Novel amino- and hydroxy-functionalized 1,2,4-trioxanes and their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via intramuscular and oral route.

Following the economic and social state of humanity, Malaria is categorized as one of the life-threatening illness epidemics in under developed countries. For the eradication of the same, 1,2,4-trioxanes 17a1-a2, 17b1-b2, 17c1-c2 15a-c, 18 and 19 have been synthesized continuing the creation of a novel series. Additionally, these novel compounds were tested for their effectiveness against the multidrug-resistant Plasmodium yoelii nigeriensis in mice model using both oral and intramuscular (im) administration routes. The two most potent compounds of the series, 17a1 and 17a2, demonstrated 100 % protection at 48 mg/kg x 4 days via oral route, which is twice as potent as artemisinin. In this model artemisinin provided 100 % protection at a dose of 48 mg/kg × 4 days and 80 % protection at 24 mg/kg × 4 days via im route.

Novel saturated 1,2,4-trioxanes and their antimalarial activity against multidrug resistant Plasmodium yoelii nigeriensis in Swiss mice model via oral route.

Novel saturated 6-(4'-aryloxy phenyl) vinyl 1,2,4-trioxanes 12a(1-3)-12d(1-3) and 13a(1-3)-13d(1-3) have been designed and synthesized, in one single step from diimide reduction of 11a(1-3)-11d(1-3). All the newly synthesized trioxanes were evaluated for their antimalarial activity against multi-drug resistant Plasmodium yoelii nigeriensis via oral route. Cyclopentane-based trioxanes 12b1, 12c1 and 12d1, provided 100 % protection to the infected mice at 24 mg/kg × 4 days. The most active compound of the series, trioxane 12b1, provided 100 % protection even at 12 mg/kg × 4 days and 60 % protection at 6 mg/kg × 4 days. The currently used drug, ß-arteether provides only 20 % protection at 24 mg/kg × 4 days.

Emergence of exotic electronic and magnetic phases upon electron filling in Na2BO3 (B = Ta, Ir, Pt, and Tl): a first-principles study.

Competition between spin-orbit interaction and electron correlations can stabilize a variety of non-trivial electronic and magnetic ground states. Using density functional theory calculations, here we show that different exotic electronic and magnetic ground states can be obtained by electron filling of the B-site cation in the Na2BO3 family of compounds (B = Ta, Ir, Pt and Tl). Electron filling leads to a Peierls insulator state with a direct band gap to j = 1/2 spin-orbit assisted Mott-insulator to band insulator and then to negative charge-transfer half-metal transition. The magnetic ground state also undergoes a transition from a non-magnetic state to a zigzag antiferromagnetic state, a re-entrant non-magnetic state and finally to a ferromagnetic state. The electron localization function shows a ladder type dimerization or Peierls instability in Na2TaO3. Maximally localized Wannier function calculations reveal delocalization of electrons through the eg orbitals, which form a π bond, and localization of electrons through the t2g orbitals, which form a σ bond, between the neighbouring tantalum ions. Na2TlO3 shows Stoner or band ferromagnetism due to the localized moments with up-spin on oxygen ligands created by the negative charge-transfer character, interacting via the down-spin itinerant electrons of the Tl 5d-O 2p hybridized band. These findings are significant for practical applications; for instance the direct band gap insulator Na2TaO3 shows potential for utilisation in solar cells, while Na2TlO3, which exhibits ferromagnetic half metallicity, holds promise for spintronic device applications.

A Comprehensive Examination of Heterocyclic Scaffold Chemistry for Antitubercular Activity.

Tuberculosis is a communicable disease which affects humans particularly the lungs and is transmitted mainly through air. Despite two decades of intensive research aimed at understanding and combating tuberculosis, persistent biological uncertainties continue to hinder progress. Nowadays, heterocyclic compounds have proven themselves in effective treatment of tuberculosis because of their wide range of biological and pharmacological activities. Antituberculosis or antimycobacterial agents encompass a broad array of compounds utilized singly or in conjunction to combat Mycobacterium infections, spanning from tuberculosis to leprosy. Here, we summarize the synthesis of various heterocyclic compounds which includes the greener synthetic route as well as use of nano compounds as catalyst along with their anti TB activities.

Adjunct therapy with all-trans-retinoic acid improves therapeutic efficacy through immunomodulation while treating tuberculosis with antibiotics in a murine model.

Tuberculosis (TB) is the second leading infectious killer after COVID-19. Standard anti-tubercular drugs exhibit various limitations like toxicity, lengthy, and unresponsive to dormant and drug resistant organisms. Here, we report that all-trans-retinoic acid (ATRA) improves M.tb clearance in mice while treating with anti-tubercular drug isoniazid (INH). Interestingly, ATRA promoted activities of lysosomes, mitochondria, and production of various inflammatory mediators in macrophages. Furthermore, ATRA upregulated the expression of genes of lipid metabolic pathways in macrophages. Along this line, we registered that ATRA activated MEK/ERK pathway in macrophages in-vitro and MEK/ERK and p38 MAPK pathways in the mice. Finally, ATRA induced both Th1 and Th17 responses in lungs and spleens of M.tb-infected mice. Taken together, these data indicated that ATRA provides beneficial adjunct therapeutic value by modulating MEK/ERK and p38 MAPK pathways and thus warrants further testing for human use.

RNPS1 functions as an oncogenic splicing factor in cervical cancer cells.

Numerous recent studies suggest that cancer-specific splicing alteration is a critical contributor to the pathogenesis of cancer. RNA-binding protein with serine-rich domain 1, RNPS1, is an essential regulator of the splicing process. However, the defined role of RNPS1 in tumorigenesis still remains elusive. We report here that the expression of RNPS1 is higher in cervical carcinoma samples from The Cancer Genome Atlas (TCGA-cervical squamous cell carcinoma and endocervical adenocarcinoma) compared to the normal tissues. Consistently, the expression of RNPS1 was high in cervical cancer cells compared to a normal cell line. This study shows for the first time that RNPS1 promotes cell proliferation and colony-forming ability of cervical cancer cells. Importantly, RNPS1 positively regulates migration-invasion of cervical cancer cells. Intriguingly, depletion of RNPS1 increases the chemosensitivity against the chemotherapeutic drug doxorubicin in cervical cancer cells. Further, we characterized the genome-wide isoform switching stimulated by RNPS1 in cervical cancer cell. Mechanistically, RNA-sequencing analysis showed that RNPS1 regulates the generation of tumor-associated isoforms of key genes, particularly Rac1b, RhoA, MDM4, and WDR1, through alternative splicing. RNPS1 regulates the splicing of Rac1 pre-mRNA via a specific alternative splicing switch and promotes the formation of its tumorigenic splice variant, Rac1b. While the transcriptional regulation of RhoA has been well studied, the role of alternative splicing in RhoA upregulation in cancer cells is largely unknown. Here, we have shown that the knockdown of RNPS1 in cervical cancer cells leads to the skipping of exons encoding the RAS domain of RhoA, consequently causing decreased expression of RhoA. Collectively, we conclude that the gain of RNPS1 expression may be associated with tumor progression in cervical carcinoma. RNPS1-mediated alternative splicing favors an active Rac1b/RhoA signaling axis that could contribute to cervical cancer cell invasion and metastasis. Thus, our work unveils a novel role of RNPS1 in the development of cervical cancer.

An inclusive outlook on the fate and persistence of pesticides in the environment and integrated eco-technologies for their degradation.

Intensive and inefficient exploitation of pesticides through modernized agricultural practices has caused severe pesticide contamination problems to the environment and become a crucial problem over a few decades. Due to their highly toxic and persistent properties, they affect and get accumulated in non-target organisms, including microbes, algae, invertebrates, plants as well as humans, and cause severe issues. Considering pesticide problems as a significant issue, researchers have investigated several approaches to rectify the pesticide contamination problems. Several analyses have provided an extensive discussion on pesticide degradation but using specific technology for specific pesticides. However, in the middle of this time, cleaner techniques are essential for reducing pesticide contamination problems safely and environmentally friendly. As per the research findings, no single research finding provides concrete discussion on cleaner tactics for the remediation of contaminated sites. Therefore, in this review paper, we have critically discussed cleaner options for dealing with pesticide contamination problems as well as their advantages and disadvantages have also been reviewed. As evident from the literature, microbial remediation, phytoremediation, composting, and photocatalytic degradation methods are efficient and sustainable and can be used for treatment at a large scale in engineered systems and in situ. However, more study on the bio-integrated system is required which may be more effective than existing technologies.

Hole and Electron Doping Outcomes in Bi2YO4Cl.

Recognizing the deficiency in the hole and electron doping outcomes in layered bismuth-based oxyhalides intergrowths, the current study was addressed to the doping of Ca2+ and Zr4+ for Y3+ in Bi2YO4Cl. The samples were rapidly synthesized by a sol-gel auto combustion method and characterized extensively. Up to 30 mol % Y could be substituted with Ca in tetragonal symmetry and without the appearance of any additional phase. The unit cell parameters varied nonlinearly with the elongation of the Y-O bond. The Raman spectra supported the local site distortion. The calcium-substituted samples displayed selected area electron diffraction characteristics similar to those of Bi2YO4Cl. A blueshift of the absorption edge was noticed with increasing calcium content yielding optical band gap values in the 2.40-2.57 eV range. The creation of 10% Bi5+ in Bi2Y0.70Ca0.30O4Cl was established with the help of XPS measurements and redox titrations. The higher reactivity of Bi5+ in an aqueous solution has been demonstrated for the oxidation of As(III) to As(V). Electron doping through Zr4+ incorporation was possible up to 30 mol % in Bi2YO4Cl. The Y-O bonds are contracted, and the Bi-O bonds are elongated with increasing Zr4+ content. Zr4+'s incorporation induced a local distortion. The color of the sample changed from bright yellow to deep yellow with Zr inclusion, resulting in a progressive decrease in optical band gap values. The introduction of electrons caused the reduction of 13.6% of Bi(III) to Bi(0). These results have established the vulnerability of Bi2O2 chains to charge carriers in Bi2YO4Cl. Density functional theory (DFT) calculations were implemented to understand the electronic and optical properties of the pristine and doped compounds. From the band structure calculations, the chosen compounds were found to be indirect band gap semiconductors. The results of the DFT calculations were in good agreement with the experiment; however, for the doped cases, virtual crystal approximation has been used considering uniform doping at the Y-site.

External electric field, a potential catalyst for C-N cross-coupling reaction.

The present work investigates the role of the external electric field (EEF) in boosting the C-N cross-coupling reaction between 2-chlorobenzoic acid and propylamine, by computing the reaction rates and energy barrier. The investigation suggests that the reaction can become barrierless by choosing an electric field in the appropriate direction, resulting in a quadrillionfold increase in the reaction rate in the presence of an EEF. We also found that the efficiency of the electric field depends on the dipole moment of the reactants, and hence, the results of the present work are general in nature and should be applicable to a variety of C-N cross-coupling reactions.

Design, Synthesis, Antimicrobial Evaluation of Novel 2-Oxo-4-Substituted Aryl-Azetidine Benzotriazole Derivatives.

A series of compounds was synthesized and characterized to explore new antimicrobial agents. These compounds were evaluated by using the agar cup plate method. The most active compound exhibited a zone of inhibition 18±0.09 mm and 19±0.09 mm against E. Coli and S. aureus, respectively. To gain insights into the intermolecular interactions, molecular docking studies were performed at the active site of the glucosamine fructose 6 phosphate synthase (GlcN 6 p) enzyme (PDB Id: 1XFF). The results of the molecular docking studies are in agreement with the pharmacological evaluation with potent compounds, exhibiting docking scores of -11.2. However, deformability, B-factor and covariance computations showed a result that the most active compound favored molecular connections with the protein. Therefore, our research is important for the development of antimicrobial agents.

Bandgap Shrinkage and Charge Transfer in 2D Layered SnS2 Doped with V for Photocatalytic Efficiency Improvement.

Effects of electronic and atomic structures of V-doped 2D layered SnS2 are studied using X-ray spectroscopy for the development of photocatalytic/photovoltaic applications. Extended X-ray absorption fine structure measurements at V K-edge reveal the presence of VO and VS bonds which form the intercalation of tetrahedral OVS sites in the van der Waals (vdW) gap of SnS2 layers. X-ray absorption near-edge structure (XANES) reveals not only valence state of V dopant in SnS2 is ≈4+ but also the charge transfer (CT) from V to ligands, supported by V Lα,ß resonant inelastic X-ray scattering. These results suggest V doping produces extra interlayer covalent interactions and additional conducting channels, which increase the electronic conductivity and CT. This gives rapid transport of photo-excited electrons and effective carrier separation in layered SnS2 . Additionally, valence-band photoemission spectra and S K-edge XANES indicate that the density of states near/at valence-band maximum is shifted to lower binding energy in V-doped SnS2 compare to pristine SnS2 and exhibits band gap shrinkage. These findings support first-principles density functional theory calculations of the interstitially tetrahedral OVS site intercalated in the vdW gap, highlighting the CT from V to ligands in V-doped SnS2 .

External electric field to control the Diels-Alder reactions of endohedral fullerene.

The present work investigates the role of External Electric Field (EEF) on a Diels-Alder reaction of endohedral fullerene by means of chemical kinetics and quantum chemical calculations. The investigation suggests that by combining two strategies, first encapsulating the cation inside the fullerene followed by applying EEF, one can easily manipulate the energy barrier of the Diels-Alder reaction. To illustrate this general strategy, we have chosen the reaction of fullerene (C60) and 1,3 cyclohexadiene, which is associated with a high energy barrier height of ∼11.2 kcal mol-1. Our calculation reveals that this reaction can be turned into a barrierless reaction by applying the EEF oriented along a suitable direction, and at the same time by changing the direction of EEF, the EEF can also act as an inhibitor.

Assessment of Performance of Photocatalytic Nanostructured Materials with Varied Morphology Based on Reaction Conditions.

Synthesis of nanomaterials with specific morphology is an essential aspect for the optimisation of its properties and applications. The application of nanomaterials is being discussed in a wide range of areas, one of which is directly relevant to the environment through photocatalysis. To produce an effective photocatalyst for environmental applications, morphology plays an important role as it affects the surface area, interfaces, crystal facets and active sites, which ultimately affects efficiency. The method of synthesis and synthesis temperature can be the basic considerations for the evaluation of a particular nanomaterial. In this study, we have considered the aspects of morphology with a basic understanding and analyzed them in terms of nanomaterial efficacy in photocatalysis. Different morphologies of specific nanomaterials such as titanium dioxide, zinc oxide, silver phosphate, cadmium sulphide and zinc titanate have been discussed to come to reasonable conclusions. Morphologies such as nanorods, nanoflower, nanospindles, nanosheets, nanospheres and nanoparticles were compared within and outside the domain of given nanomaterials. The different synthesis strategies adopted for a specific morphology have been compared with the photocatalytic performance. It has been observed that nanomaterials with similar band gaps show different performances, which can be linked with the reaction conditions and their nanomorphology as well. Materials with similar morphological structures show different photocatalytic performances. TiO2 nanorods appear to have the best features of efficient photocatalyst, while the nanoflowers show very low efficiency. For CdS, the nanoflower is the best morphology for photocatalysis. It appears that high surface area is the key apart from the morphology, which controls the efficiency. The overall understanding by analyzing all the available information has enumerated a path to select an effective photocatalyst amongst the several nanomaterials available. Such an analysis and comparison is unique and has provided a handle to select the effective morphology of nanomaterials for photocatalytic applications.

Recombinant organophosphorus hydrolase (OPH) expression in E. coli for the effective detection of organophosphate pesticides.

Accumulation and exposure of organophosphate pesticides are of great concern today owing to their abundant usage and potential health hazards. Harmful effects of organophosphate pesticide exposure and limitations of the available treatment methods necessitate the development of reliable, selective, cost-effective, and sensitive methods of detection. We developed a novel biosensor based on the enzymatic action of recombinant organophosphorus hydrolase (OPH) expressed in E. coli. We report the development of colorimetric biosensors made of His-Nus-OPH as well as His-Nus-OPH loaded alginate microspheres. The colorimetric detection method developed using solution-phase and alginate-encapsulated His-Nus-OPH exhibited detection limits of 0.045 and 0.039 mM, respectively, for ethyl paraoxon, and 0.101 and 0.049 mM, respectively, for methyl parathion. Additionally, fluorescence measurement using pH-sensitive fluorescein isothiocyanate (FITC) was used to sense the quantity of organophosphorus pesticides. The fluorometric detection method using solution-phase His-Nus-OPH, with ethyl paraoxon and methyl parathion as the substrate, reveals the lower limit of detection as 0.014 mM and 0.044 mM, respectively. Our results demonstrate the viability of His-Nus-OPH for OP detection with good sensitivity, LOD, and linear range. We report the first use of N-terminal His-NusA-tagged OPH, which enhances solubility significantly and presents a significant advance for the scientific community.

Sodium sulphide promoted synthesis of fused quinoline at room temperature.

A novel, simple and eco-friendly strategy for the synthesis of thiopyrano[4,3-b]quinolin-1-ones and pyrrolo[3,4-b]quinolin-1-ones from 2-alkynylquinoline-3-carbonitriles and sodium sulphide (Na2S·9H2O) under catalyst-free conditions at room temperature has been described. In this reaction, a readily available inorganic salt (Na2S·9H2O) serves as the sulphur source and leads to the generation of diverse functionalized thiopyrano[4,3-b]quinolin-1-ones and pyrrolo[3,4-b]quinolin-1-ones in moderate to excellent yields through sulfuration, annulation, and aerial oxidation.

A novel biosensor for the detection of organophosphorus (OP)-based pesticides using organophosphorus acid anhydrolase (OPAA)-FL variant.

Indiscriminate use of organophosphorus (OP)-based insecticides is a great concern to human health because of bioaccumulation-induced health hazards. Potentially fatal consequences and limited treatment methods of OP poisoning necessitate the need for the development of reliable, selective, cost-effective, and sensitive methods of OP detection. To tackle this issue, the development of effective devices and methods is required to sensitively detect as well as degrade OPs. Enzymatic sensor systems have gained popularity due to high catalytic activity, enhanced detection limits, and high sensitivity with the environmentally benign operation. Organophosphorus acid anhydrolase (OPAA) from Alteromonas sp. JD6.5 is capable of hydrolyzing the P-F, P-O, P-S, and P-CN bonds, in OPs, including nerve agents of the G/V-series. Several mutants of OPAA are reported which have greater activity against various OPs. In this study, recombinant expression of the OPAA-FL variant in Escherichia coli was performed, purified, and subsequently tested for activity against ethyl paraoxon. OPAA-FL variant showed its optimum activity at pH 8.5 and 50 °C. Colorimetric and fluorometric assays were used for estimation of ethyl paraoxon based on p-nitrophenol and fluorescein isothiocyanate (FITC) fluorescence intensity, respectively. Colorimetric and fluorometric assay estimation indicates that ethyl paraoxon can be estimated in the linear range of 0.01 to 1 mM and 0.1 to 0.5 mM, with LOD values 0.04 mM and 0.056 mM, respectively. Furthermore, the OPAA-FL variant was immobilized into alginate microspheres for colorimetric detection of ethyl paraoxon and displayed a linear range of 0.025 to 1 mM with a LOD value of 0.06 mM. KEY POINTS: • Biosensing of paraoxon with purified and encapsulated OPAA-FL variant. • Colorimetric and fluorometric biosensing assay developed using OPAA-FL variant for paraoxon. • First report on alginate encapsulation of OPAA-FL variant for biosensing of paraoxon. Graphical abstract.

Interaction of coumarin triazole analogs to serum albumins: Spectroscopic analysis and molecular docking studies.

The interaction of triazole substituted 4-methyl-7-hydroxycoumarin derivatives (CUM1-4) with serum albumin (bovine serum albumin [BSA] and human serum albumin [HSA]) have been studied employing ultraviolet-visible (UV-Vis), fluorescence, circular dichroism (CD) spectroscopy, and molecular docking methods at physiological pH 7.4. The fluorescence quenching occurred with increasing concentration of CUMs, and the binding constant of CUM derivatives with BSA and HSA obtained from fluorescence quenching experiment was found to be ~ 104 L mol-1 . CD study showed conformational changes in the secondary structure of serum albumin upon titration of CUMs. The observed experimental results were further validated by theoretical studies involving density functional theory (DFT) and molecular docking.

Advances in detection of hazardous organophosphorus compounds using organophosphorus hydrolase based biosensors.

Agricultural advancements focusing on increasing crop production have led to excessive usage of insecticides and pesticides, resulting in leaching and accumulation of these highly toxic chemicals in soil, water, and the food-chain. Organophosphorus (OP) compounds are the most commonly used insecticides and pesticides, which cause a wide range of long-lasting and life-threatening conditions. Due to the acute toxicity and long-term side effects of OP compounds, their timely, on-the-spot and rapid detection has gained importance, for efficient healthcare management. In this respect, several OP degrading enzymes have gained the spotlight in developing the enzyme-based biosensors, owing to their high activity and broad specificity. Among these enzymes, organophosphorus hydrolase (OPH) has emerged as a promising candidate for the detection of OP compounds, due to its ability to act on a broad range of substrates having a variety of bonds, like P─F, P─O, P─S, and P─CN. Various techniques employing OPH in free/immobilized/conjugated forms into sensing devices were reported to accurately detect OP compounds. The transduction mechanisms of bio-sensing are electrochemical, optical as well as novel methods like magnetoelastic/surface plasmon resonance. Furthermore, to improve the detection limits and sensitivity, nanoparticles and quantum dots are often employed in conjunction with OPH. Here, we highlight the recent advances in sensing OP compounds using OPH based biosensors, compare specifications of sensing methods, and evaluate the influence of different materials used in developing sensors. This review will also enable researchers to design and configure highly sensitive and accurate sensing systems, leading to the development of point-of-care devices for real-time analysis.

Insight into the interaction of benzothiazole tethered triazole analogues with human serum albumin: Spectroscopy and molecular docking approaches.

The interaction of four benzothiazole tethered triazole analogues (MS43, MS70, MS71, and MS78) with human serum albumin (HSA) was investigated using various spectroscopic techniques (ultraviolet-visible (UV-vis) light absorption, fluorescence, circular dichroism (CD), molecular docking and density functional theory (DFT) studies). Fluorescence quenching constants (~1012 ) revealed a static mode of quenching and binding constants (Kb ~104 ) indicating the strong affinity of these analogues for HSA. Further alteration in the secondary structure of HSA in the presence of these analogues was also confirmed by far UV-CD spectroscopy. The intensity loss in CD studied at 222 nm indicated an increase in random coil/ß-sheet conformations in the protein. Binding energy values (MS71 (-9.3 kcal mol-1 ), MS78 (-8.02 kcal mol-1 ), MS70 (-7.16 kcal mol-1 ) and MS43 (-6.81 kcal mol-1 )) obtained from molecular docking revealed binding of these analogues with HSA. Molecular docking and DFT studies validated the experimental results, as these four analogues bind with HSA at site II through hydrogen bonding and hydrophobic interactions.

Absence of Azole or Echinocandin Resistance in Candida glabrata Isolates in India despite Background Prevalence of Strains with Defects in the DNA Mismatch Repair Pathway.

Candida glabrata infections are increasing worldwide and exhibit greater rates of antifungal resistance than those with other species. DNA mismatch repair (MMR) gene deletions, such as msh2Δ, in C. glabrata resulting in a mutator phenotype have recently been reported to facilitate rapid acquisition of antifungal resistance. This study determined the antifungal susceptibility profiles of 210 C. glabrata isolates in 10 hospitals in India and investigated the impact of novel MSH2 polymorphisms on mutation potential. No echinocandin- or azole-resistant strains and no mutations in FKS hot spot regions were detected among the C. glabrata isolates, supporting our in vitro susceptibility testing results. CLSI antifungal susceptibility data showed that the MICs of anidulafungin (geometric mean [GM], 0.12 µg/ml) and micafungin (GM, 0.01 µg/ml) were lower and below the susceptibility breakpoint compared to that of caspofungin (CAS) (GM, 1.31 µg/ml). Interestingly, 69% of the C. glabrata strains sequenced contained six nonsynonymous mutations in MSH2, i.e., V239L and the novel mutations E459K, R847C, Q386K, T772S, and V239/D946E. Functional analysis of MSH2 mutations revealed that 49% of the tested strains (40/81) contained a partial loss-of-function MSH2 mutation. The novel MSH2 substitution Q386K produced higher frequencies of CAS-resistant colonies upon expression in the msh2Δ mutant. However, expression of two other novel MSH2 alleles, i.e., E459K or R847C, did not confer selection of resistant colonies, confirming that not all mutations in the MSH2 MMR pathway affect its function or generate a phenotype of resistance to antifungal drugs. The lack of drug resistance prevented any correlations from being drawn with respect to MSH2 genotype.