Trifluoroacetic acid-mediated synthesis of xanthene constructs and their extensive anti-tuberculosis evaluation.

A diverse range of 9-substituted 1,8-dioxohexahydroxanthenes was conceptualized and synthesized through a TFA-mediated approach in near quantitative yields without the use of column chromatography. From a series of 25 compounds, we found that compounds 14c and 14r exhibited promising anti-tuberculosis potential against avirulent and virulent strains of Mycobacterium tuberculosis with a Minimal Inhibitory Concentration (MIC) of 8 µg ml-1, achieving 99% bactericidal activity at the same concentration. This series of compounds was found to be inactive against common Gram-positive and Gram-negative pathogens, indicating that the activity is mycobacteria-specific. Since the strategies for treating tuberculosis employ a combinatorial therapy, we tested and observed that the two lead compounds displayed synergistic behavior with known anti-TB drugs (ATDs) and a significant (16-32 fold) decrease in MIC values of both leads was observed in combination with either RIF or INH. Interestingly the lead molecule 14c displayed only time-dependent kill kinetics and sterilized the whole culture of Mycobacterium tuberculosis H37Rv in just 48 hours.

HFIP-mediated C-3-alkylation of indoles and synthesis of indolo[2,3-b]quinolines & related natural products.

An expeditious metal free C-3 alkylation of indoles and its NIS-mediated deviation to indolo[2,3-b]quinolines is reported. This protocol, executed in aqueous HFIP has broad substrate scope and is well inclined towards the ideas of sustainable chemistry. Applications of these strategies in accessing bioactive natural products like vibrindole, norcryptotakeine, neocryptolepine and indenoindolone scaffolds has also been demonstrated.

Gastrointestinal parasites of the wild ungulates (Mammalia: Cetartiodactyla) in the Hemis National Park, Ladakh, India.

We evaluated the gastrointestinal parasitic prevalence and intensity of wild ungulates in the Hemis National Park of Ladakh by examining their fresh faecal samples. A total of 327 fresh faecal samples from three wild ungulates, blue sheep Pseudois nayaur (n = 127), Ladakh urial Ovis vignei vignei (n = 110), and Himalayan ibex Ibex siberica (n = 90) were collected between June 2021 and May 2022. The techniques of flotation and sedimentation were used to find parasite eggs and oocysts from the faecal samples. Out of 327 samples examined, 165 samples were infected with gastrointestinal parasites making an overall prevalence of 50.45%. Seven parasitic taxa, including one protozoan (Eimeria spp.), five nematodes (Nematodirus spp., Strongyloides spp., Haemonchus sp., Trichuris sp., and Trichostrongylus spp.), and one cestode (Monezia spp.), were found during the current investigation. Mixed infection was reported in 36 (11%) of the total examined samples. The prevalence of gastrointestinal parasites was found to be highest in blue sheep (55.11%), followed by Ladakh urial (49.09%) and Himalayan ibex (45.55%). The highest prevalence was recorded in the summer (64.42%), and the lowest in the winter (33.82%). A significant difference in parasitic prevalence was observed across seasons in each of the three wild ungulate hosts. However, there was no significant difference in the prevalence of parasites between these hosts.

Genome-wide SNP discovery and genotyping delineates potential QTLs underlying major yield-attributing traits in buckwheat.

Buckwheat (Fagopyrum spp.) is an important nutritional and nutraceutical-rich pseudo-cereal crop. Despite its obvious potential as a functional food, buckwheat has not been fully harnessed due to its low yield, self-incompatibility, increased seed cracking, limited seed set, lodging, and frost susceptibility. The inadequate availability of genomics resources in buckwheat is one of the major reasons for this. In the present study, genome-wide association mapping (GWAS) was conducted to identify loci associated with various morphological and yield-related traits in buckwheat. High throughput genotyping by sequencing led to the identification of 34,978 single nucleotide polymorphisms that were distributed across eight chromosomes. Population structure analysis grouped the genotypes into three sub-populations. The genotypes were also characterized for various qualitative and quantitative traits at two diverse locations, the analysis of which revealed a significant difference in the mean values. The association analysis revealed a total of 71 significant marker-trait associations across eight chromosomes. The candidate genes were identified near 100 Kb of quantitative trait loci (QTLs), providing insights into several metabolic and biosynthetic pathways. The integration of phenology and GWAS in the present study is useful to uncover the consistent genomic regions, related markers associated with various yield-related traits, and potential candidate genes having implications for being utilized in molecular breeding for the improvement of economically important traits in buckwheat. Moreover, the identified QTLs will assist in tracking the desirable alleles of target genes within the buckwheat breeding populations/germplasm.

Indeno-Annulation of o-Formyl-Ynones, o-Bis-Ynones, and p-Bis-o-Formyl-Ynones with Dimethyl Acetone-1,3-Dicarboxylate: One Flask Cascade Synthesis of Functionally Endowed 9-Fluorenols and Indeno[1,2-b]fluorenols.

A mild, scalable, one-pot access to multifunctional 9-fluorenols from o-formyl-ynones and o-bis-ynones on reaction with dimethylacetone-1,3-dicarboxyate through tandem Michael addition-Aldol condensation cascade has been conceptualized and executed. The scope and utility of this synthetic approach have been further amplified for one-pot entry into functionally enhanced, higher order fluorenols like pentacyclic indeno[1,2-b]fluorene-6,12-diols and further to indeno[1,2-b]fluorene-6,12-diones through the implementation of "double indeno-annulation" tactic on p-bis-o-formyl ynones and dimethylacetone-1,3-dicarboxylate. Besides several green attributes, the current approach is also compatible with the emerging time and energy economy features and is a swift gateway to build complexity.

A micelle-mediated approach enables facile access to bridged oxabicyclo[n.3.1]alkene scaffolds.

Oxabicyclo[n.3.1]alkene scaffolds present in a diverse range of complex natural products have been accessed by reacting 2-cycloalkenones with 1,3-cycloalkadiones in a micellar medium. This reaction occurring in a micellar confinement environment operates through a Michael addition/enolization/oxygen addition cascade to furnish highly functionalized constructs using a sustainable organic synthesis protocol. NMR analysis confirms that the locus of the solubilizates is within the palisade and stern regions of the micellar cavity.

Gastrointestinal helminth parasites of wild ungulates in Hirpora Wildlife Sanctuary, Kashmir, India.

Parasitic infection represents an emerging threat to wild ungulates and a challenge to their management. Although a lot of work has been carried out on helminth parasitic infestation of domestic ungulates of Kashmir but the data pertaining to this aspect of wild ungulates has been ignored. The study on gastrointestinal helminth parasitic infestation of wild ungulates was carried out during post livestock grazing period (November to May) of 2018/2019 in Hirpora Wildlife sanctuary (HWLS) to fill the gap in the existing literature. During the study fresh faecal samples of musk deer Moschus spp. (n = 44) and markhor Capra falconeri (n = 41) were collected and examined qualitatively and quantitatively for gastrointestinal helminth parasites. A total of seven helminth parasites were recorded which are arranged in the descending order of their overall prevalence as Haemonchus spp. (44.70%), Nematodirus spp. (40%), Trichuris spp. (37.64%), Strongyloides spp. (34.11%) Trichostrongylus spp. (28.23%) Moniezia spp. (23.52%) and Fasciola spp. (20%). The mean EPG (eggs per gram) of different parasites showed a considerable variation in both the wild ungulates. The highest mean EPG was that of Haemonchus spp. and the lowest mean EPG was that of Fasciola spp. in both hosts. A statistically significant difference was observed in the mean EPG of different parasites between two wild hosts (t = 3.606, p = 0.01) .

Polyphenolics, antioxidant characterization and DNA barcoding of Kala zeera [Bunium persicum (Boiss.) Fedtsch] through multiple barcode analysis to unravel best barcode combination.

BACKGROUND: Kala zeera [Bunium persicum (Boiss.) Fedtsch] is one of the important spice crops of North Western Himalayas with lot of medicinal and culinary values. In spite of having great importance, this crop is under the threat of extinction due to loss of habitat and lack of awareness. The limited availability of the seeds has ultimately increased the economic value of this spice. The upmarket of Kala zeera leads to its adulteration with other black seeds and cumin seeds. The present investigation was undertaken to evaluate polyphenolics and antioxidant properties of Kala zeera genotypes collected from North Western Himalayas and to develop DNA barcodes that can ensure their purity and can also guide in conservation of selected Kala zeera germplasm lines. METHODS AND RESULTS: Various locations of North Western Himalayas were explored for collecting 31 diverse germplasm lines of Kala zeera. The collected germplasm was maintained at our experimental stations during 2019-2020 and 2020-2021. These genotypes were evaluated for different seed traits and the methanolic extract from Kala zeera seeds was examined for total phenolic content, total flavonoid content, antioxidant activities by DPPH and FRAP. The results revealed significant variation in seed traits, polyphenolic content and antioxidant properties. 100 seed weight ranged from 0.05 to 0.35 g, TPC ranged from 7.5 to 22.56 mg/g, TFC ranged from 0.58 to 4.15 mg/g, antioxidant properties DPPH ranged from 168 to 624.4 µg/ml and FRAP ranged from 0.72 to 6.91 mg/g. Further, three different barcodes (ITS, rbcL and psbA-trnH) were used to reveal the authenticity of selected Kala zeera. MEGA 5 software was used for clustering and the barcodes did clustering based on geographical distribution of Kala zeera germplasm. CONCLUSION: Based on molecular barcoding, best barcode combination was identified that may discriminate the Kala zeera germplasm vis-a-vis can authenticate their purity. Moreover, the identified DNA barcodes will have significant role in studying the evolutionary biology of Bunium species and will be important for designing a strategy to conserve the selected Kala zeera germplasm lines. The identified genotypes with high phenolic content and antioxidant activity can further be utilized in Kala zeera breeding programmes.

Micelle-guided Morita-Baylis-Hillman reaction of ketones in water.

A novel Morita-Baylis-Hillman reaction employing electron-deficient alkenes like acrylonitrile with a wide range of aryl and aliphatic ketones using cooperative catalysis in micellar media has been delineated. This transformation executed in water under mild reaction conditions in a confined environment of micelles is aligned to the ideas of sustainable and green chemistry. The site of the reaction was established by incisive proton NMR studies in the palisade region of the micellar assembly. This study is expected to encourage the use of micellar catalysis for energetically less favorable chemical reactions.

Platanic Acid-Aryl Enones as Potential Anticancer Compounds: Synthesis and Biological Profiling against Breast, Prostate and Lung Cancer Cell Lines.

A series of rationally designed platanic acid-based compounds derived from naturally occurring betulinic acid were synthesized through a sequence of Lemieux-Johnson oxidation and Aldol condensation reaction. All the compounds were screened for cytotoxicity against a panel of human cancer and normal cell lines using MTT assay. From the biological data, it was observed that some of these semi-synthetic congeners exhibited potent biological profiles compared to platanic acid. One of the compounds with the p-tolyl substitution was found to be most active in this study, and its cytotoxicity against two of the cell lines, MDA-MB 231 and A-549 were in tune with the standard compound, 5-fluorouracil.

Conceptualization and Synthesis of the First Inosito-Inositol (Decahydroxydecalin, DHD): In†silico Binding to ß-Amyloid Protein.

Previously unknown entities in the form of 1,2,3,4,5,6,7,8,9,10-decahydroxydecalins (DHDs) have been conceptualized and the first member of this class, an inosito-inositol, has been synthesized from aromatic hydrocarbon naphthalene following a flexible strategy that is amenable to diversity creation. The DHD accessed here has been subjected to preliminary in silico evaluation with Aß and may hold some promise in Alzheimer's disease therapeutics.

Carbon-Carbon Bond Formation Facilitated by π-Complexed Organometallic Auxiliaries: An Overview.

Organometallic moieties attached to substrates via π-complexation play an important role as auxiliaries. As described in the present review, η-linked auxiliaries have been employed to overcome numerous synthesis obstacles that continue to present significant challenges for catalyzed reactions. This has been particularly true in carbon-carbon bond forming reactions involving highly unsaturated systems such as arenes, dienes and allenes, which are emphasized here.

In vitro antimycobacterial activity of 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione: a new chemical entity against Mycobacterium tuberculosis.

This study reports on the in vitro antituberculosis potential of 2-(((2-hydroxyphenyl) amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (PAMCHD) against Mycobacterium tuberculosis H37Rv. PAMCHD has been proven to be a tuberculostatic as well as a tuberculocidal agent by agar and broth dilution methods with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values equivalent to some standard antituberculosis drugs (ATDs). The dynamics of M. tuberculosis killing revealed the time- as well as concentration-dependent antituberculosis activity of PAMCHD and it sterilized M. tuberculosis culture at or above 10.0 µg/mL. PAMCHD acts either synergistically or additively with ATDs. Isoniazid (INH) and PAMCHD post-antibiotic effects increased with concentration from 16.18 ± 13.30 and 31.64 ± 13.30 to 127.9 ± 27.60 and 138.71 ± 16.42 h, respectively, from 1 × MIC to 8 × MIC; no significant difference was observed between INH and PAMCHD post-antibiotic effects. M. tuberculosis mutation frequency against PAMCHD is lower than that of INH. Mutant prevention concentration (MPC) of INH, rifampin (RIF) and PAMCHD were observed to be 40, 160 and 160 µg/mL, respectively, and their MPC/MIC values were 128, 2051 and 64, respectively; this lowest MPC/MIC highlights the advantage of PAMCHD over RIF and INH.

The synthesis, biological evaluation and structure-activity relationship of 2-phenylaminomethylene-cyclohexane-1,3-diones as specific anti-tuberculosis agents.

The present study utilised whole cell based phenotypic screening of thousands of diverse small molecules against Mycobacterium tuberculosis H37Rv (M. tuberculosis) and identified the cyclohexane-1,3-dione-based structures 5 and 6 as hits. The selected hit molecules were used for further synthesis and a library of 37 compounds under four families was synthesized for lead generation. Evaluation of the library against M. tuberculosis lead to the identification of three lead antituberculosis agents (37, 39 and 41). The most potential compound, 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (39) showed an MIC of 2.5 µg mL-1, which falls in the range of MICs values found for the known antituberculosis drugs ethambutol, streptomycin and levofloxacin. Additionally, this compound proved to be non-toxic (<20% inhibition at 50 µM concentration) against four human cell lines. Like first line antituberculosis drugs (isoniazid, rifampicin and pyrazinamide) this compound lacks activity against general Gram positive and Gram negative bacteria and even against M. smegmatis; thereby reflecting its highly specific antituberculosis activity.

Dimethoate Induced Behavioural Changes in Juveniles of Cyprinus carpio var. communis under Temperate Conditions of Kashmir, India.

The present study was designed to investigate acute toxicity of dimethoate on juvenile Cyprinus carpio var. communis. Fishes weighing 10 ± 2 gms were selected and mortality data was statistically evaluated by Finney's Probit Method. The 96-hour LC50 value for Cyprinus carpio was found as 1.1 ppm in static bioassay system. Mean values of physicochemical parameters of aquarium waters determined during bioassay depicted slight variation indicating that the mortality in aquarium fishes occurred due to pesticide exposure and not suffocation. Lab. temperature ranged from 12 to 13°C; water temperature ranged from 11 to 12°C; dissolved oxygen ranged from 3.90 to 4.56 mg/L; pH ranged from 6.90 to 7.05; total dissolved solids ranged from 2.66 to 3.0 × 10(3) mg/L, while CO2 remained at a constant value of 2.0 mg/L. The fishes elicited various behavioural responses such as uncoordinated movements, convulsions, excessive mucus secretion, and imbalanced swimming which ended in a collapse to the bottom of the aquarium. Prior to death, the clinical signs like scale erosion, pale body colour, and hemorrhagic patches over the body were noticed which became more vivid up to the termination of experiments. Results of the study indicate potential toxicity of dimethoate in fingerlings of common carp for which the natural waterbodies must be continuously monitored to reduce its impact across food chains.

Asymmetric Protonation of Cumulenolates: Synthesis of Allenyl Aldehydes Facilitated by an Organomanganese Auxiliary.

Chiral ammonium salts were used to catalyze the isomerization of organomanganese-complexed alkynyl aldehydes to chiral allenal building blocks in moderate to good enantiomeric excesses. Normally, conjugated alkynyl aldehydes do not isomerize to their thermodynamically less stable allene isomers. However, with a manganese auxiliary in place to promote allene formation, asymmetric protonation of cumulenolate intermediates was realized using a variety of cinchonidinium salts in a weakly basic biphasic reaction system. Optimal results were realized using a novel cinchonidinium geranyl derivative with its C-9 hydroxyl group playing a crucial role in enantioselectivity.

Promise of Retinoic Acid-Triazolyl Derivatives in Promoting Differentiation of Neuroblastoma Cells.

Retinoic acid induces differentiation in various types of cells including skeletal myoblasts and neuroblasts and maintains differentiation of epithelial cells. The present study demonstrates synthesis and screening of a library of retinoic acid-triazolyl derivatives for their differentiation potential on neuroblastoma cells. Click chemistry approach using copper(I)-catalyzed azide-alkyne cycloaddition was adopted for the preparation of these derivatives. The neurite outgrowth promoting potential of retinoic acid-triazolyl derivatives was studied on neuroblastoma cells. Morphological examination revealed that compounds 8a, 8e, 8f, and 8k, among the various derivatives screened, exhibited promising neurite-outgrowth inducing activity at a concentration of 10 µM compared to undifferentiated and retinoic acid treated cells. Further on, to confirm this differentiation potential of these compounds, neuroblastoma cells were probed for expression of neuronal markers such as NF-H and NeuN. The results revealed a marked increase in the NF-H and NeuN protein expression when treated with 8a, 8e, 8f, and 8k compared to undifferentiated and retinoic acid treated cells. Thus, these compounds could act as potential leads in inducing neuronal differentiation for future studies.

Regenerative γ-Lactone Annulations: A Modular, Iterative Approach to Oligo-tetrahydrofuran Molecular Stairs and Related Frameworks.

A unified, stereocontrolled, regenerative γ-butyrolactone annulation approach has been conceptualized and validated through syntheses of a range of oligo-THFs. The new protocol is short (four steps), simple (table-top reagents), and efficient (50-61% overall yields). Although the scope of this approach is unlimited, it has been demonstrated up to five iterations on commercial γ-butyrolactone to assemble six fused tetrahydrofuran moieties in a staircase-like architecture. A selection of exploratory transformations is presented to exemplify the potential applications of this protocol.

Organo-manganese η2-auxiliary directed reactions: a diastereoselective approach to 2,3-allenols.

Propargyl aldehydes underwent isomerization to allenyl aldehydes under mildly basic conditions when complexed to an organo-manganese auxiliary using methylcyclopentadienyl manganese tricarbonyl (MMT). This traceless auxiliary magnifies the axial chirality of the allene moiety, allowing for highly diastereoselective additions to the aldehyde carbonyl and subsequent access to an array of 2,3-allenols. Using this strategy, a nitrile-substituted 2,3-allenol was prepared and efficiently converted to Hagen's gland lactone.

Annulation reactions of allenyl esters: an approach to bicyclic diones and medium-sized rings.

A flexible approach to construct sterically congested bicyclo-alkenedione frameworks is reported. Under the action of potassium carbonate, α-sulphonyl cycloalkanones are added to functionalized allenyl esters, leading to a lactone intermediate that is subsequently reduced to initiate an intramolecular aldol cyclization to [3.2.1], [3.3.1], and [4.3.1] bicycles. Oxidation then affords bicyclic diones in good three-step yields. Under exceptionally mild conditions, these bicycles are converted to highly functionalized medium-sized rings through a Grob-type fragmentation.