyrase inhibitory activity, compared with novobiocin as a reference DNA gyrase inhibitor. The results revealed that compounds (3a, 3b, 4a, 9b, and 12b) had the highest inhibitory capacity, with IC50 values of 2.26–5.87 µM (that of novobiocin is equal to 4.17 µM). Docking studies were performed to identify the mode of binding of the tested compounds to the active site of E. coli DNA gyrase B.

Urea transporters (UTs) are transmembrane proteins selectively permeable to urea and play an important role in urine concentration. UT-knockout mice exhibit the urea-selective urine-concentrating defect, without affecting electrolyte balance, suggesting that UT-B inhibitors have the potential to be developed as novel diuretics. In this study, we characterized a novel compound 5-ethyl-2-methyl-3-amino-6-methylthieno[2,3-b]pyridine-2,5-dicarboxylate (CB-20) with UT inhibitory activity as novel diuretics with excellent pharmacological properties. This compound was discovered based on high-throughput virtual screening combined with the erythrocyte osmotic lysis assay. Selectivity of UT inhibitors was assayed using transwell chambers. Diuretic activity of the compound was examined in rats and mice using metabolic cages. Pharmacokinetic parameters were detected in rats using LC–MS/MS. Molecular docking was employed to predict the potential binding modes for the CB-20 with human UT-B. This compound dose-dependently inhibited UT-facilitated urea transport with IC 50 values at low micromolar levels. It exhibited nearly equal inhibitory activity on both UT-A1 and UT-B. After subcutaneous administration of CB-20, the animals showed polyuria, without electrolyte imbalance and abnormal metabolism. CB-20 possessed a good absorption and rapid clearance in rat plasma. Administration of CB-20 for 5 days did not cause significant morphological abnormality in kidney or liver tissues of rats. Molecular docking showed that CB-20 was positioned near several residues in human UT-B, including Leu364, Val367, and so on. This study provides proof of evidence for the prominent diuretic activity of CB-20 by specifically inhibiting UTs. CB-20 or thienopyridine analogs may be developed as novel diuretics.

Our knowledge of the mechanisms of platelet-mediated thrombosis has increased dramatically over the last 40 years. This increased understanding has identified treatment strategies for acute coronary syndromes (ACS) by targeting key mediators of platelet activation and aggregation processes. Aspirin (acetylsalicylic acid) monotherapy improves patient outcomes by irreversibly inhibiting the cyclooxygenase (COX)-1 enzyme in the arachidonic acid pathway. The later-developed thienopyridines, prodrugs that irreversibly inhibit the P2Y 12 receptor, and therefore adenosine diphosphate (ADP) binding, further enhance platelet inhibition and patient outcomes. The thienopyridine clopidogrel has been the standard of care, but it is limited by variable response and treatment failure. A more potent thienopyridine, prasugrel, requires fewer hepatic metabolic steps for activation, and elicits significantly improved outcomes for patients with ACS. The increased potency of prasugrel is associated with an increase in Thrombolysis in Myocardial Infarction (TIMI)-defined major bleeding compared with clopidogrel. Ticagrelor represents a new chemical class of agents called the cyclopentyltriazolopyrimidines. It interacts reversibly with the platelet P2Y 12 receptor, and does not require metabolic bioactivation for activity. Data show a significant improvement in ischaemic outcomes, including mortality, for ticagrelor compared with clopidogrel, without an increase in overall major bleeding, although non-coronary artery bypass graft bleeding is increased. Glycoprotein IIb/IIIa targeted agents (abciximab, tirofiban and eptifibatide) are also used in ACS patients undergoing percutaneous coronary interventions. These inhibitors utilize a different mechanism of action by preventing fibrinogen-mediated platelet aggregation. Other therapeutic strategies for platelet inhibition are being evaluated, including the investigative protease-activated receptor (PAR)-1 and thromboxane A 2 antagonists. This review highlights the mechanisms of action of these agents, and the continuing evolution of ACS therapy.

A series of novel functionalized methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates 2a–2h were synthesized by C-C Pd-catalyzed Suzuki-Miyaura cross-coupling of methyl 3-bromothieno[3,2-b]pyridine-2-carboxylate with (hetero)aryl pinacol boranes, trifluoro potassium boronate salts or boronic acids. Their antitumoral potential was evaluated in two triple negative breast cancer (TNBC) cell lines—MDA-MB-231 and MDA-MB-468, by sulforhodamine B assay. Their effects on the non-tumorigenic MCF-12A cells were also evaluated. The results demonstrated that three compounds caused growth inhibition in both TNBC cell lines, with little or no effect against the non-tumorigenic cells. The most promising compound was further studied concerning possible effects on cell viability (by trypan blue exclusion assay), cell proliferation (by bromodeoxyuridine assay) and cell cycle profile (by flow cytometry). The results demonstrated that the GI50 concentration of compound 2e (13 μM) caused a decreased in MDA-MB-231 cell number, which was correlated with a decreased in the % of proliferating cells. Moreover, this compound increased G0/G1 phase and decreased S phases, when compared to control cells (although was not statistic significant). Interestingly, compound 2e also reduced tumor size using an in ovo CAM (chick chorioallantoic membrane) model. This work highlights the potential antitumor effect of a novel methyl 3-arylthieno[3,2-b]pyridine-2-carboxylate derivative.

The rate of microbial resistance has continued to rise significantly as the availability of new antibiotics has declined. A new series of pyridine and thienopyridine derivatives were designed, synthesized and tested as antimicrobial agents. The reaction of 4-bromo acetophenone and vetraldehyde (3,4-dimethoxy benzaldehyde) in ethanol and sodium hydroxide solution afforded the corresponding chalcone which was used as a suitable precursor to prepare a new series of pyridine derivatives. The treatment of the latter chalcone with 2-cyanothioacetamide afforded the corresponding pyridinethione which was used as a precursor to synthesize the targeted thienopyridine derivatives in good to excellent yield by the reaction with 2-chloro- N -arylacetamide derivatives, α-haloketones, methyl iodide or chloroacetonitrile in one or two steps. The structure of the synthesized compounds was confirmed chemically by their preparations with other pathways and their spectral data. The newly synthesized pyridine and thienopyridine derivatives exhibited good to strong antimicrobial activity against microbial strains E. coli , B. mycoides and C. albicans . With maximal antimicrobial activity against B. mycoides (33 mm) and C. albicans (29 mm), respectively, compounds 12a and 15 demonstrated the highest inhibition zone. Compound 12a prevented the growth of E. coli , at MIC level of 0.0195 mg/mL, and B. mycoides and C. albicans at MIC level below than 0.0048 mg/mL, respectively. Additionally, compound 15 prevented the visible growth of E. coli , B. mycoides , and C. albicans at MIC values of >0.0048, 0.0098, and 0.039 mg/mL, respectively. The relation between the chemical structure of the synthesized pyridine and thienopyridine compounds and their antimicrobial properties was discussed in the SAR study.

In this trial, vorapaxar, a protease-activated–receptor 1 antagonist that inhibits thrombin-induced platelet activation, was not effective in reducing the primary cardiovascular efficacy end point, and it increased rates of bleeding, including serious bleeding and intracranial hemorrhage. The risk of recurrent ischemic complications among patients with acute coronary syndromes without ST-segment elevation remains high despite contemporary treatment strategies, including the use of early revascularization and dual antiplatelet therapy. 1 , 2 Hence, the assessment of new platelet inhibitors has continued to be an important avenue of investigation. 3 – 5 Thrombin activates platelets through two protease-activated receptors (PARs), PAR-1 and PAR-4. 6 PAR-1 is activated by lower concentrations of thrombin than PAR-4 and mediates a more rapid platelet-activation response. 7 In preclinical models, selective PAR-1 blockade resulted in potent inhibition of thrombin-induced platelet aggregation but appeared to preserve primary hemostatic function. 8 Vorapaxar (SCH . . .

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).

Anticipating the risk of gastrointestinal bleeding (GIB) when initiating antithrombotic treatment (oral antiplatelets or anticoagulants) is limited by existing risk prediction models. Machine learning algorithms may result in superior predictive models to aid in clinical decision-making. To compare the performance of 3 machine learning approaches with the commonly used HAS-BLED (hypertension, abnormal kidney and liver function, stroke, bleeding, labile international normalized ratio, older age, and drug or alcohol use) risk score in predicting antithrombotic-related GIB. This retrospective cross-sectional study used data from the OptumLabs Data Warehouse, which contains medical and pharmacy claims on privately insured patients and Medicare Advantage enrollees in the US. The study cohort included patients 18 years or older with a history of atrial fibrillation, ischemic heart disease, or venous thromboembolism who were prescribed oral anticoagulant and/or thienopyridine antiplatelet agents between January 1, 2016, and December 31, 2019. A cohort of patients prescribed oral anticoagulant and thienopyridine antiplatelet agents was divided into development and validation cohorts based on date of index prescription. The development cohort was used to train 3 machine learning models to predict GIB at 6 and 12 months: regularized Cox proportional hazards regression (RegCox), random survival forests (RSF), and extreme gradient boosting (XGBoost). The performance of the models for predicting GIB in the validation cohort, evaluated using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value, and prediction density plots. Relative importance scores were used to identify the variables that were most influential in the top-performing machine learning model. In the entire study cohort of 306 463 patients, 166 177 (54.2%) were male, 193 648 (63.2%) were White, the mean (SD) age was 69.0 (12.6) years, and 12 322 (4.0%) had experienced a GIB. In the validation data set, the HAS-BLED model had an AUC of 0.60 for predicting GIB at 6 months and 0.59 at 12 months. The RegCox model performed the best in the validation set, with an AUC of 0.67 at 6 months and 0.66 at 12 months. XGBoost was similar, with AUCs of 0.67 at 6 months and 0.66 at 12 months, whereas for RSF, AUCs were 0.62 at 6 months and 0.60 at 12 months. The variables with the highest importance scores in the RegCox model were prior GI bleed (importance score, 0.72); atrial fibrillation, ischemic heart disease, and venous thromboembolism combined (importance score, 0.38); and use of gastroprotective agents (importance score, 0.32). In this cross-sectional study, the machine learning models examined showed similar performance in identifying patients at high risk for GIB after being prescribed antithrombotic agents. Two models (RegCox and XGBoost) performed modestly better than the HAS-BLED score. A prospective evaluation of the RegCox model compared with HAS-BLED may provide a better understanding of the clinical impact of improved performance.

Stroke remains a leading cause of death worldwide and the first cause of disability in the western world. Ischemic stroke (IS) accounts for almost 80% of the total cases of strokes and is a complex and multifactorial disease caused by the combination of vascular risk factors, environment and genetic factors. Investigations of the genetics of atherosclerosis and IS has greatly enhanced our knowledge of this complex multifactorial disease. In this article we sought to review common single-gene disorders relevant to IS, summarize candidate gene and genome-wide studies aimed at discovering genetic stroke risk factors and subclinical phenotypes, and to briefly discuss pharmacogenetics related to stroke treatments. Genetics of IS is, in fact, one of the most promising research frontiers and genetic testing may be helpful for novel drug discoveries as well as for appropriate drug and dose selection for treatment of patients with cerebrovascular disease.