Noninvasive cardiac-specific biomarkers for the diagnosis and prevention of vascular stenosis in cardiovascular disorder.

Background: The most frequent lesion in the blood vessels feeding the myocardium is vascular stenosis, a condition that develops slowly but can prove to be deadly in a long run. Non-invasive biomarkers could play a significant role in timely diagnosis, detection and management for vascular stenosis events associated with cardiovascular disorders. Aims: The study aimed to investigate high sensitivity troponin I (hs-TnI), cardiac troponin I (c-TnI) and high sensitivity C-reactive protein (hs-CRP) that may be used solely or in combination in detecting the extent of vascular stenosis in CVD patients. Methodology: 274 patients with dyspnea/orthopnea complaints visiting the cardiologists were enrolled in this study. Angiographic study was conducted on the enrolled patients to examine the extent of stenosis in the five prominent vessels (LDA, LCX, PDA/PLV, RCA, and OM) connected to the myocardium. Samples from all the cases suspected to be having coronary artery stenosis were collected, and subjected to biochemical evaluation of certain cardiac inflammatory biomarkers (c-TnI, hsTn-I and hs-CRP) to check their sensitivity with the level of vascular stenosis. The extent of mild and culprit stenosis was detected during angiographic examination and the same was reported in the form significant (≥50% stenosis in the vessels) and non-significant (<50% stenosis in the vessels) Carotid Stenosis. Ethical Clearance for the study was provided by Dr. Ram Manohar Lohia Institute of Medical Sciences Institutional Ethical Committee. Informed consent was obtained from all the participants enrolled in the study. Results: We observed that 85% of the total population enrolled in this study was suffering from hypertension followed by 62.40% detected with sporadic episodes of chest pain. Most of the subjects (42% of the total population) had stenosis in their LAD followed by 38% who had stenosis in their RCA. Almost 23% patients were reported to have stenosis in their LCX followed by OM (18% patients), PDA/PLV (13%) and only 10% patients had blockage problem in their diagonal. 24% of the subjects were found to have stenosis in a single vessel and hence were categorized in the Single Vessel Disease (SVD) group while 76% were having stenosis in two or more than two arteries (Multiple Vessel Disease). hs-TnI level was found to be correlated with the levels of stenosis and was higher in the MVD group as compared to the SVD group. Conclusion: hs-TnI could be used as a novel marker as it shows prominence in detecting the level of stenosis quite earlier as compared to c-TnI which gets detected only after a long duration in the CVD patients admitted for angiography. hs- CRP gets readily detected as inflammation marker in these patients and hence could be used in combination with hs-TnI to detect the risk of developing coronary artery disease.

Design of a Humidity Sensor for a PPE Kit Using a Flexible Paper Substrate.

The present work reports the rapid sweat detection inside a PPE kit using a flexible humidity sensor based on hydrothermally synthesized ZnO (zinc oxide) nanoflowers (ZNFs). Physical characterization of ZNFs was done using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transmission infrared spectroscopy (FTIR), UV-visible, particle size analysis, Raman analysis, and X-ray photoelectron spectroscopy (XPS) analysis, and the hydrophilicity was investigated by using contact angle measurement. Fabrication of a flexible sensor was done by deposition on the paper substrate using the spin coating technique. It exhibited high sensitivity and low response and recovery times in the humidity range 10-95%RH. The sensor demonstrated the highest sensitivity of 296.70 nF/%RH within the humidity range 55-95%RH, and the rapid response and recovery times were also calculated and found as 5.10/1.70 s, respectively. The selectivity of the proposed sensor was also analyzed, and it is highly sensitive to humidity. The humidity sensing characteristics were theoretically witnessed in terms of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and electronic properties of sensing materials in ambient and humid conditions. These theoretical results are evidence of the interaction of ZnO with humidity. Overall, the present study provides a scope of architecture-enabled paper-based humidity sensors for the detection of sweat levels inside PPE kits for health workers.

Metformin: Past, Present, and Future.

PURPOSE OF REVIEW: This review provides the most recent update of metformin, a biguanide oral antihyperglycemic drug used as a first-line treatment in type 2 diabetes mellitus. RECENT FINDINGS: Metformin continues to dominate in the world of antidiabetics, and its use will continue to rise because of its high efficiency and easy availability. Apart from type 2 diabetes, research is exploring its potential in other conditions such as cancer, memory loss, bone disorders, immunological diseases, and aging. Metformin is the most prescribed oral antidiabetic worldwide. It has been in practical use for the last six decades and continues to be the preferred drug for newly diagnosed type 2 diabetes mellitus. It reduces glucose levels by decreasing hepatic glucose production, reducing intestinal glucose absorption, and increasing insulin sensitivity. It can be used as monotherapy or combined with other antidiabetics like sulfonylureas, DPP-4 inhibitors, SGLT-2 inhibitors, or insulin, improving its efficacy. Metformin can be used once or twice daily, depending on requirements. Prolonged usage of metformin may lead to abdominal discomfort, deficiency of Vitamin B12, or lactic acidosis. It should be used carefully in patients with renal impairment. Recent studies have explored additional benefits of metformin in polycystic ovarian disease, gestational diabetes mellitus, cognitive disorders, and immunological diseases. However, more extensive studies are needed to confirm these additional benefits.

1,2,4,5-Tetraoxane derivatives/hybrids as potent antimalarial endoperoxides: Chronological advancements, structure-activity relationship (SAR) studies and future perspectives.

Malaria is a life-threatening disease that affects tropical and subtropical regions worldwide. Various drugs were used to treat malaria, including artemisinin and derivatives, antibiotics (tetracycline, doxycycline), quinolines (chloroquine, amodiaquine), and folate antagonists (sulfadoxine and pyrimethamine). Since the malarial parasites developed drug resistance, there is a need to develop new chemical entities with high efficacy and low toxicity. In this context, 1,2,4,5-tetraoxanes emerged as an essential scaffold and have shown promising antimalarial activity. To improve activity and overcome resistance to various antimalarial drugs; 1,2,4,5-tetraoxanes were fused with various aryl/heteroaryl/alicyclic/spiro moieties (steroid-based 1,2,4,5-tetraoxanes, triazine-based 1,2,4,5-tetraoxanes, aminoquinoline-based 1,2,4,5-tetraoxanes, dispiro-based 1,2,4,5-tetraoxanes, piperidine-based 1,2,4,5-tetraoxanes and diaryl-based 1,2,4,5-tetraoxanes). The present review aims to focus on covering the relevant literature published during the past 30 years (1992-2022). We summarize the most significant in vitro, in vivo results and structure-activity relationship studies of 1,2,4,5-tetraoxane-based hybrids as antimalarial agents. The structural evolution of different hybrids can provide the framework for the future development of 1,2,4,5-tetraoxane-based hybrids to treat malaria.

Screening of Individuals with Type 2 Diabetes on Anti-Diabetic Agents for Probable Hypoglycaemia Using the Stanford Hypoglycemia Questionnaire (SHQ) in Outpatient Settings: A Cross-Sectional Study from Outpatient Diabetes Care Centres in North India.

Introduction: The study was aimed at identifying the incidence of unreported probable hypoglycaemia in individuals with type 2 diabetes (T2DM) on anti-diabetic medications, using the screening Stanford Hypoglycemia Questionnaire (SHQ) in real-world situations. Methods: It was a multicentre cross-sectional study on consecutive individuals attending 10 diabetes care centres in Lucknow, Uttar Pradesh, India. The inclusion criteria were as follows: known individuals with T2DM, literate, age greater than or equal to 18 years, on at least one anti-diabetic agent for more than a month and not engaged in regular self-monitoring of blood glucose (SMBG). Results: This study was conducted from August 2017 to April 2018, involving 1198 participants. The mean age of the individuals enrolled was 53.45 years (±10.83), with males comprising 55.3% of the population. It was found that 63.6% of patients were on sulphonylurea (SU), 14.5% were on pioglitazone, 92.2% on metformin, 62.3% on Dipeptidyl peptidase (DPP4i) and 12.8% on Sodium-glucose cotransporter (SGLT2i). The mean SHQ score was 1.81 (±1.59). Probable hypoglycaemia was mild in 57.59%, moderate in 14.69% and severe in 1.41%. Those with diabetic neuropathy (P = <0.001), retinopathy (P = <0.001) and nephropathy (P = <0.001) had significantly higher SHQ scores. Insulin or SU use was associated with a significantly higher SHQ score. Concomitant statin use was associated with a lower incidence of mild, moderate and severe hypoglycaemia (P = 0.01). On multivariate analysis, we found that age, sex, systolic blood pressure (SBP), insulin use and fasting blood sugar were the most important factors associated with an increased risk of hypoglycaemia with an R2 cut-off of 0.7. Conclusion: SHQ was discovered to be a simple and cost-effective screening tool for outpatient detection of hypoglycaemia in an Indian setting, and it can add value to management.

Transformation of PMMA from sunlight-blocking to sunlight-activated coupled with DNH photocatalytic platform for oxidative coupling of amines and generation/regeneration of LDC/NADH.

The photocatalytic oxidation and generation/regeneration of amines to imines and leucodopaminechrome (LDC)/NADH are subjects of intense interest in contemporary research. Imines serve as crucial intermediates for the synthesis of solar fuels, fine chemicals, agricultural chemicals, and pharmaceuticals. While significant progress has been made in developing efficient processes for the oxidation and generation/regeneration of secondary amines, the oxidation of primary amines has received comparatively less attention until recently. This discrepancy can be attributed to the high reactivity of imines generated from primary amines, which are prone to dehydrogenation into nitriles. In this study, we present the synthesis and characterization of a novel polymer-based photocatalyst, denoted as PMMA-DNH, designed for solar light-harvesting applications. PMMA-DNH incorporates the light-harvesting molecule dinitrophenyl hydrazine (DNH) at varying concentrations (5%, 10%, 20%, 30%, and 40%). Leveraging its high molar extinction coefficient and slow charge recombination, the 30% DNH-incorporated PMMA photocatalyst proves to be particularly efficient. This photocatalytic system demonstrates exceptional yields (96.5%) in imine production and high generation/regeneration rates for LDC/NADH (65.27%/78.77%). The research presented herein emphasizes the development and application of a newly engineered polymer-based photocatalyst, which holds significant promise for direct solar-assisted chemical synthesis in diverse commercial applications.

Antifungal Activity of N-Arylbenzoquinaldinium Derivatives against a Clinical Strain of M. canis.

Background: Microsporum canis (Bodin, 1902) is a dermatophyte, which is widely represented in the developing and the developed world alike. Commonly transmitted from domestic animals it is particularly dangerous for immunosuppressed patients due to AIDS, cancer or transplant surgery. Search for new perspective antimycotic derivatives becomes an urgent task in the disease containment. Previously, several quinolinium analogs were screened for their antibacterial activity (E. coli, St. aurous) by our research team. Furthermore, some N-phenylbenzoquinaldinium derivatives have shown antifungal activity against Candida albicans and Candida krusei. Aims: In this study, we sought to investigate fungicidal properties of N-arylbenzoquinaldinium derivatives against a clinical strain of Microsporum canis for future medicinal applications. Materials and Methods: N-phenyl-[f]-benzoquinaldinium salts were prepared by a variation of the previously described technique and tested against a clinical strain of the fungus of Microsporum canis 114 harvested from pathogenic material of a patient (Perm, Russia, 2014). Results: N-phenyl-[f]-benzoquinaldinium tetrafluoroborate has shown antifungal activity par to (or exceeding) that of commercially available medication. Moreover, this benzoquinaldinium analog can be potentially labelled with tritium by our nuclear-chemical method, making it amenable for the sensitive pharmacokinetic studies. Conclusions: N-phenyl-[f]-benzoquinaldinium tetrafluoroborate has been shown as a promising compound for the further development of potent antifungal agents as well as radiotracers for further elucidation of biological pathways of antifungal activity.

Chemo-/Regio-Selective Synthesis of Novel Functionalized Spiro[pyrrolidine-2,3'-oxindoles] under Microwave Irradiation and Their Anticancer Activity.

A novel series of nitrostyrene-based spirooxindoles were synthesized via the reaction of substituted isatins 1a-b, a number of α-amino acids 2a-e and (E)-2-aryl-1-nitroethenes 3a-e in a chemo/regio-selective manner using [3+2] cycloaddition (Huisgen) reaction under microwave irradiation conditions. The structure elucidation of all the synthesized spirooxindoles were done using 1H and 13C NMR and HRMS spectral analysis. The single crystal X-ray crystallographic study of compound 4l was used to assign the stereochemical arrangements of the groups around the pyrrolidine ring in spiro[pyrrolidine-2,3'-oxindoles] skeleton. The in vitro anticancer activity of spiro[pyrrolidine-2,3'-oxindoles] analogs 4a-w against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines shows promising results. Out of the 23 synthesized spiro[pyrrolidine-2,3'-oxindoles], while five compounds (4c, 4f, 4m, 4q, 4t) (IC50 = 34.99-47.92 µM; SI = 0.96-2.43) displayed significant in vitro anticancer activity against human lung (A549) cancer cell lines, six compounds (4c, 4f, 4k, 4m, 4q, 4t) (IC50 = 41.56-86.53 µM; SI = 0.49-0.99) displayed promising in vitro anticancer activity against human liver (HepG2) cancer cell lines. In the case of lung (A549) cancer cell lines, these compounds were recognized to be more efficient and selective than standard reference artemisinin (IC50 = 100 µM) and chloroquine (IC50 = 100 µM; SI: 0.03). However, none of them were found to be active as compared to artesunic acid [IC50 = 9.85 µM; SI = 0.76 against lung (A549) cancer cell line and IC50 = 4.09 µM; SI = 2.01 against liver (HepG2) cancer cell line].

Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies.

Leishmaniasis is a neglected tropical disease, and there is an emerging need for the development of effective drugs to treat it. To identify novel compounds with antileishmanial properties, a novel series of functionalized spiro[indoline-3,2'-pyrrolidin]-2-one/spiro[indoline-3,3'-pyrrolizin]-2-one 23a-f, 24a-f, and 25a-g were prepared from natural-product-inspired pharmaceutically privileged bioactive sub-structures, i.e., isatins 20a-h, various substituted chalcones 21a-f, and 22a-c amino acids, via 1,3-dipolar cycloaddition reactions in MeOH at 80 °C using a microwave-assisted approach. Compared to traditional methods, microwave-assisted synthesis produces higher yields and better quality, and it takes less time. We report here the in vitro antileishmanial activity against Leishmania donovani and SAR studies. The analogues 24a, 24e, 24f, and 25d were found to be the most active compounds of the series and showed IC50 values of 2.43 µM, 0.96 µM, 1.62 µM, and 3.55 µM, respectively, compared to the standard reference drug Amphotericin B (IC50 = 0.060 µM). All compounds were assessed for Leishmania DNA topoisomerase type IB inhibition activity using the standard drug Camptothecin, and 24a, 24e, 24f, and 25d showed potential results. In order to further validate the experimental results and gain a deeper understanding of the binding manner of such compounds, molecular docking studies were also performed. The stereochemistry of the novel functionalized spirooxindole derivatives was confirmed by single-crystal X-ray crystallography studies.

Phylogeny-guided genome mining of roseocin family lantibiotics to generate improved variants of roseocin.

Roseocin, the two-peptide lantibiotic from Streptomyces roseosporus, carries extensive intramolecular (methyl)lanthionine bridging in the peptides and exhibits synergistic antibacterial activity against clinically relevant Gram-positive pathogens. Both peptides have a conserved leader but a diverse core region. The biosynthesis of roseocin involves post-translational modification of the two precursor peptides by a single promiscuous lanthipeptide synthetase, RosM, to install an indispensable disulfide bond in the Rosα core along with four and six thioether rings in Rosα and Rosß cores, respectively. RosM homologs in the phylum actinobacteria were identified here to reveal twelve other members of the roseocin family which diverged into three types of biosynthetic gene clusters (BGCs). Further, the evolutionary rate among the BGC variants and analysis of variability within the core peptide versus leader peptide revealed a phylum-dependent lanthipeptide evolution. Analysis of horizontal gene transfer revealed its role in the generation of core peptide diversity. The naturally occurring diverse congeners of roseocin peptides identified from the mined novel BGCs were carefully aligned to identify the conserved sites and the substitutions in the core peptide region. These selected sites in the Rosα peptide were mutated for permitted substitutions, expressed heterologously in E. coli, and post-translationally modified by RosM in vivo. Despite a limited number of generated variants, two variants, RosαL8F and RosαL8W exhibited significantly improved inhibitory activity in a species-dependent manner compared to the wild-type roseocin. Our study proves that a natural repository of evolved variants of roseocin is present in nature and the key variations can be used to generate improved variants.

Natural-product-inspired bioactive alkaloids agglomerated with potential antioxidant activity: Recent advancements on structure-activity relationship studies and future perspectives.

Alkaloids derived from natural sources have been shown to have substantial antioxidant activity, suggesting that these natural-product-inspired bioactive entities may have major beneficial influence on human health and food processing sector. The primary process intricates in the etiology of several disorders such as neurodegenerative, inflammatory cardiovascular, and other chronic diseases appear to be either oxidative injury or a cellular damage caused by reactive oxygen species (ROS) or free-radicals. The alkaloid class of bio-heterocycles have been divided into numerous groups based on their biosynthetic precursor and heterocyclic ring systems i.e., piperidine, imidazole, purine, pyrrolizidine, indole, quinolozidine, isoquinoline, tropane, and pyrrolidine alkaloids. Distinct biological properties have been attributed to various compounds belonging to this chemical groups, including antirheumatic, cardiovascular, antispasmodic, anti-ulcer, anti-inflammatory, antibacterial, antinociceptive etc. For many years, natural products and their analogs have been recognized as a possible source of medicinal agents. Recently, research has been concentrated on the synthesis, separation/purification, and identification of new alkaloids derived from a variety of natural sources. This book chapter aims to summarize on the latest developments on the current knowledge on the relationship between the structural features of promising class of bioactive alkaloids with their antioxidant activities.

Effect of size variation of fibre-shaped waste tyre rubber as fine aggregate on the ductility of self-compacting concrete.

Abandoning shredded waste tyre rubber (WTR) in cement-based mixes facilitates safe waste tyre disposal and conserves the natural resources used in construction materials. The engineering properties of such environment-friendly materials needed to be evaluated for field applications. This study examined integrating WTR fibre on microstructural, static load, and ductility properties of self-compacting concrete (SCC). The WTR fibre of 0.60-1.18-, 1.18-2.36-, and 2.36-4.75-mm sizes was used as fine aggregate at 10%, 20%, and 30% replacement levels. Microstructural characterisation of hardened concrete specimens was done by scanning electron microscopy. The compressive strength and static modulus of elasticity tests were used to examine static load resistance, while drop weight and rebound impact tests were used to investigate impact load resistance. The water permeability test was performed as a measure of the durability of SCC with WTR fibre. Relationships have been studied between dynamic MOE and impact tests and rebound and drop weight impact testing. The Weibull two-parameter distribution was used to analyse the drop weight test statically. The results show that WTR fibre size variations efficiently lowered the concrete stiffness reducing the brittleness. Furthermore, incorporating WTR fibre improved the impact resistance of SCC.

Regiodivergent Cu-Promoted, AcOH-Switchable Distal Versus Proximal Direct Cyanation of 1-Aryl-1H-indazoles and 2-Aryl-2H-indazoles via Aerobic Oxidative C-H Bond Activation.

A copper-promoted regiodivergent, AcOH-switchable, distal and proximal direct cyanation of N-aryl-(1H/2H)-indazoles via aerobic oxidative C(sp2)-H bond activation has been developed. The inclusion or exclusion of AcOH as an additive is the foremost cause for the positional switch in the C-CN bond formation method that results in (C-2')-cyanated 2-aryl-2H-indazoles 3a-j, (C-2')-cyanated 1-aryl-1H-indazoles 4a-j [distal], or C-3 cyanated 2-aryl-2H-indazoles 5a-i [proximal] products in good to excellent yields and showed various functional group tolerance. The cyanide (CN-) ion surrogate was generated via the unification of dimethylformamide and ammonium iodide (NH4I). The utilization of molecular oxygen (aerobic oxidative strategy) as a clean and safe oxidant is liable for generous value addition. The further pertinence of the developed protocol has been demonstrated by transforming the synthesized cyanated product into numerous other functional groups, which will, undoubtedly, accomplish utilization in the synthetic area of biologically important compounds and medicinal chemistry.

TMEDA-Catalyzed Regioselective Decarboalkoxy C-N Bond Formation: A Unified Direct Access to Indolo[2,1-a]isoquinoline and Dibenzopyrrocoline Alkaloids.

An unprecedented TMEDA-catalyzed, regioselective, decarboethoxy direct C-N coupling protocol towards the synthesis of dibenzopyrrocolines 17 a-i and 5,6-dihydroindolo[2,1-a]isoquinoline 15 a-f/18 a-c alkaloids via the identification of N,N,N',N'-tetramethylethylenediamine (TMEDA) as a homogeneous catalyst is reported. The transition-metal-free, TMEDA-catalytic novel protocol is operationally simple and showed a wide range of functional group tolerance and substrate compatibility. The gram-scale application and synthesis of naturally occurring Cryptaustoline (dibenzopyrrocoline) alkaloid, further highlights the importance and versatile nature of the developed protocol. This finding also offers a TMEDA-catalyzed direct synthesis of dibenzopyrrocolines and substituted 5,6-dihydroindolo[2,1-a]isoquinoline compounds in a one-pot. The probable reaction pathway involves the free-radical sequential approach via a single electron transfer (SET) mechanism.

Biological Evaluation in Resistant Cancer Cells and Study of Mechanism of Action of Arylvinyl-1,2,4-Trioxanes.

1,2,4-trioxane is a pharmacophore, which possesses a wide spectrum of biological activities, including anticancer effects. In this study, the cytotoxic effect and anticancer mechanism of action of a set of 10 selected peroxides were investigated on five phenotypically different cancer cell lines (A549, A2780, HCT8, MCF7, and SGC7901) and their corresponding drug-resistant cancer cell lines. Among all peroxides, only 7 and 8 showed a better P-glycoprotein (P-gp) inhibitory effect at a concentration of 100 nM. These in vitro results were further validated by in silico docking and molecular dynamic (MD) studies, where compounds 7 and 8 exhibited docking scores of -7.089 and -8.196 kcal/mol, respectively, and remained generally stable in 100 ns during MD simulation. Further experiments revealed that peroxides 7 and 8 showed no significant effect on ROS accumulations and caspase-3 activity in A549 cells. Peroxides 7 and 8 were also found to decrease cell membrane potential. In addition, peroxides 7 and 8 were demonstrated to oxidize a flavin cofactor, possibly elucidating its mechanism of action. In conclusion, apoptosis induced by 1,2,4-trioxane was shown to undergo via a ROS- and caspase-3-independent pathway with hyperpolarization of cell membrane potential.

Oxidant-Switched Palladium-Catalyzed Regioselective Mono- versus Bis-ortho-Aroylation of 1-Aryl-1H-indazoles with Aldehydes via C-H Bond Activation.

A highly efficient oxidant-switched palladium-catalyzed regioselective C(sp2)-H/C(sp2)-H cross-dehydrogenative coupling (CDC) for direct mono/bis-ortho-aroylation of substituted 1-phenyl-1H-indazoles 1a-j with various substituted aldehydes 3a-t via C(sp2)-H bond activation has been developed. In this study, Pd-catalyzed chelation-assisted mono- or bis-aroylation of substituted 1-phenyl-1H-indazoles depends on the type of oxidant being used for the CDC reaction. While mono-ortho-aroylation of substituted 1-phenyl-1H-indazole was obtained using dicumylperoxide (DCP) as the oxidant, the bis-ortho-aroylation product has been afforded by the use of tert-butyl hydroperoxide (TBHP). Regardless of the greater activity at the C-3 position of 1H-indazoles, the greater coordinating capacity of the N atom directed the aroylating group to the ortho position, leaving behind the nondirected metalation pathway. The Pd-catalyzed operationally simplified methodology proceeded in the presence of oxidants with either DCP or TBHP in dichloroethane as the solvent at 110 °C for 16 h, which generated a miscellaneous variety of monosubstituted o-benzoyl/acyl-1-aryl-1H-indazoles 4a-t/5a-i and bis-substituted o-benzoyl-1-aryl-1H-indazoles 6a-j in ≤88% yields. The probable mechanistic pathway involves a free radical chelation-assisted approach that could be accomplished by the addition of an in situ-generated oxidant-promoted benzoyl/acyl radical to the ortho position of 1-phenyl-1H-indazoles. A wide range of substrates, a high functional group tolerance, gram-scale synthesis, control/competitive experiments, and a variety of synthetic applications further exemplify the versatility of the developed methodology.

Effect of mechanically treated and untreated zinc tailing waste as cement substitute in concrete production: an experimental and statistical analysis.

Zinc tailing waste is a type of mine waste generated during the extraction of zinc metal. Disposal of a huge amount of mine tailing waste is an open area and tailing dam causing a negative impact on the natural ecosystem and human health. In this research study, the mechanical properties and durability performance of concrete containing zinc mine tailing waste was investigated through an experimental and statistical analysis. The mechanically treated and untreated zinc tailing waste was used as a cement substitute in concrete production. Concrete specimens were fabricated by replacing cement (0%, 5%, 10%, 15%, and 20%) with the mechanically treated and untreated zinc mine tailing waste. The effect of the zinc mine tailing waste was investigated by conducting the various mechanical (compressive strength and elastic modulus) tests, durability (ultrasonic pulse velocity, water absorption, chloride penetration, carbonation, sulfate attack) tests. The X-ray diffraction (XRD) analysis and scanning electron microscopy (SEM) on concrete samples were also conducted for microstructure analysis. According to the various tests conducted, all concrete properties showed comparable results at the 5% cement substitution in concrete by mechanically treated zinc tailing waste. However, the zinc tailing waste concrete was shown to be more sulphate resistance than the control concrete. Test findings suggest that it is feasible to use 10% mechanically treated and 5% untreated zinc tailing waste as a substitute for cement in concrete to reduce the adverse effect on the environment.

Discovery of Natural Product Inspired 3-Phenyl-1H-isochromen-1-ones as Highly Potent Antioxidant and Antiplatelet Agents: Design, Synthesis, Biological Evaluation, SAR and In Silico Studies.

BACKGROUND: Several natural/synthetic molecules having a structure similar to 1H-isochromen- 1-ones have been reported to display promising antioxidants and platelet aggregation inhibitory activity. Isocoumarin (1H-2-benzopyran-1-one) skeleton, either whole or as a part of the molecular framework, has been explored for its antioxidant or antiplatelet activities. INTRODUCTION: Based on the literature, a new prototype, i.e., 3-phenyl-1H-isochromen-1-ones based compounds, has been rationalized to possess both antioxidant as well as antiplatelet activities. Consequently, no reports are available regarding its inhibition either by cyclooxygenase-1 (COX-1) enzyme or by arachidonic acid (AA)-induced platelet aggregation. This prompted us to investigate 3-phenyl-1H-isochromen-1-ones towards antioxidant and antiplatelet agents. METHODS: The goal of this work was to identify new 3-phenyl-1H-isochromen-1-ones based compounds via synthesis of a series of analogues, followed by performing in vitro antioxidant as well as AA-induced antiplatelet activities. Then, identification of potent compounds by SAR and molecular docking studies was carried out. RESULTS: Out of all synthesized 3-phenyl-1H-isochromen-1-ones analogues, five compounds showed 7-fold to 16-fold more highly potent antioxidant activities than ascorbic acid. Altogether, ten 3-phenyl-1H-isochromen- 1-one analogues displayed antioxidant activities in 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Almost all the 3-phenyl-1H-isochromen-1-one analogues exhibited potent AA-induced antiplatelet activity; few of them displayed 7-folds more activity as compared to aspirin. Further, in silico analysis validated the wet results. CONCLUSION: We disclose the first detailed study for the identification of 3-phenyl-1H-isochromen-1-one analogues as highly potent antioxidant as well as antiplatelet agents. The article describes the scaffold designing, synthesis, bioevaluation, structure-activity relationship, and in silico studies of a pharmaceutically privileged bioactive 3-phenyl-1H-isochromen-1-one class of heterocycles.

Hedgehog/GLI1 Transcriptionally Regulates FANCD2 in Ovarian Tumor Cells: Its Inhibition Induces HR-Deficiency and Synergistic Lethality with PARP Inhibition.

Ovarian cancer (OC) is one of the most lethal type of cancer in women due to a lack of effective targeted therapies and high rates of treatment resistance and disease recurrence. Recently Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown promise as chemotherapeutic agents; however, their efficacy is limited to a small fraction of patients with BRCA mutations. Here we show a novel function for the Hedgehog (Hh) transcription factor Glioma associated protein 1 (GLI1) in regulation of key Fanconi anemia (FA) gene, FANCD2 in OC cells. GLI1 inhibition in HR-proficient OC cells induces HR deficiency (BRCAness), replication stress and synergistic lethality when combined with PARP inhibition. Treatment of OC cells with combination of GLI1 and PARP inhibitors shows enhanced DNA damage, synergy in cytotoxicity, and strong in vivo anticancer responses.