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.

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.

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.

Pyrazolo[1,5-a]pyrimidine as a Prominent Framework for Tropomyosin Receptor Kinase (Trk) Inhibitors-Synthetic Strategies and SAR Insights.

Tropomyosin receptor kinases (Trks) are transmembrane receptor tyrosine kinases named TrkA, TrkB, and TrkC and encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These kinases have attracted significant attention and represent a promising therapeutic target for solid tumor treatment due to their vital role in cellular signaling pathways. First-generation TRK inhibitors, i.e., Larotrectinib sulfate and Entrectinib, received clinical approval in 2018 and 2019, respectively. However, the use of these inhibitors was significantly limited because of the development of resistance due to mutations. Fortunately, the second-generation Trk inhibitor Repotrectinib (TPX-0005) was approved by the FDA in November 2023, while Selitrectinib (Loxo-195) has provided an effective solution to this issue. Another macrocycle-based analog, along with many other TRK inhibitors, is currently in clinical trials. Two of the three marketed drugs for NTRK fusion cancers feature a pyrazolo[1,5-a] pyrimidine nucleus, prompting medicinal chemists to develop numerous novel pyrazolopyrimidine-based molecules to enhance clinical applications. This article focuses on a comprehensive review of chronological synthetic developments and the structure-activity relationships (SAR) of pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors. This article will also provide comprehensive knowledge and future directions to the researchers working in the field of medicinal chemistry by facilitating the structural modification of pyrazolo [1,5-a]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors.

Deciphering soil-plant-animal continuum in relation to trace elements in middle Gangetic plain region of India.

The soil-plant-animal continuum represents an evolving realm in biological research that's why this study was undertaken in the middle Gangetic plain region of India. Trace and ultra-trace elements were analyzed in 100 soil samples, 147 feed and fodder samples, as well as 69 blood and 127 hair samples with the help of inductively coupled plasma optical emission spectroscopy (ICP-OES). The levels of trace and ultra-trace elements in the soil were significantly higher than those in the feed, and similarly, the concentrations in the feed were notably higher than those in the blood of dairy cattle. Blood and hair samples from the cattle showed deficiencies in copper (Cu) and manganese (Mn), with reaching approximately 20% and 50%, respectively. Correlation analysis indicated significant (P < 0.05) associations between the trace and ultra-trace elements in plants and the corresponding elements found in cattle's hair, specifically for iron (Fe) and molybdenum (Mo). Conversely, a significant (P < 0.05) negative correlation was observed between soil composition and cattle's blood, while a positive correlation was evident only in the case of silver content between plant and cattle's hair. Regression analyses revealed positive linear relationships between minerals in soils and plants, as well as between plants and cattle. However, the correlation coefficients were statistically insignificant. The regression equations established to predict mineral concentrations in cattle based on soil and plant mineral contents indicated a positive relationship for both trace and ultra-trace elements, suggesting the potential to measure the mineral status in dairy cattle through this approach.

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.

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.

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.

Roseocin, a novel two-component lantibiotic from an actinomycete.

Lantibiotics are lanthionine ring containing natural products that belong to the class of ribosomally synthesized and posttranslationally modified peptides (RiPPs). Recent expansion in the availability of microbial genome data and in silico analysis tools have accelerated the discovery of these promising alternatives to antibiotics. Following the genome-mining approach, a biosynthetic gene cluster for a putative two-component lantibiotic, roseocin, was identified in the genome of an Actinomycete, Streptomyces roseosporus NRRL 11379. Posttranslationally modified lanthipeptides of this cluster were obtained by heterologous expression of the genes in Escherichia coli, and were in vitro reconstituted to their bioactive form by exploiting commercial proteases like endoproteinase GluC, and proteinase K. The two peptides displayed synergistic antimicrobial activity against Gram-positive bacteria including the WHO high-priority pathogens, MRSA and VRE. Structural characterization confirmed the installation of four (methyl)lanthionine rings with an indispensable disulfide bond in the α-peptide, and six (methyl)lanthionine rings in the ß-peptide, by a single promiscuous lanthionine synthetase, RosM. Roseocin is the first two-component lantibiotic from a non-Firmicute, with extensive lanthionine bridging.

Artemisinin-derived antimalarial endoperoxides from bench-side to bed-side: Chronological advancements and future challenges.

According to WHO World Malaria Report (2018), nearly 219 million new cases of malaria occurred and a total no. of 435 000 people died in 2017 due to this infectious disease. This is due to the rapid spread of parasite-resistant strains. Artemisinin (ART), a sesquiterpene lactone endoperoxide isolated from traditional Chinese herb Artemisia annua, has been recognized as a novel class of antimalarial drugs. The 2015 "Nobel Prize in Physiology or Medicine" was given to Prof Dr Tu Youyou for the discovery of ART. Hence, ART is termed as "Nobel medicine." The present review article accommodates insights from the chronological advancements and direct statistics witnessed during the past 48 years (1971-2019) in the medicinal chemistry of ART-derived antimalarial endoperoxides, and their clinical utility in malaria chemotherapy and drug discovery.

Organocatalyst in Direct C(sp2)-H Arylation of Unactivated Arenes: [1-(2-Hydroxyethyl)-piperazine]-Catalyzed Inter-/Intra-molecular C-H Bond Activation.

This article describes the identification of 1-(2-hydroxyethyl)-piperazine as a new, cost-effective, highly efficient organocatalyst, which promotes both inter- and intra-molecular direct C(sp2)-H arylations of unactivated arenes in the presence of potassium tert-butoxide. While the inter-molecular C-H arylation of unactivated benzenes with aryl halides (Ar-X; X = I, Br, Cl) toward biaryl syntheses underwent smoothly in the presence of only 10 mol % organocatalyst, the intra-molecular C-H arylation catalytic system composed of 40 mol % each of the catalyst and the additive (4-dimethylaminopyridine (DMAP)). The novel catalyst was also able to perform both inter- and intra-molecular direct arylations simultaneously in a single pot. The mechanistic studies confirmed the involvement of aryl radical anions and proceeded via a single-electron-transfer (SET) mechanism. The large substrate scope, high functional group tolerance, competition experiments, gram-scale synthesis, and kinetic studies further highlight the importance and versatile nature of the methodology as well as the compatibility of the new catalyst. To the best of our knowledge, this is the first report on any organocatalyst that reported detailed investigations of both inter- and intra-molecular direct C(sp2)-H arylations of unactivated arenes in a single representation.

Bu4NI-catalyzed, oxidative C(sp2)-C(sp3) cross dehydrogenative coupling for the regioselective direct C-3 benzylation of 2H-indazoles.

A Bu4NI-catalyzed, DTBP-promoted, regioselective C(sp2)-C(sp3) cross dehydrogenative coupling (CDC) protocol for the direct C-3 benzylation of 2H-indazoles is reported. The metal-free protocol is operationally simple and proceeds mechanistically via the generation of stable benzylic free-radicals followed by regioselective addition at the C-3 position of 2H-indazoles which afforded C-3 benzylated 2H-indazoles up to 87% yields. The methodology showed a varied array of functional group tolerance and wide substrate compatibility. The gram-scale synthesis further highlights the importance and versatile nature of this methodology.

COVID-19: What have we learnt, and plan for the future.

Coronavirus disease (COVID-19) has spread like wildfire and affected almost every stratum of society. It has brought humans together and taught us to have compassion and collaboration among individuals, governments and organisations. Adequate protection of healthcare workers who are at the frontline must be taken care of. Good hygiene and social distancing go a long way in controlling an epidemic. We must strive towards building more balanced and sustainable models and healthcare systems in the future as we try to successfully emerge from this outbreak.

Mask fatigue.

Extended wearing of mask, which has become a part of routine life, has led to the emergence of 'mask fatigue'. Mask fatigue is defined as the lack of energy that accompanies, and/or follows prolonged wearing of a mask. This communication describes the various aspects of mask fatigue, and shares pragmatic tips on its reduction. This discussion is relevant to all health care professionals and to general public to some extent, in the present scenario.

Initiation of basal bolus insulin therapy.

Most practice guidelines recommend the use of longacting or pre-mixed insulin at the initiation of insulin therapy in type 2 diabetes, especially in patients not achieving glycaemic goals. Nonetheless, there are some specific indications where basal bolus insulin is the preferred regimen for insulin initiation. These include the "5S" situations - 'Severe' hyperglycaemia, 'Symptomatic' diabetes, 'Sick' diabetes (acute or chronic comorbidity), 'Special' situations (pregnancy, childhood, adolescence) and 'Secondary' diabetes (pancreatic, drug-induced, endocrine disorders). This review describes a practical approach to initiation and follow up of basal bolus insulin regimens.

Precision medicine in diabetes.

This review presents the dynamic and fast growing concept of precision medicine in a simple and succinct manner. It describes the potential of precision medicine in diabetes praxis, under three headings: diagnosis of type of diabetes, choice of pharmacotherapy for glucose lowering, and management of complications of diabetes. This review should make the scope of precision medicine easy to understand for the practicing physician.

The Lipo- Phenotypic Screening Tool for Familial Hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is a common disorder of lipid metabolism. However, it is rarely diagnosed in time, leading to a high burden of preventable cardiovascular (CV) morbidity. The authors describe a lipophenotypic screening tool, which can be used by clinicians to screen for FH. This simple construct is based on history, physical examination, lipid profile and non-invasive cardioimaging. Structured as a bidirectional three column rubric, this tool should be able to improve clinical skills and teaching related to FH.

Central Diabetes Insipidus in an Off-pump Coronary Artery Bypass Grafting Surgery.

Polyuria in perioperative coronary artery bypass grafting (CABG) surgery is common and mostly benign. Diabetes insipidus (DI) post-CABG is however very rare and mostly have been related with use of cardiopulmonary bypass (CPB) pump. The patient recovered completely with transient requirement of exogenous vasopressin. The central DI may be considered as a differential diagnosis in case of polyuria in the perioperative period of CABG surgery. HOW TO CITE THIS ARTICLE: Nasa P, Varma G, Kulkarni A, Chaudhary S, Sagar P. Central Diabetes Insipidus in an Off-pump Coronary Artery Bypass Grafting Surgery. IJCCM 2019;23(11):523-525.

Proteomic profiling of extracellular vesicles released from vascular smooth muscle cells during initiation of phosphate-induced mineralization.

Purpose/Aim: Elevated serum phosphate is one of the major factors contributing to vascular calcification. Studies suggested that extracellular vesicles released from vascular smooth muscle cells significantly contribute to the initiation and progression of this pathology. Recently, we have demonstrated that elevated phosphate stimulates release of extracellular vesicles from osteogenic cells at the initiation of the mineralization process. Here, we used MOVAS cell line as an in vitro model of vascular calcification to examine whether vascular smooth muscle cells respond to high phosphate levels in a similar way and increase formation of extracellular vesicles. MATERIALS AND METHODS: Vesicles residing in extracellular matrix as well as vesicles released to culture medium were evaluated by nanoparticle tracking analyses. In addition, using mass spectrometry and protein profiling, protein composition of extracellular vesicles released by MOVAS cells under standard growth conditions and upon exposure to high phosphate was compared. RESULTS: Significant increase of the number of extracellular vesicles was detected after 72 h of exposure of cells to high phosphate. Elevated phosphate levels also affected protein composition of extracellular vesicles released from MOVAS cells. Finally, the comparative analyses of proteins in extracellular vesicles isolated from extracellular matrix and from conditioned medium identified significant differences in protein composition in these two groups of extracellular vesicles. CONCLUSIONS: Results of this study demonstrate that exposure of MOVAS cells to high phosphate levels stimulates the release of extracellular vesicles and changes their protein composition.