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Guanine deaminase (GDA) deaminates guanine to xanthine. Despite its significance, the study of human GDA remains limited compared to other metabolic deaminases. As a result, its substrate and inhibitor repertoire are limited, and effective real-time activity, inhibitory, and discovery assays are missing. Herein, we explore two emissive heterocyclic cores, based on thieno[3,4-d]pyrimidine (thN) and isothiazole[4,3-d]pyrimidine (tzN), as surrogate GDA substrates. We demonstrate that, unlike the thieno analog, thGN, the isothiazolo guanine surrogate, tzGN, does undergo effective enzymatic deamination by GDA and yields the spectroscopically distinct xanthine analog, tzXN. Further, we showcase the potential of this fluorescent nucleobase surrogate to provide a visible spectral window for a real-time study of GDA and its inhibition.

BackgroundThe BYLieve trial (NCT03056755) confirmed efficacy and safety of alpelisib with fulvestrant for hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC), after cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with an aromatase inhibitor (AI) as immediate prior therapy. Further analyses were performed to compare efficacy from BYLieve with effectiveness of standard treatment in the real-world setting.Materials and methodsPatients who progressed on a CDK4/6i plus AI and were treated with alpelisib with fulvestrant in BYLieve were matched with a real-world patient cohort who received standard-of-care from a deidentified clinico-genomics database (CGDB). Primary and secondary endpoints were to compare progression-free survival (PFS), estimated by the Kaplan-Meier method, and the proportion of patients remaining progression-free at 6 months, respectively, between the two cohorts.ResultsA total of 855 patients with PIK3CA-mutant disease who had prior CDK4/6i plus hormone therapy were selected from the CGDB; further matching to 120 patients from BYLieve selected 95 patients without exposure to HER2-targeting agents, clinical study drug, or alpelisib. In unadjusted and postmatching results, primary and secondary endpoints favored treatment with alpelisib with fulvestrant in BYLieve more than standard treatments in the real-world cohort. Postadjustment, median PFS for patients treated with alpelisib in BYLieve was 7.3 versus 3.7 months in the real-world cohort, and 6-month PFS was 54.6% versus 40.1%, respectively.ConclusionMatched/weighted analysis comparing BYLieve with the real-world setting further supports the clinical benefit of alpelisib with fulvestrant for treatment of HR+, HER2-, PIK3CA-mutant ABC after CDK4/6i treatment.Implications for practiceApproximately 40% of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) have PIK3CA-mutated tumors, which have been associated with endocrine therapy resistance. Alpelisib, an α-selective phosphatidylinositol-3-kinase inhibitor, demonstrated significantly improved progression-free survival in SOLAR-1 and demonstrated clinical efficacy in BYLieve when combined with fulvestrant. Data are limited in comparing the efficacy of alpelisib combined with fulvestrant with effectiveness of standard therapy after CDK4/6i treatment. Using real-world data, this is the first analysis comparing alpelisib combined with fulvestrant with standard treatments for HR+, HER2-, PIK3CA-mutant ABC in the post-CDK4/6i setting.

PurposeIn the phase III SOLAR-1 trial (NCT02437318), the PI3Kα-selective inhibitor and degrader alpelisib significantly improved median progression-free survival when added to fulvestrant in patients with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. We assessed health-related quality of life using patient-reported outcome measures in these patients.Materials and methodsIn the PIK3CA-mutant cohort, 341 patients were randomly assigned 1:1 to receive alpelisib 300 mg daily or placebo plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Patient-reported outcomes were evaluated with the European Organisation for Research and Treatment of Cancer QoL of Cancer Patients and Brief Pain Inventory-Short Form questionnaires. Changes from baseline and time to 10% deterioration were analyzed using repeated measurement models and Cox models, respectively.ResultsGlobal Health Status/QoL and functional status were maintained from baseline (mean changes < 10 points) in the alpelisib (overall change from baseline [95% CI], -3.50 [-8.02 to 1.02]) and placebo arms (overall change from baseline [95% CI], 0.27 [-4.48 to 5.02]). Overall treatment effect in Global Health Status/QoL was not significantly different between arms (-3.77; 95% CI, -8.35 to 0.80; P = .101). Time to 10% deterioration for Global Health Status/QoL was similar between arms (hazard ratio, 1.03; 95% CI, 0.72 to 1.48). Compared with placebo, deterioration in social functioning and in diarrhea, appetite loss, nausea or vomiting, and fatigue symptom subscales occurred with alpelisib. Numerical improvement in Worst Pain was observed with alpelisib versus placebo (42% v 32%, week 24; P = .090).ConclusionIn SOLAR-1, there was no statistical difference in deterioration of Global Health Status/QoL between arms, whereas symptom subscales favored placebo for diarrhea, appetite loss, nausea or vomiting, and fatigue, known side effects of alpelisib. Treatment decisions must consider efficacy and tolerability; taken with clinical efficacy, these results support the benefit-risk profile of alpelisib in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative PIK3CA-mutated advanced breast cancer.

Across many species, endocannabinoids play an important role in regulating social play, reward, and anxiety. These processes are mediated through at least two distinct cannabinoid receptors (CB), CB1 and CB2. CB1 expression is found in appreciable densities across regions of the brain that integrate memory with socio-spatial information; many of these regions have been directly linked to the neurobiology of pair bonding in monogamous species. Using receptor autoradiography, we provide the first distributional map of CB1 within the brains of closely related monogamous prairie voles and promiscuous meadow voles, and compare receptor densities across sexes and species in limbic regions. We observe CB1-specific signal using [3H] CP-55,940 and [3H] SR141716A, though the latter exhibited a lower signal to noise ratio. We confirmed the presence of CB2 in prairie vole spleen tissue using [3H] CP-55,940. However, we found no evidence of CB2 in the brain using either [3H] CP-55,940 or [3H] A-836,339. The overall distribution of putative CB1 in the brain was similar across vole species and followed the pattern of CB1 expression observed in other species-high intensity binding within the telencephalon, moderate binding within the diencephalon, and mild binding within the mesencephalon and metencephalon (aside from the cerebellar cortex). However, we found profound differences in CB1 densities across species, with prairie voles having higher CB1 binding in regions implicated in social attachment and spatial memory (e.g., periaqueductal gray, hippocampus). These findings suggest that CB1 densities, but not distribution, correlate with the social systems of vole species.

The article highlights recent findings regarding hydroxychloroquine (HCQ) dosing in systemic lupus erythematosus (SLE), the use of anti-CD19 chimeric antigen receptor (CAR) T cells in treating juvenile dermatomyositis (JDM), and the effectiveness of allopurinol and febuxostat in managing gout flares. Topics discussed include hospitalization rates related to HCQ, successful CAR T cell therapy in JDM, and the STOP Gout trial analysis.

Mapping the gene-regulatory networks dysregulated in human disease would allow the design of network-correcting therapies that treat the core disease mechanism. However, small molecules are traditionally screened for their effects on one to several outputs at most, biasing discovery and limiting the likelihood of true disease-modifying drug candidates. Here, we developed a machine-learning approach to identify small molecules that broadly correct gene networks dysregulated in a human induced pluripotent stem cell (iPSC) disease model of a common form of heart disease involving the aortic valve (AV). Gene network correction by the most efficacious therapeutic candidate, XCT790, generalized to patient-derived primary AV cells and was sufficient to prevent and treat AV disease in vivo in a mouse model. This strategy, made feasible by human iPSC technology, network analysis, and machine learning, may represent an effective path for drug discovery.

ObjectiveTo assess whether Alzheimer disease (AD) clinical presentation and APOE4 relate to the burden and topography of β-amyloid (Aβ) and tau pathologies using in vivo PET imaging.MethodsWe studied 119 Aβ-positive symptomatic patients aged 48-95 years, including 29 patients with logopenic variant primary progressive aphasia (lvPPA) and 21 with posterior cortical atrophy (PCA). Pittsburgh compound B (PiB)-Aβ and flortaucipir (tau)-PET standardized uptake value ratio (SUVR) images were created. General linear models assessed relationships between demographic/clinical variables (phenotype, age), APOE4, and PET (including global cortical and voxelwise SUVR values) while controlling for disease severity using the Clinical Dementia Rating Sum of Boxes.ResultsPiB-PET binding showed a widespread cortical distribution with subtle differences across phenotypes and was unrelated to demographic/clinical variables or APOE4. Flortaucipir-PET was commonly elevated in temporoparietal regions, but showed marked phenotype-associated differences, with higher binding observed in occipito-parietal areas for PCA, in left temporal and inferior frontal for lvPPA, and in medial temporal areas for other AD. Cortical flortaucipir-PET binding was higher in younger patients across phenotypes (r = -0.63, 95% confidence interval [CI] -0.72, -0.50), especially in parietal and dorsal prefrontal cortices. The presence of APOE4 was associated with a focal medial temporal flortaucipir-SUVR increase, controlling for all other variables (entorhinal: + 0.310 SUVR, 95% CI 0.091, 0.530).ConclusionsClinical phenotypes are associated with differential patterns of tau but not amyloid pathology. Older age and APOE4 are not only risk factors for AD but also seem to affect disease expression by promoting a more medial temporal lobe-predominant pattern of tau pathology.

ObjectiveThe purpose of this study was to compare the diagnostic accuracy of antemortem 11 C-Pittsburgh compound B (PIB) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) versus autopsy diagnosis in a heterogenous sample of patients.MethodsOne hundred one participants underwent PIB and FDG PET during life and neuropathological assessment. PET scans were visually interpreted by 3 raters blinded to clinical information. PIB PET was rated as positive or negative for cortical retention, whereas FDG scans were read as showing an Alzheimer disease (AD) or non-AD pattern. Neuropathological diagnoses were assigned using research criteria. Majority visual reads were compared to intermediate-high AD neuropathological change (ADNC).ResultsOne hundred one participants were included (mean age = 67.2 years, 41 females, Mini-Mental State Examination = 21.9, PET-to-autopsy interval = 4.4 years). At autopsy, 32 patients showed primary AD, 56 showed non-AD neuropathology (primarily frontotemporal lobar degeneration [FTLD]), and 13 showed mixed AD/FTLD pathology. PIB showed higher sensitivity than FDG for detecting intermediate-high ADNC (96%, 95% confidence interval [CI] = 89-100% vs 80%, 95% CI = 68-92%, p = 0.02), but equivalent specificity (86%, 95% CI = 76-95% vs 84%, 95% CI = 74-93%, p = 0.80). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% (95% CI = 92-100%) and specificity was 98% (95% CI = 93-100%). Nine of 24 patients with incongruent reads were found to have co-occurrence of AD and non-AD pathologies.InterpretationIn our sample enriched for younger onset cognitive impairment, PIB-PET had higher sensitivity than FDG-PET for intermediate-high ADNC, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, whereas mixed pathology should be considered when PIB and FDG are incongruent. ANN NEUROL 2021;89:389-401.

ObjectiveThe purpose of this study was to compare the diagnostic accuracy of antemortem 11 C-Pittsburgh compound B (PIB) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) versus autopsy diagnosis in a heterogenous sample of patients.MethodsOne hundred one participants underwent PIB and FDG PET during life and neuropathological assessment. PET scans were visually interpreted by 3 raters blinded to clinical information. PIB PET was rated as positive or negative for cortical retention, whereas FDG scans were read as showing an Alzheimer disease (AD) or non-AD pattern. Neuropathological diagnoses were assigned using research criteria. Majority visual reads were compared to intermediate-high AD neuropathological change (ADNC).ResultsOne hundred one participants were included (mean age = 67.2 years, 41 females, Mini-Mental State Examination = 21.9, PET-to-autopsy interval = 4.4 years). At autopsy, 32 patients showed primary AD, 56 showed non-AD neuropathology (primarily frontotemporal lobar degeneration [FTLD]), and 13 showed mixed AD/FTLD pathology. PIB showed higher sensitivity than FDG for detecting intermediate-high ADNC (96%, 95% confidence interval [CI] = 89-100% vs 80%, 95% CI = 68-92%, p = 0.02), but equivalent specificity (86%, 95% CI = 76-95% vs 84%, 95% CI = 74-93%, p = 0.80). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% (95% CI = 92-100%) and specificity was 98% (95% CI = 93-100%). Nine of 24 patients with incongruent reads were found to have co-occurrence of AD and non-AD pathologies.InterpretationIn our sample enriched for younger onset cognitive impairment, PIB-PET had higher sensitivity than FDG-PET for intermediate-high ADNC, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, whereas mixed pathology should be considered when PIB and FDG are incongruent. ANN NEUROL 2021;89:389-401.

Osteoclasts, bone-specified multinucleated cells produced by monocyte/macrophage, are involved in numerous bone destructive diseases such as arthritis, osteoporosis, and inflammation-induced bone loss. The osteoclast differentiation mechanism suggests a possible strategy to treat bone diseases. In this regard, we recently examined the in vivo impact of kalkitoxin (KT), a marine product obtained from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), on the macrophage colony-stimulating factor (M-CSF) and on the receptor activator of nuclear factor κB ligand (RANKL)-stimulated in vitro osteoclastogenesis and inflammation-mediated bone loss. We have now examined the molecular mechanism of KT in greater detail. KT decreased RANKL-induced bone marrow-derived macrophages (BMMs) tartrate-resistant acid phosphatase (TRAP)-multinucleated cells at a late stage. Likewise, KT suppressed RANKL-induced pit area and actin ring formation in BMM cells. Additionally, KT inhibited several RANKL-induced genes such as cathepsin K, matrix metalloproteinase (MMP-9), TRAP, and dendritic cell-specific transmembrane protein (DC-STAMP). In line with these results, RANKL stimulated both genes and protein expression of c-Fos and nuclear factor of activated T cells (NFATc1), and this was also suppressed by KT. Moreover, KT markedly decreased RANKL-induced p-ERK1/2 and p-JNK pathways at different time points. As a result, KT prevented inflammatory bone loss in mice, such as bone mineral density (BMD) and osteoclast differentiation markers. These experiments demonstrated that KT markedly inhibited osteoclast formation and inflammatory bone loss through NFATc1 and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, KT may have potential as a treatment for destructive bone diseases.

Feline calicivirus (FCV) causes upper respiratory tract disease (URTD) and sporadic outbreaks of virulent systemic disease (FCV-VSD). The basis for the increased pathogenicity of FCV-VSD viruses is incompletely understood, and antivirals for FCV-VSD have yet to be developed. We investigated the clinicoepidemiology and viral features of three FCV-VSD outbreaks in Australia and evaluated the in vitro efficacy of nitazoxanide (NTZ), 2'-C-methylcytidine (2CMC) and NITD-008 against FCV-VSD viruses. Overall mortality among 23 cases of FCV-VSD was 39%. Metagenomic sequencing identified five genetically distinct FCV lineages within the three outbreaks, all seemingly evolving in situ in Australia. Notably, no mutations that clearly distinguished FCV-URTD from FCV-VSD phenotypes were identified. One FCV-URTD strain likely originated from a recombination event. Analysis of seven amino-acid residues from the hypervariable E region of the capsid in the cultured viruses did not support the contention that properties of these residues can reliably differentiate between the two pathotypes. On plaque reduction assays, dose-response inhibition of FCV-VSD was obtained with all antivirals at low micromolar concentrations; NTZ EC50, 0.4-0.6 µM, TI = 21; 2CMC EC50, 2.7-5.3 µM, TI > 18; NITD-008, 0.5 to 0.9 µM, TI > 111. Investigation of these antivirals for the treatment of FCV-VSD is warranted.

Hepatocellular carcinoma (HCC) is the sixth most common primary cancer with an unsatisfactory long-term survival. Gain of function mutations of PIK3CA occur in a subset of human HCC. Alpelisib, a selective PIK3CA inhibitor, has been approved by the FDA to treat PIK3CA mutant breast cancers. In this manuscript, we evaluated the therapeutic efficacy of alpelisib, either alone or in combination, for the treatment of HCC. We tested alpelisib in mouse HCC induced by hydrodynamic injection of c-Met/PIK3CA(H1047R) (c-Met/H1047R), c-Met/PIK3CA(E545K) (c-Met/E545K), and c-Met/sgPten gene combinations. Alpelisib slowed down the growth of c-Met/H1047R and c-Met/E545K HCC but was ineffective in c-Met/sgPten HCC. Mechanistically, alpelisib inhibited p-ERK and p-AKT in c-Met/H1047R and c-Met/E545K HCC progression but did not affect the mTOR pathway or genes involved in cell proliferation. In human HCC cell lines transfected with PIK3CA(H1047R), alpelisib synergized with the mTOR inhibitor MLN0128 or the CDK4/6 inhibitor palbociclib to suppress HCC cell growth. In c-Met/H1047R mice, alpelisib/MLN0128 or alpelisib/palbociclib combination therapy caused tumor regression. Our study demonstrates that alpelisib is effective for treating PIK3CA-mutated HCC by inhibiting MAPK and AKT cascades. Furthermore, combining alpelisib with mTOR or CDK4/6 inhibitors has a synergistic efficacy against PIK3CA-mutated HCC, providing novel opportunities for precision medicine against HCC.

Zinc is an essential cofactor for bacterial metabolism, and many Enterobacteriaceae express the zinc transporters ZnuABC and ZupT to acquire this metal in the host. However, the probiotic bacterium Escherichia coli Nissle 1917 (or "Nissle") exhibits appreciable growth in zinc-limited media even when these transporters are deleted. Here, we show that Nissle utilizes the siderophore yersiniabactin as a zincophore, enabling Nissle to grow in zinc-limited media, to tolerate calprotectin-mediated zinc sequestration, and to thrive in the inflamed gut. We also show that yersiniabactin's affinity for iron or zinc changes in a pH-dependent manner, with increased relative zinc binding as the pH increases. Thus, our results indicate that siderophore metal affinity can be influenced by the local environment and reveal a mechanism of zinc acquisition available to commensal and pathogenic Enterobacteriaceae.

Since the 1970s, eight closely related serotypes of classical human astroviruses (HAstV) have been associated with gastrointestinal illness worldwide. In the late 2000s, three genetically unique human astrovirus clades, VA1-VA3, VA2-VA4, and MLB, were described. While the exact disease associated with these clades remains to be defined, VA1 has been associated with central nervous system infections. The discovery that VA1 could be grown in cell culture, supports exciting new studies aimed at understanding viral pathogenesis. Given the association of VA1 with often lethal CNS infections, we tested its susceptibility to the antimicrobial drug, nitazoxanide (NTZ), which we showed could inhibit classical HAstV infections. Our studies demonstrate that NTZ inhibited VA1 replication in Caco2 cells even when added at 12 h post-infection, which is later than in HAstV-1 infection. These data led us to further probe VA1 replication kinetics and cellular responses to infection in Caco-2 cells in comparison to the well-studied HAstV-1 strain. Overall, our studies highlight that VA1 replicates more slowly than HAstV-1 and elicits significantly different cellular responses, including the inability to disrupt cellular junctions and barrier permeability.

Glioblastoma (GBM) is the most common and lethal primary intrinsic tumour of the adult brain and evidence indicates disease progression is driven by glioma stem cells (GSCs). Extensive advances in the molecular characterization of GBM allowed classification into proneural, mesenchymal and classical subtypes, and have raised expectations these insights may predict response to targeted therapies. We utilized GBM neurospheres that display GSC characteristics and found activation of the PI3K/AKT pathway in sphere-forming cells. The PI3Kα selective inhibitor alpelisib blocked PI3K/AKT activation and inhibited spheroid growth, suggesting an essential role for the PI3Kα catalytic isoform. p110α expression was highest in the proneural subtype and this was associated with increased phosphorylation of AKT. Further, employing the GBM BioDP, we found co-expression of PIK3CA with the neuronal stem/progenitor marker NES was associated with poor prognosis in PN GBM patients, indicating a unique role for PI3Kα in PN GSCs. Alpelisib inhibited GSC neurosphere growth and these effects were more pronounced in GSCs of the PN subtype. The antineoplastic effects of alpelisib were substantially enhanced when combined with pharmacologic mTOR inhibition. These findings identify the alpha catalytic PI3K isoform as a unique therapeutic target in proneural GBM and suggest that pharmacological mTOR inhibition may sensitize GSCs to selective PI3Kα inhibition.

BackgroundAberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway is common in many malignancies, including head and neck squamous cell carcinoma (HNSCC). Despite pre-clinical and clinical studies, outcomes from targeting the PI3K pathway have been underwhelming and the development of drug resistance poses a significant barrier to patient treatment. In the present study, we examined mechanisms of acquired resistance to the PI3Kα inhibitor alpelisib (formerly BYL719) in HNSCC cell lines and patient-derived xenografts (PDXs).MethodsFive unique PDX mouse models and three HNSCC cell lines were used. All cell lines and xenografts underwent genomic characterization prior to study. Serial drug treatment was conducted in vitro and in vivo to develop multiple, clinically-significant models of resistance to alpelisib. We then used reverse phase protein arrays (RPPAs) to profile the expression of proteins in parental and drug-resistant models. Top hits were validated by immunoblotting and immunohistochemistry. Flow cytometric analysis and RNA interference studies were then used to interrogate the molecular mechanisms underlying acquired drug resistance.ResultsProlonged treatment with alpelisib led to upregulation of TAM family receptor tyrosine kinases TYRO3 and AXL. Importantly, a significant shift in expression of both TYRO3 and AXL to the cell surface was detected in drug-resistant cells. Targeted knockdown of TYRO3 and AXL effectively re-sensitized resistant cells to PI3Kα inhibition. In vivo, resistance to alpelisib emerged following 20-35 days of treatment in all five PDX models. Elevated TYRO3 expression was detected in drug-resistant PDX tissues. Downstream of TYRO3 and AXL, we identified activation of intracellular MAPK signalling. Inhibition of MAPK signalling also re-sensitized drug-resistant cells to alpelisib.ConclusionsWe have identified TYRO3 and AXL receptors to be key mediators of resistance to alpelisib, both in vitro and in vivo. Our findings suggest that pan-TAM inhibition is a promising avenue for combinatorial or second-line therapy alongside PI3Kα inhibition. These findings advance our understanding of the role TAM receptors play in modulating the response of HNSCC to PI3Kα inhibition and suggest a means to prevent, or at least delay, resistance to PI3Kα inhibition in order to improve outcomes for HNSCC patients.

The present microreview systematizes recent advances in the synthetic approaches for novel thiazolo[4,5-b]-pyridines and summarizes pharmacological effects they were found to possess. In particular, modern synthetic techniques for thiazolo[4,5-b]pyridine bicyclic scaffold construction starting from thiazole or thiazolidine derivatives followed by pyridine annulation, which results in the target fused thiazolo[4,5-b]pyridines, are analyzed. [ABSTRACT FROM AUTHOR]

Background: Thiazole ring is one of the most important heterocycle scaffolds in organic and medicinal chemistry due to this scaffold being the backbone of numerous drugs and their significant activities against various diseases have made it one of the best candidates for industrial production. According to the literature, the number of drugs that have this ring on their structures is increasing. In fact, drugs containing thiazole scaffold have taken a significant share in the last decade, which reached its maximum number of 8 drugs in 2019. Objective: In This current review, we focus on essential advances of antimicrobial, anti-inflammatory, and anticancer activities of structures containing thiazole scaffold and various groups’ effects on this scaffold against the broad spectrum of bacterial strains, fungal strains, inflammatory cells, and cancer cells. Also, we analyzed and investigated thiazole hybrids with potential antimicrobial, anti-inflammatory, and anticancer activities. Results: More than 100 research articles were found, we selected about 100 research articles from 2014 to 2022 that had outstanding results.

This study presents a novel halogen dance reaction using 4,5‐dibromo‐2,4'‐bithiazole, which demonstrates a long‐range effect. The reaction involves the migration of a bromo group from the C5‐position to the C2'‐position of another thiazole ring when treated with lithium hexamethyldisilazide (LiHMDS), resulting in the formation of a non‐symmetric brominated bithiazole. In contrast, the base‐induced C2'‐bromination of 4‐bromobithiazole was found to be inefficient in synthesizing the desired brominated bithiazole due to its poor deprotonation selectivity. [ABSTRACT FROM AUTHOR]

We present the first total synthesis of the thiamyxins A–C and the now fully characterized thiamyxin E, an interesting class of thiazole‐ and thiazoline‐rich depsipeptides with diverse antiviral activity. The synthesis features a parallel closing of two methyl thiazoline units, with low epimerization of the very labile adjacent stereocenter. It also includes the three‐step synthesis of an uncommon hydroxy acid and the oxidation‐free elimination of a phenylselenide to form a dehydroalanine moiety. The exploitation of the acid‐labile stereocenter at the isoleucine moiety and the reopening of the macrolactones gave access to the four thiamyxins with good yields and diastereomeric purities from a single precursor. The modular total synthesis allows further testing of the biological activity and gives opportunities to explore the pharmacophore and antiviral target through derivatization. [ABSTRACT FROM AUTHOR]

A highly efficient and simple route for the synthesis of 2-substituted benzo[d]thiazoles has been developed by nickel catalyzed cross-coupling of 2-methylthiobenzo[d]thiazoles with aryl and alkenylaluminum reagents. Various 2-(hetero)aryl and 2-alkenyl substituted benzo[d]thiazoles derivatives can be obtained with 31–94% isolated yields using 4 mol% NiCl2(dppf)/4 mol% 2,2′-bipyridine as the catalyst under mild reaction conditions. The coupling reaction can be carried out smoothly whether the electron donor group or electron withdrawing group is on the aromatic ring of organic aluminum reagents or 2-methylthiobenzo[d]thiazoles derivatives. Furthermore, the broad substrate scope and the typical maintenance of vigorous efficiency on a gram scale make this protocol a potentially practical method to synthesize 2-substituted benzo[d]thiazoles derivatives. On the basis of the experimental results, a possible catalytic cycle has been proposed. [ABSTRACT FROM AUTHOR]

In last few decades, nitrogen‐containing heterocycles have maintained their status as an important core of FDA‐approved drugs and medicinally active compounds. Quinoxaline is one such class of nitrogen‐containing scaffold that has become a subject of extensive research as it possess a plethora of biological activities. Molecular hybridization is a versatile and rational approach to drug design that involves the combination of two bioactive molecules possessing distinct intrinsic activity into a single scaffold for enhancing their therapeutic potential. In view of this, the advancement and potential of quinoxaline hybrids bearing thiazole, triazole, oxadiazole, pyrrolizines, pyrazole, etc. have attracted the keen attention of researchers to explore their therapeutic ability against different biological targets. The present review includes the research in the recent years (2018–2023) and addresses the graceful advancements in the studies related to quinoxaline‐based small molecules including their synthetic routes, biological activities and structure‐activity relationships. We anticipate that this review article will provide comprehensive knowledge of pharmacological importance of quinoxaline analogues and will fulfill the need of scientific community in designing and developing efficacious novel molecules. [ABSTRACT FROM AUTHOR]

Aim: To investigate the effect of benzothiazole derivatives (Rosline) on ovarian cancer and the potential mechanism. Methods: Ovarian cancer tissues were collected clinically and immunohistochemistry was used to detect the expression of p53 and p21. Ovarian cancer cells were exposed to 0, 2.5, 5, 10 μmol/L Rosline for 24 h. 100 nmol/L Pifithrin‐α pre‐incubation was used to inhibit the transcriptional activity of p53. CCK‐8 and BrdU assays were used to detect the effects of different concentrations of rosline on the proliferation and cell cycle of OVCAR420 and SKOV3 cells. Flow cytometry assay was used to detect cell cycle. The transcriptional and translational expression of p21 and p53 were detected by RT‐qPCR and Western blot. Results: p21 was expressed in ovarian cancer tissues without p53 expression. Rosline inhibits the proliferation of ovarian cancer cells and blocks the cell cycle progression. Meanwhile, Rosline promotes p21 expression in ovarian cancer cells at both mRNA and protein levels, but with no significant effect on p53 expression. Besides, Rosline promotes p21 expression, inhibits cell proliferation, and blocks the cell cycle via the p53‐independent pathway. Conclusion: Rosline promoted p21 expression thereby inhibiting cell proliferation and blocks the cell cycle via p53‐independent pathway. [ABSTRACT FROM AUTHOR]

A series of novel thiadiazole-incorporated aminothiazole derivatives were synthesized and characterized by IR and 1H NMR and 13C NMR spectroscopy, ESI mass spectrometry, and elemental analysis. All the synthesized compounds were tested for their in vitro anticancer activity against MCF-7, A549, and HeLa human cancer cell lines by the MTT assay. 5-(1-{2-[4-(4-Nitrophenyl)thiazol-2-yl]hydrazono}ethyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-imine and 5-(1-{2-[4-(4-bromophenyl)-3-ethylthiazol-2(3H)-ylidene]hydrazono}ethyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-imine showed a remarkable activity against three cancer cell lines, when compared to the reference drug cisplatin. The products were also tested for antibacterial activity against S.aureuss, P. aeruginosa, and E. coli bacteria and antifungal activity against A. Niger and C. albicans fungi. 5-(1-{2-[4-(4-Methoxyphenyl)thiazol-2-yl]hydrazono}ethyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-imine was found to be much more potent antibacterial agent than the other synthesized compounds. [ABSTRACT FROM AUTHOR]

The recent developments of multicomponent reactions for the synthesis of biologically active molecules containing the pyrazole moiety were reviewed by J.-C. Castillo and coworkers. They reported on the main methods of synthesis, which include Friedländer condensation, synthesis from anthranilic acid derivatives, multicomponent synthesis, and others, and the use of this class of compounds as potential fluorescent sensors and biologically active compounds. Pyrazole and its derivatives are considered privileged I N i -heterocycles with immense therapeutic potential. They also reported synthetic methods used for their synthesis, starting from a pre-formed pyrazole or pyridine, as well as the biomedical applications of such compounds. [Extracted from the article]

Novel diarylethenes with a 1,3-thiazole bridge connected by a hydrazinomethylene spacer with tetrazolo[1,5-a]quinoline substituents were synthesized. They exhibit photochromic properties in acetonitrile or in a semiaqueous acetonitrile solution when exposed to the 436 nm light, associated with isomerization into a colored ring-closed form. The reverse reaction occurs under irradiation with visible 540 nm light. The compounds obtained demonstrate ionochromic "naked eye" effects in the presence of fluoride anions or nickel(II) and zinc(II) cations due to a change in the coloration of the solution from yellow to blue or crimson, respectively. Test strips containing diarylethenes were prepared for the easy detection of these ions. [ABSTRACT FROM AUTHOR]

In this paper, thiazolo[3,2-a]pyrimidine-2,3-dicarboxylate and oxazolo[3,2-a]pyrimidine-2,3-dicarboxylate derivatives are produced in excellent yields via the multicomponent reaction of anilines, ethyl acetoacetate, aldehydes, urea or thiourea, activated acetylenic esters and triphenylphosphine in the presence of Ag/KF/CP@MWCNT as a high efficient catalyst in aqueous media at ambient temperature. The Ag/KF/CP@MWCNT is generated by water extract of rhizome Petasites hybridus as an environmentally media and moderate base. Also, Ag/KF/CP@MWCNT leads to increasing of yield of products and has notable reusability. Antioxidant ability of the resulted compounds is studied by DPPH (radical trapping of diphenyl-picrylhydrazine) and ferric reduction power tests. Also, the antimicrobial activity of some products is determined with the disk diffusion experiment on Gram-positive and Gram-negative bacteria. The advantages of this protocol include of short reaction time, high efficiency and easy separation of products and use of simple catalyst. Green chemistry is the use of a set of principles to reduce or eliminate the use or generation of unsafe materials in the design, fabrication and applications of chemical products. Among solvents, water is a green solvents and very suitable for performing organic reaction. The present procedure avoids the use of toxic solvent. Compounds bearing fused thiazole and pyrimidine units play important role in organisms because they have good biological potentials. Thiazolopyrimidines are an interesting group of heterocyclic compounds and among them the thiazolo[3,2-a]pyrimidine skeleton are a key constructions and have vital biological activities and are widely found in important drugs such as Alzheimer's disease, anticancer, antimicrobial, anti-inflammatory, antioxidant, anti-human cytomegalovirus activity, antiparkinsonian, antitumor and antiviral. [ABSTRACT FROM AUTHOR]

In the structure of the title compound, C17H14N4O2, the triazole ring exhibits inter-planar angles of 63.86 (2) and 76.96 (2)° with the phenyl and benzo-thiazole planes, respectively. The C--C--C angle at the methylene group is rather wide at 114.28 (4)°. The packing involves three borderline C--H...N contacts, two of which combine to form layers parallel to ac, and a pairing of the triazole rings across an inversion centre [inter-planar distance of 3.1852 (2) Å]. [ABSTRACT FROM AUTHOR]

Under the standard reaction conditions, methyl, phenyl, and 2-pyridyl sulfinates all engaged in the C-H sulfonylation with thiazole I N i -oxide B 2a b to furnish the corresponding thiazole sulfones B 3aa b - B ac b . Subjecting sulfone B 3f b to the copper-catalyzed reactions with an aryl iodide or iodonium salt led to clean conversion of B 3f b to the parent thiazole B 4f b , reminiscent of an observation made in our previous studies. Keywords: silyloxymethanesulfinate; C-H functionalization; modular synthesis; azole N -oxides; sulfonylazoles EN silyloxymethanesulfinate C-H functionalization modular synthesis azole N -oxides sulfonylazoles 1447 1451 5 07/11/23 20230725 NES 230725 Graph Due to the unique pharmacophoric properties associated with heteroaromatic systems, azoles are often considered as scaffolds of choice in designing medicinally active agents. 2021, 23: 8554 12 Thierry, T. Pfund, E. Lequeux, T. Chem. Eur. J. 2021, 27: 14826 13 Shaaban, S. Liang, S. Liu, N.-W. Manolikakes, G. Org. [Extracted from the article]

This study presents a quantitative estimation of the B–Hb⋯π interaction of diborane with heteroarenes (pyrrole, furan, oxazole, isoxazole, thiophene, thiazole, and isothiazole) and anionic arenes (cyclopentadienyl anion and pentazolate ion). The DFT-D3 method at the B3LYP-D3/6-311++G(d,p) level of theory was exclusively used for geometry optimization and scrutinizing the stability of the complexes. The results indicated the formation of weakly stable complexes with heterocycles and pentazolate ion (ΔE < 6.0 kcal mol−1). The complex formed between diborane and the cyclopentadienyl anion is very stable (ΔE > 12.0 kcal mol−1) with dispersive interaction playing a secondary role. The stability of the complexes suggested from MP2 calculation and other DFT (ωB97X-D and M06-2X) methods is consistent with the results obtained from the DFT-D3 method. The process of complexation is enthalpy driven, except for the complex between diborane and the cyclopentadienyl ion. The spontaneity of the process is mainly governed by the entropy factor. The plot of NCI was used to visualize the non-covalent interaction regions. NBO analysis was also performed to estimate the strength of the donor-acceptor interaction. The asymmetric and symmetric stretching of the B–Hb⋯π vibrational modes and 1H NMR shift in the free diborane and that in the complexes were also analysed. [ABSTRACT FROM AUTHOR]

In a precarious world of rapidly growing pandemics, the field of vaccine production has witnessed considerable growth. Bacillus Calmette-Guérin (BCG) is a live-attenuated vaccine and a part of the immunization program in 157 countries. The quality control is based on a potency test through viable cell enumeration. The colony-forming unit (CFU) assay is the official method, however, it often yields fluctuating results, suffers from medium cracking, and requires lengthy analysis (~ 28 days). Flow cytometric analysis was proposed earlier, but it was coupled with a Coulter counter for measuring the entire bacterial population (live/dead). In the present study, thiazole orange/propidium iodide dyes supplemented with fluorogenic reference beads were employed for viable counting, eliminating the need for a Coulter counter. Both the flow cytometry and the colorimetric technique employing tetrazolium salt were validated and compared to the CFU assay. The colorimetric assay displayed high precision, accuracy, and a strong positive correlation with the CFU assay. The flow cytometry assay demonstrated high precision and a notable ability to distinguish different forms of BCG cells (live, injured, and dead). It also exhibited a perfect positive correlation with the CFU assay. Both methods reduced the analysis time by > 26 days and eliminated the need for human intervention by automating the test. [ABSTRACT FROM AUTHOR]

Pollution of water by heavy metal ions such as Pb2+ and Hg2+ is considered as an important issue, because of the potential toxic effects these ions impose on environmental ecosystems and human health. A new Zn-based metal–organic framework, [Zn2(DPTTZ) (OBA)2] (IUST-2), was synthesized through a solvothermal method by the reaction of 2, 5-di (4- pyridyl) thiazolo [5, 4-d] thiazole ligand (DPTTZ), the "V-shape" 4,4'-oxybis (benzoic acid) ligand (OBA) and zinc nitrate (Zn(NO3)2·6H2O). This novel MOF has been characterized by several analysis techniques such as fourier transform infrared spectroscopy (FT-IR), elemental analysis (EA), powder x-ray diffraction (PXRD), thermogravimetry analysis (TGA), differential thermal analysis (DTA), field emission scanning electron microscopy (FE-SEM), Brunauer–Emmett–Teller (BET) surface area analysis and single-crystal X-ray diffraction (SXRD). This 3D MOF was tested for removing Pb2+ and Hg2+ ions from water. The factors that were investigated on the elimination of Pb2+ and Hg2+ ions were of pH, adsorption time, and the effect of initial ions concentration. According to the results, this particular Zn-MOF had significant performance in eliminating Pb2+ and Hg2+ ions from water with a removal efficiency of more than 97% and 87% within 3 min, respectively. [ABSTRACT FROM AUTHOR]

Introduction: The identification of chemical compounds that interfere with SARSCoV- 2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the appliedmodels are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence. Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy-performed in a large and diverse chemolibrary- complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening. Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC50 = 25 µM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC50 = 0.12-20 µM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC50 7-45 µM). Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known "garbage in, garbage out" machine learning principle. [ABSTRACT FROM AUTHOR]

QSAR studies of a set of previously synthesized azole derivatives tested against human cytomegalovirus (HCMV) were performed using the OCHEM web platform. The predictive ability of the classification models has a balanced accuracy (BA) of 73–79%. The validation of the models using an external test set proved that the models can be used to predict the activity of newly designed compounds with a reasonable accuracy within the applicability domain (BA = 76–83%). The models were applied to screen a virtual chemical library with expected activity of compounds against HCMV. The five most promising new compounds were identified, synthesized and their antiviral activities against HCMV were evaluated in vitro. Two of them showed some activity against the HCMV strain AD169. According to the results of docking analysis, the most promising biotarget associated with HCMV is DNA polymerase. The docking of the most active compounds 1 and 5 in the DNA polymerase active site shows calculated binding energies of -8.6 and -7.8 kcal/mol, respectively. The ligand's complexation was stabilized by the formation of hydrogen bonds and hydrophobic interactions with amino acids Lys60, Leu43, Ile49, Pro77, Asp134, Ile135, Val136, Thr62 and Arg137. [ABSTRACT FROM AUTHOR]

Heterocyclic compounds are the main class of medicinally important compounds. Many heterocyclic compounds bearing a fivemembered ring in their structure have a good spectrum of biological activities. In medicinal chemistry, thiazole and its analogues are promising scaffolds. Many of them have been reported to exhibit a variety of biological responses, including anti-hyperlipidemic, anti- HIV, anticancer, anti-Alzheimer, antihypertensive, anti-inflammatory, antimicrobial, anticonvulsant, antiviral, antimalarial, and antidiabetic activities. In this study a modern approach has been undertaken to identify new hits of thiazole derivatives as antimalarials targeting against Pf-DHFR. It has been conceived, synthesised, and tested for potential anti-malarial action to create a number of new thiazole derivatives. The antimalarial activity of the synthesized thiazole derivatives was assessed against human pathogenic malarial strain viz. Plasmodium falciparum while quinine was taken as the standard drug. compound 1a-1e was found to be most promising which exhibited strongest inhibitory activity against Pf-DHFR which was higher than the reference drug quinine. The aim of this research is to identify and try making a SAR (Structure Activity Relationship) of substituted thiazole nucleus as possible new antimalarials as shown in compound 1a-1e. The result of molecular docking studies showed that compounds 1a, 1b, 1c, 1d and 1e showed good docking scores with protein (protein ID-7CTZ). The compounds with the greatest docking scores were 1a and 1b (-9.9 and -9.8). Contrarily, compounds 1a, 1b, 1c, 1d, and 1e displayed favorable docking results and important interactions with amino acid residues such Gly150, leu146, Phe197, Val198, Asp145, Asp148, Thr152, Thr149, Glu144, and Ala178. The results of biological activity and docking studies showed that an electron-withdrawing group at the fourth position of the attached phenyl ring of thiazole derivatives is essential for better anti-malarial activity and a favorable drug-like profile that can lead to the emergence of a potential drug molecule in further development. [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]

The benzo[d]thiazole derivatives 4a-c were synthesized and used for the synthesis of thiophene derivatives 6a-f. They form the arylhydrazone derivatives 8a-i which were capable to form pyridazine derivatives 9a-i and 10a-i. The latter compounds reacted with thioglycolic acid to produce the thiazole derivatives 12a-i and 13a-i, respectively. The thiazole derivatives 15a-c were also produced from 4a-c through their reactions with elemental sulfur and phenylisothiocyanate. Further heterocyclization reactions of 15a were carried out to produce thiophene derivatives. Evaluations of the synthesized products were carried out against some selected cancer cell lines and the most active compounds were further evaluated against the seventeen cancer cell lines classified according to the disease. Morphological changes of A549 cell line by the effect of compounds 13c and 13h were studied using microenvironment of the lung tissue where an excellent result was obtained. [ABSTRACT FROM AUTHOR]

Objective Gout flares during urate-lowering therapy (ULT) initiation are common, but predictors of these flares are poorly understood. The aim of this study was to determine whether serum CA72-4 is an independent predictor for gout flares during ULT initiation. Methods A prospective cohort study was conducted between March 2021 and January 2022. Men with gout, at least one gout flare in the past year, and at least three serum CA72-4 measurements in the previous six months were enrolled. Participants were grouped according to their highest recorded serum CA72-4 levels (above or within the normal range). All participants took oral febuxostat 20 mg daily without flare prophylaxis therapy, and attended face-to-face visits every four weeks until 24 weeks. The incidence of gout flare was compared between the two groups. Backward stepwise logistic regression analyses were used to identify risk factors associated with flares. Receiver operating characteristic curve analysis was used to evaluate prediction efficacy. Results A total of 193 completed the study (79 with high CA72-4; 114 with normal CA72-4). The cumulative incidence of at least one gout flare was 48.1% (62.1% in the high CA72-4 group, 38.4% in the normal CA72-4 group, P  = 0.001), and recurrent (≥2) flares was 33.0% (47.1% in the high CA72-4 group, 23.2% in the normal CA72-4, P  < 0.001). High CA72-4, disease duration, intra-articular tophus size, glucose, high-density lipoprotein-cholesterol and ESR were independent risk factors for gout flares. Serum CA72-4 alone predicted recurrent flares with an area under the curve of 0.63 (95% CI = 0.54, 0.71), and 0.78 (95% CI = 0.71, 0.85) when combined with other independent variables. Conclusion High serum CA72-4 predicts the risk of gout flares during ULT initiation. Trial registration ChiCTR; https://www.chictr.org.cn/ ; ChiCTR2100043573. [ABSTRACT FROM AUTHOR]

2,3,4-trisubstituted thiazoles 3a–i, having a methyl group in position four, were synthesized by the reaction of 1,4-disubstituted thiosemicarbazides with chloroacetone in ethyl acetate/Et3N at room temperature or in ethanol under reflux. The structures of new compounds were determined using NMR spectroscopy, mass spectrometry, and elemental analyses. Moreover, the structure of compound 3a was unambiguously confirmed with X-ray analysis. The cell viability assay of 3a–i at 50 µM was greater than 87%, and none of the tested substances were cytotoxic. Compounds 3a–i demonstrated good antiproliferative activity, with GI50 values ranging from 37 to 86 nM against the four tested human cancer cell lines, compared to the reference erlotinib, which had a GI50 value of 33 nM. The most potent derivatives were found to be compounds 3a, 3c, 3d, and 3f, with GI50 values ranging from 37 nM to 54 nM. The EGFR-TK and BRAFV600E inhibitory assays' results matched the antiproliferative assay's results, with the most potent derivatives, as antiproliferative agents, also being the most potent EGFR and BRAFV600E inhibitors. The docking computations were employed to investigate the docking modes and scores of compounds 3a, 3c, 3d, and 3f toward BRAFV600E and EGFR. Docking computations demonstrated the good affinity of compound 3f against BRAFV600E and EGFR, with values of −8.7 and −8.5 kcal/mol, respectively. [ABSTRACT FROM AUTHOR]

A great proportion of molecular crystals can be made to grow as twisted fibrils. Typically, this requires high crystallization driving forces that lead to spherulitic textures. Here, it is shown how micron size channels fabricated from poly(dimethylsiloxane) (PDMS) serve to collimate the circular polycrystalline growth fronts of optically banded spherulites of twisted crystals of three compounds, coumarin, 2,5‐bis(3‐dodecyl‐2‐thienyl)‐thiazolo[5,4‐d]thiazole, and tetrathiafulvalene. The relationships between helicoidal pitch, growth front coherence, and channel width are measured. As channels spill into open spaces, collimated crystals "diffract" via small angle branching. On the other hand, crystals grown together from separate channels whose bands are out of phase ultimately become a single in‐phase bundle of fibrils by a cooperative mechanism yet unknown. The isolation of a single twist sense in individual channels is described. We forecast that such chiral molecular crystalline channels may function as chiral optical wave guides. [ABSTRACT FROM AUTHOR]

New 1,3-thiazol-2-yl-, 1,3-thiazol-4-yl-, and 1,3-thiazol-5-yl-containing derivatives of N-arylalkyl- and N-carboxyalkyl-substituted rhodanines were synthesized via Knoevenagel condensation and tested against 60 cancer cell lines of NCI panel. Among these compounds, N-[2-(4-methoxyphenyl)ethyl], N-[2-(3,4-dimethoxyphenyl)ethyl], and N-carboxydecyl rhodanines with 1,3-thiazol-4-yl or 1,3-thiazol-5-yl fragments were the most effective agents causing growth inhibition of more than 50% of the individual lines of the panel. Their activity was characterized by calculated mean values of 50% growth inhibition (GI50), total growth inhibition (TGI), and 50% cell killing (LC50). For sensitive cell lines of the total panel, mean GI50 and mean TGI were similar for compounds bearing N-[2-(4-methoxyphenyl) ethyl] and N-[2-(3,4-dimethoxyphenyl)ethyl] substituents, and significantly lower for compound with N-carboxydecyl substituent. The increase in the activity of the 1,3-thiazol-5-yl-containing derivative of N-carboxyalkyl-substituted rhodanine was accompanied by a decrease in the number of cell lines sensitive to its inhibitory effects. According to the in vitro data, some of the cancer cell lines were targeted by this compound with activity ranging from submicromolar to micromolar levels. Based on molecular docking results, the possible targets for anticancer activity of the thiazole-containing rhodanine derivatives were considered. [ABSTRACT FROM AUTHOR]

Inhibition of the cyclin dependent kinase 2 (CDK2) is a well-known cancer treatment approach. Based on the molecular docking simulation analysis, two new series of 2-(1-(4-methoxyphenyl)-2-(phenylsulfonyl)ethylidene)hydrazineylidene)-2,5-dihydrothiazole as CDK-2 inhibitors were designed. The lead compound IV (5-benzoyl-N2-phenyl-1,3-thiazole-2,4-diamine) was modified and optimized prior to this analysis. In contrast to Roniciclib (−8.6 kcal/mol), docking results of CDK2 hits showed high affinity and docking scores ranging from −9.1 to −10.3 kcal/mol. All of the compounds studied were evaluated in vitro for CDK2 inhibitory activity. In comparison to Roscovitine's IC50 of 0.432 µM, compound 11b had a maximum IC50 of 0.416 µM. Additionally, all hits were tested for antiproliferative activities against PC-3 human prostate cancer cells, HEPG-2 human hepatocellular carcinoma, and MCF-7 breast adenocarcinoma cell lines. The arylhydrazine moiety of the tested compounds 11a–e demonstrated high potency against HEPG-2, with 11b (IC50 = 0.11 µM) being more active than doxorubicin (IC50 = 0.12 µM). In addition, compound 11b (IC50 = 0.245 µM) was nearly as effective as doxorubicin (IC50 = 0.246 µM) against MCF-7 cancer cells. 11d showed superior antiproliferative activity against PC-3 cell line (IC50= 0.23 µM) relative to doxorubicin (IC50 = 0.29 µM). [ABSTRACT FROM AUTHOR]

Organic solar cells (OSCs) have achieved much progress with rapidly increasing power conversion efficiencies (PCEs). It should be noted that the top‐performance OSCs are generally consisted of active materials with complex chemical structures, resulting in high costs. Here, combining the material design and morphology control, high‐efficiency OSCs are fabricated by a low‐cost donor: acceptor blend. A completely non‐fused electron acceptor named Tz is designed and synthesized via introducing thiazole units on both sides of a bithiophene core, which shows an outstanding PCE of 13.3% with a typical polythiophene donor. More importantly, optimization guidelines are presented to get excellent morphology for low‐cost donor:acceptor systems. Three polythiophenes are selected, poly(3‐hexylthiophene) and its two derivatives with electron‐withdrawing substitutions (PDCBT and PDCBT‐2F), as donors to fabricate the cell devices. The computational and experimental data reveal that decreasing the electrostatic interaction between polythiophene and Tz is the key to getting a suppressed miscibility and thus a high phase purity. This study provides insight into the molecular design and donor:acceptor matching requirements for high‐efficiency and low‐cost OSCs. [ABSTRACT FROM AUTHOR]

A series of thiazolo[5,4-d]thiazoles with bipolar character has been designed and synthesized. Compounds 4a–d and 5a,b consist of a central thiazolo[5,4-d]thiazole as the electron acceptor (A) and a terminal 9,9′-spirobifluorene fragment as the electron-donor (D). Both key structural features are connected through the thiophene π-linker. The structure of all the compounds is fully π-conjugated providing proximity of the frontier molecular orbitals (FMO). Accordingly, thiazolo[5,4-d]thiazole-based compounds 4a–d and 5a,b exhibit excellent electronic structures with energy gaps falling in the range of 2.5–3.0 eV. Appropriate thermal stability and valuable photophysical properties make these molecules valuable for applications in optoelectronic materials. Hence, electroluminescent devices with 4b and 5b as host materials showed yellowish-green and yellow-green emissions, which is quite unique for organic-small molecules demonstrating their potential in the development of novel, low-weight and fully organic dopants for electroluminescent (EL) devices. [ABSTRACT FROM AUTHOR]

Microbial infections are currently a widespread disease in hospitals and community health centres and are a major cause of death worldwide. In pursuit of searching new antimicrobial agents, coumarin linked to thiazoles, pyridines and pyrazoles have been developed and evaluated for their antimicrobial properties against two Gram + bacteria, two Gram − bacteria as well as two fungi. Some of the prepared coumarins displayed high to moderate activity against the tested microorganisms with respect to the reference drugs. However, compound 3 exhibited antimicrobial effect equal to the reference drug Ciprofloxacin for Gram − baceria Enterobacter cloacae. Compound 12 was found to be the most potent compound against Bacillus pumilis with MIC of 7.69 (µmol/ml). Compounds 3, 4 and 12 showed remarkable activity against Streptococcus faecalis with MIC of 14.34, 3.67 and 15.36 (µmol/ml), respectively. Regarding Escherichia coli, most compounds recorded high to moderate MIC values (4.73–45.46 µmol/ml). Moreover, in case of E. cloacae compound 9 was the most potent compound with MIC value of 22.76 (µmol/ml). [ABSTRACT FROM AUTHOR]

New series of biologically active triazole and pyrazole compounds containing 2, 4-disubstituted thiazole analogues (12a-l) were synthesized from p-hydroxy benzaldehyde and phenyl hydrazine in excellent yields and purity. All the synthesized compounds were unambiguously identified based on their spectral data analyses (IR, 1H-NMR, 13C-NMR spectra, and HRMS). The final derivatives were evaluated for their in vitro anti-microbial activity after thorough purification. Among all the tested compounds, the compound 12e, 12f and 12 k possess the highest growth inhibitory activity at MIC values of 4.8, 5.1 and 4.0 μg/ml respectively. The antioxidant properties of these compounds demonstrated and revealed remarkable activity compared to the standard antioxidant by using the DPPH free radical-scavenging assay. Moreover, molecular docking studies to evaluate the probable interactions with the catalytic domain of the gram-positive S. aureus topoisomerase IV enzyme may provide new insights for developing these new hybrids as potential antimicrobial agents. The binding affinities of compounds 12a-l were ranging from − 10.0 to − 11.0 kcal/mol with topoisomerase IV enzyme and with COVID-19 main protease binding affinities are ranging from − 8.2 to − 9.3 kcal/mol. These docking studies reveal that the compounds 12a-l could be the best inhibitors for the novel SARS Cov-2 virus and have more future in discovery of potent drug candidates. [ABSTRACT FROM AUTHOR]

This research sought to synthesize a new set of heteroaromatic thiazole-based polyurea derivatives with sulfur links in the polymers' main chains, which were denoted by the acronyms PU1–5. Using pyridine as a solvent, a diphenylsulfide-based aminothiazole monomer (M2) was polymerized via solution polycondensation with varied aromatic, aliphatic, and cyclic diisocyanates. Typical characterization methods were used to confirm the structures of the premonomer, monomer, and fully generated polymers. The XRD results revealed that aromatic-based polymers had higher crystallinity than aliphatic and cyclic derivatives. SEM was used to visualize the surfaces of PU1, PU4, and PU5, revealing spongy and porous shapes, shapes resembling wooden planks and sticks, and shapes resembling coral reefs with floral shapes at various magnifications. The polymers demonstrated thermal stability. The numerical results for PDTmax are listed in the following order, ranked from lowest to highest: PU1 < PU2 < PU3 < PU5 < PU4. The FDT values for the aliphatic-based derivatives (PU4 and PU5) were lower than those for the aromatic-based ones (616, 655, and 665 °C). PU3 showed the greatest inhibitory impact against the bacteria and fungi under investigation. In addition, PU4 and PU5 demonstrated antifungal activities that, in contrast with the other products, were on the lower end of the spectrum. Furthermore, the intended polymers were also tested for the presence of the proteins 1KNZ, 1JIJ, and 1IYL, which are frequently utilized as model organisms for E. coli (Gram-negative bacteria), S. aureus (Gram-positive bacteria), and C. albicans (fungal pathogens). This study's findings are consistent with the outcomes of the subjective screening. [ABSTRACT FROM AUTHOR]