Network pharmacology-guided therapeutic exploration of a new trihydroxy fatty ester isolated from rhizomes of Trillium govanianum.

One new previously undescribed trihydroxy fatty ester (1) and three known aliphatic alkenes (2-4) have been isolated from the rhizomes of Trillium govanianum Wall. ex D.Don. The structures of isolated molecules were elucidated using extensive spectroscopic techniques including NMR, HR-ESI-MS, and FT-IR, respectively. This is the first report on the isolation of compounds 3 and 4 from the Trillium genus. Moreover, through a network pharmacology approach, the therapeutic potential of the isolated molecules was investigated. This analysis revealed that these fatty alkenes can be utilised for managing health conditions such as pneumonitis, inflammatory pain, and endothelial dysfunction.

Chiral amino acids: evolution in atroposelective C-H activation.

This review covers the journey of chiral amino acids as ligands in atroposelective C-H bond activation/functionalization via transition metal catalysis. Herein, we intend to demonstrate how these chiral amino acids have evolved and flourished in this stimulating field. Unprotected amino acids, mono-N-protected amino acids, and di-N-protected amino acids have been devised for atroposelective C-H activation. In each section, we have briefly discuss the key successes of amino acids in the atroposelective synthesis of biaryls, heterobiaryls, and non-biaryl atropisomers and their advantages in atroposelective C-H activation.

Co(III)-Catalyzed Regioselective Functionalization of Isoquinolones with Naphthoquinones.

A strategy for Co(III)-catalyzed C(sp2)-H alkenylation of N-protected isoquinolones with 1,4-naphthoquinones has been disclosed. The developed protocol was efficiently applied for diversely substituted isoquinolones. Preliminary mechanistic experiments revealed the involvement of a five-membered cobaltacycle as an intermediate. Deuterium labeling experiments suggested the reversible nature of the C-H activation step. The scale-up reaction was also carried out, and the product was utilized as a chemosensor to detect Fe3+ ions.

Hydroalkylation of styrenes enabled by boryl radical mediated halogen atom transfer.

In this study, we present an inexpensive, stable, and easily available boryl radical source (BPh4Na) employed in a Halogen Atom Transfer (XAT) methodology. This mild and convenient strategy unlocks the use of not only alkyl iodides as radical precursors but also of the more challenging alkyl and aryl bromides to generate C-centered radicals. The generated radicals were further engaged in the anti-Markovnikov hydroalkylation of electronically diverse styrenes, therefore achieving the formation of C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds. A series of experimental and computational studies revealed the prominent role of BPh4Na in the halogen abstraction step.

Inherent directing group-enabled Co(III)-catalyzed C-H allylation/vinylation of isoquinolones.

Co(III)-catalysed site-selective C8-allylation and vinylation of isoquinolones with allyl acetate and vinyl acetates has been accomplished. The oxo group of isoquinolone has been utilised as an inherent directing group. Based on preliminary mechanistic studies, a plausible mechanism for the developed reaction has also been delineated. Broad substrate scope with good to excellent yields and post-synthetic transformations of allylated and vinylated isoquinolines highlight the importance of the reaction.

Exploring Steroidal Saponin Composition and Morphometric Characteristics of Rhizomes from Trillium govanianum Wall. ex D. Don: Inference for Medicinal Properties and Genetic Stock Improvement.

Trillium govanianum, a medicinal herb, exhibiting diverse morphometric traits and phytochemicals across developmental stages of plants. The changes in the chemical profile and steroidal saponin levels in the rhizome of T. govanianum across different developmental stages were previously unknown. This study categorizes rhizomes into three types based on scar presence: juvenile (5-10 scars, Type I), young (11-19 scars, Type II), and mature (21-29 scars, Type III). Rhizomes show varying sizes (length 1.2-4.7 cm, girth 0.3-1.6 cm), weight (0.18-5.0 g), and extractive yields (9.7-16.1 % w w-1), with notable differences in saponin content (5.95-21.9 mg g-1). Ultra-high performance liquid chromatography-MS/MS (UHPLC-QTOF-MS/MS)-based chemical profiling identifies 31 phytochemicals, mainly including diverse saponins. Ultra-high performance liquid chromatography coupled with evaporative light scattering detection (UHPLC-ELSD)-based quantitative analysis of seven key saponins reveals stage-specific accumulation patterns, with protodioscin (P) and dioscin (DS) predominant in mature rhizomes. Statistical analysis confirms significant variation (p=0.001) in saponin levels across developmental stages with chemical constituent protodioscin (P=4.03±0.03-15.76±0.14 mg g-1, PAve=9.79±3.03 mg g-1) and dioscin (DS=1.23±0.06-3.93±0.07 mg g-1, DSAve=2.59±0.70 mg g-1), with acceptable power (p=0.738; |δ|>0.5) statistics for effective sample size (n=27 samples used in the study) of T. govanianum. Principal Component Analysis (PCA) and Euclidean clustering further highlighted chemotype distinctions.

NADES extraction, UHPLC-ELSD-based quantification, and network pharmacology-guided target identification of fourteen specialised metabolites from Trillium govanianum Wall. ex D.Don.

INTRODUCTION: Trillium govanianum Wall. ex D.Don is a folk medicinal herb rich in structurally diverse steroidal saponins. The annual demand for this herb in India is about 200-500 metric tons, highlighting the need for a thorough quality assessment. OBJECTIVE: The objective of this study is to develop an easy and reliable ultrahigh-performance liquid chromatography-evaporative light scattering detector (UHPLC-ELSD)-based quality assessment method with 14 specialised metabolites of T. govanianum and identify the potential targets of this herb using network pharmacology. MATERIAL AND METHODS: A UHPLC-ELSD method was developed and validated with 14 markers of T. govanianum. The developed method and natural deep eutectic solvent (NADES)-assisted extraction were utilised for the recovery enhancement study of targeted specialised metabolites from rhizome samples (collected from five geographically distinct areas). In addition, the network pharmacology approach was performed for these 14 markers to predict the plausible biological targets of T. govanianum. RESULT: The developed method showed good linearity (r2: 0.940-0.998), limit of detection (LOD) (2.4-9.0 µg), limit of quantification (LOQ) (7.92-29.7 µg), precision (intra-day relative standard deviations [RSDs] 0.77%-1.96% and inter-day RSDs 2.19-4.97%), and accuracy (83.24%-118.90%). NADES sample TG-1* showed the highest recovery (yield: 167.66 ± 4.39 mg/g of dry weight) of total saponin content (TSC) as compared to its hydroethanolic extract (yield: 103.95 ± 5.36 mg/g of dry weight). Sample TG-1* was the most favourable (yield: 167.66 ± 4.39 mg/g) in terms of TSC as compared to other analysed samples (32.68 ± 1.04-88.22 ± 6.79 mg/g). Govanoside D (yield: 3.43-28.06 mg/g), 22ß-hydroxyprotodioscin (yield: 3.22-114.79 mg/g), and dioscin (yield: 1.07-20.82 mg/g) were quantified as the major metabolites. Furthermore, network pharmacology analysis of targeted 14 markers indicated that these molecules could be possible therapeutic agents for managing neuralgia, diabetes mellitus, and hyperalgesia. CONCLUSION: The current study represents the first report for the simultaneous quantification and a network pharmacology-based analysis of 14 chemical marker compounds isolated from T. govanianum.

Chemometric guided isolation of new triterpenoid saponins as acetylcholinesterase inhibitors from seeds of Achyranthes bidentata Blume.

Achyranthes bidentata Blume (Amaranthaceae) is an annual or perennial herb widely used as ethnomedicine in Traditional Chinese Medicine for treating fever, cold, ulcers, mensural pain, dementia, and osteoporosis. In the current study, UPLC-IM-Q-TOF-MS/MS-based chemometric approach was adopted for the tentative identification of fifty-six compounds in the extract and fractions of A.bidentata seeds. Further, the chemometric-guided isolation led to the isolation of two previously undescribed oleanane-type triterpenoid saponins, named achyranosides A-B (27 and 30), along with three known compounds (31, 44, and 23) from water fraction of A. bidentata seeds. The structures of new compounds were elucidated based on the detailed analysis of NMR, HR-ESI-MS, FT-IR spectral data, and GC-FID techniques. The isolated compounds in vitro acetylcholinesterase inhibitory activity revealed the promising activity of chikusetsusaponin IVa (23) (IC50 = 63.7 µM) with mixed type of AChE inhibition in enzyme kinetic studies. Additionally, in silico binding free energy of isolated compounds disclosed the greater stability of enzyme-ligand complex owing to underlying multiple H-bond interactions. Overall, the study demonstrates the effectiveness of a chemometric-guided approach for the phytochemical exploration and isolation of new oleanane-type triterpenoid saponins from A. bidentata seeds.

Two new alkaloids from the roots of Cocculus hirsutus (L.) W. Theob.

Two undescribed alkaloids, 15-carboxydihydroerysotrine (1) and (14 R)-4-methoxy-13,14-dihydrooxypalmatine (2), along with six known compounds, 1,6-didehydro-3,15,16-trimethoxy-9-methylerythrinanium (3), 8-oxytetrahydropalmatine (4), 20-hydroxyecdysone (5), makisterone A (6) turkesterone (7) and magnoflorine (8) were isolated from the root part of Cocculus hirsutus (L.) W. Theob. Their structures were established based on detailed analysis of NMR, UV-Vis, HRESIMS, and single-crystal XRD spectroscopic experiments. Compounds 3, 4 and 7 were reported for the first time from the genus Cocculus. All the compounds were analysed in silico to investigate their human acetylcholinesterase inhibition potential. This analysis revealed that compounds 1 and 8 interacted well with the selected protein, which suggested their further exploration as acetylcholinesterase inhibitors via in vitro and in vivo investigation.

Cyperus rotundus L.: Invasive weed plant with insecticidal potential against Aphis craccivora Koch and Planococcus lilacinus (Cockerell).

Cyperus rotundus L. is a widely distributed invasive weed plant with vast traditional medicinal uses. Herein, the methanolic root extract of C. rotundus and its fractions (n-hexane, chloroform, n-butanol, and aqueous) were evaluated for insecticidal activity against nymphs of Aphis craccivora Koch and crawlers of Planococcus lilacinus (Cockerell) to find promising lead (s). In contact topical assay, among extract/fractions, n-hexane fraction exhibited more toxicity against A. craccivora (LD50 = 1.12 µg/insect) and P. lilacinus (LD50 = 0.94 µg/insect). The chemical analysis of n-hexane fraction revealed a volatile composition similar to that of the essential oil (EO) of C. rotundus roots. Hence, EO was extracted using water and deep eutectic solvents (DESs) as cosolvent, which revealed enhancement in EO yield (from 0.28 to 0.46% w/w) on implementing DESs. A total of 35 diverse volatile metabolites were identified in all EO samples, accounting for 85.0 to 91.8% of chemical composition, having cyperotundone, cyperene mustakone, isolongifolen-5-one, boronia butenal as major constituents. The EO obtained with DES-7 [choline chloride: ethylene glycol (1:4)] and DES-6 [choline chloride: lactic acid (1:3)] were found effective against A. craccivora (LD50 = 0.62-0.87 µg/insect) and P. lilacinus (LD50= 0.59-0.67 µg/insect) after 96 h. NMR analysis of EO revealed cyperotundone as a major compound, which was isolated along with cyperene and cyperene epoxide. All the molecules were found effective against P. lilacinus, whereas against A. craccivora cyperotundone, cyperene and cyperene epoxide showed promising toxicity (LD50 = 0.74-0.86 µg/insect). Extract/fractions, EO, and isolated molecules showed a significant reproductive inhibition rate of A. craccivora at higher concentrations. All the tested concentrations of cyperotundone showed significant inhibition of acetylcholinesterase (AChE) and glutathione-S-transferase (GST) in A. craccivora and P. lilacinus. Based upon the present study, C. rotundus can be recommended to control targeted insects in the greenhouse/field conditions after performing bio-efficacy and phytotoxicity studies.

Going with the µFlow: Reinterpreting Energy Input in Organic Synthesis.

The popularity of microflow chemistry has skyrocketed in the last 20 years, more and more chemists are switching from macro-batch reactors to miniaturized flow devices. As a result, microfluidics is paving its way into the future by consolidating its position in organic chemistry not only as a trend but as a new, effective, and sustainable way of conducting chemistry, that clearly will continue to grow and evolve. This perspective highlights the most relevant examples of innovative enhancing technologies applied to microflow reactors aimed to improve and intensify chemical processes. The extensive applicability of microflow chemistry is further illustrated by briefly discussing examples of complex integrated microsystems and scale-up technologies, demonstrating ultimately that microflow chemistry has the potential to become the ideal technology for the future.

Identification of Novel, Potent, and Selective Compounds against Malaria Using Glideosomal-Associated Protein 50 as a Drug Target.

Phylum apicomplexan consists of parasites, such as Plasmodium and Toxoplasma. These obligate intracellular parasites enter host cells via an energy-dependent process using specialized machinery, called the glideosome. In the present study, we used Plasmodium falciparum GAP50, a glideosome-associated protein, as a target to screen 951 different compounds from diverse chemical libraries. Using different screening methods, eight compounds (Hayatinine, Curine, MMV689758 (Bedaquiline), MMV1634402 (Brilacidin), and MMV688271, MMV782353, MMV642550, and USINB4-124-8) were identified, which showed promising binding affinity (KD < 75 µM), along with submicromolar range antiparasitic efficacy and selectivity index > 100 fold for malaria parasite. These eight compounds were effective against Chloroquine-resistant PfINDO and Artemisinin-resistant PfCam3.1R359T strains. Studies on the effect of these compounds at asexual blood stages showed that these eight compounds act differently at different developmental stages, indicating the binding of these compounds to other Plasmodium proteins, in addition to PfGAP50. We further studied the effects of compounds (Bedaquiline and USINB4-124-8) in an in vivoPlasmodium berghei mouse model of malaria. Importantly, the oral delivery of Bedaquiline (50 mg/kg b. wt.) showed substantial suppression of parasitemia, and three out of seven mice were cured of the infection. Thus, our study provides new scaffolds for the development of antimalarials that can act at multiple Plasmodium lifecycle stages.

Innate functions of natural products: A promising path for the identification of novel therapeutics.

In the course of evolution, living organisms have become well equipped with diverse natural products that serve important functions, including defence from biotic and abiotic stress, growth regulation, reproduction, metabolism, and epigenetic regulation. It seems to be the organism's ecological niche that influences the natural product's structural and functional diversity. Indeed, natural products constitute the nuts and bolts of molecular co-evolution and ecological relationships among different life forms. Since natural products in the form of specialized secondary metabolites exhibit biological functions via interactions with specific target proteins, they can provide a simultaneous glimpse of both new therapeutics and therapeutic targets in humans as well. In this review, we have discussed the innate role of natural products in the ecosystem and how this intrinsic role provides a futuristic opportunity to identify new drugs and therapeutic targets rapidly.

Govanosides C-F, unprecedented steroidal saponins with rare sugars from rhizomes of Trillium govanianum and their antagonistic effects on acetylcholinesterase.

Four previously undescribed steroidal saponins named govanosides C-F (1-4) and nine known compounds (5-13) were isolated from the rhizomes of Trillium govanianum Wall. ex D.Don. Govanosides C-E contained a rare sugar moiety i.e., 6-deoxy allose, while govanoside F has acetylated rhamnose moiety in its glycan part. Also, this is the first report on the isolation of feruloyl sucrose derivatives (11-12) and (E)-4-hydroxy-dodec-2-enedioic acid (13) from the Trillium genus. The structure of isolated compounds was deduced using 1D and 2D NMR, HRESIMS, LC-MS/MS, GC-MS, and saccharide linkage analysis. Steroidal scaffold isolates (1-10) were evaluated for their antagonistic effects on acetylcholinesterase inhibitory activity. Govanoside C (1) significantly inhibited acetylcholinesterase (IC50: 2.38 µM). Molecular docking experiments have also been performed to depict the molecule's interaction and binding free energy with acetylcholinesterase.

Construction of unsymmetrical heterobiaryls via the Cp*Rh(III)-catalysed C-H/C-H coupling of heteroarenes.

Herein, a concise method for the Rh(III)-catalyzed, directing-group-assisted C-H/C-H cross-coupling of N-heterocycles (quinolines, indolines, indoles, pyridines, pyrimidines, pyrazoles) with other heteroarenes (benzoxazoles, benzofurans, and thiophenes) is disclosed for the synthesis of unsymmetrical heterobiaryl compounds in good to excellent yields. A plausible catalytic cycle has been delineated based on experimental and computational mechanistic studies.

Chiral phosphoric acids: a chiral lobby for enantioselective C-H activation.

Enantioselective C-H activation is one of the promising methods to obtain enantiopure molecules in high enantiomeric excess with excellent control of regio and chemo-selectivity. The chiral phosphoric acids have evolved as the leading ligands in the enantioselective C-H activation. Chiral phosphoric acids can interact in different ways with the substrate to induce chirality into the system. This review summarizes the use of chiral phosphoric acids in the exciting field of enantioselective C-H activation.

Experimental and Computational Studies on RuII -Catalyzed C7-Allylation of Indolines with Allyl Bromide.

The selective C7-allylation of indolines with allyl bromide under ruthenium catalysis has been revealed here. Under established reaction conditions, C7-allylation of various indolines, including drug compounds, was accomplished with good selectivity and yields. Based on combined experimental and density functional theory (DFT) studies, the olefin insertion route was energetically favorable among four possible pathways. Experimental and DFT studies further revealed that the C-H activation is a reversible rate-limiting step.

Shatavarin-IV saponin adjuvant elicits IgG and IgG2b responses against Staphylococcus aureus bacterin in a murine model.

Asparagus adscendens Roxb. also known as "safed musli" or "shatavari" is a medicinal plant commonly found in South Asian countries. Shatavari is effective for the treatment of gastric ulcers, renal stones, bronchitis, diabetes, diabetic neuropathy, irritable bowel syndrome, alcohol withdrawal and has reported immunostimulatory effects. In this study, the adjuvant potential of Shatavarin-IV saponin against Staphylococcus aureus bacterin in mice was investigated. Shatavarin-IV was evaluated for its toxicity and immunomodulatory potential against S. aureus bacterin in mice. Cellular and humoral immune responses were assessed. Shatavarin-IV was isolated from the fruit extract of Asparagus adscendens. The confirmation of the isolated molecule as Shatavarin-IV was done via TLC-based comparison with the standard molecule. Further, the structure was confirmed by using extensive spectroscopic analyses and comparing the observed data with literature reports. It was found safe up to the dose of 0.1 mg in the mice model. Shatavarin-IV adjuvant elicited IgG and IgG2b responses at the dose of 40 µg against S. aureus bacterin. However, the cell-mediated immune response was lesser as compared with the commercial Quil-A saponin . We demonstrated that Shatavarin-IV saponin adjuvant produced an optimum humoral immune response against S. aureus bacterin. These results highlight the potential of Shatavarin-IV as an adjuvant in a combination adjuvant in vaccine formulations for induction of potent immune response.

Light-Driven Four-Component Reaction with Boronic Acid Derivatives as Alkylating Agents: An Amine/Imine-Mediated Activation Approach.

Herein, we describe a one-pot aminoalkylation of styrene derivatives with boronic acids (BAs) and boronic acid pinacol esters as radical precursors for the synthesis of complex secondary amines in moderate to high yields through a mild and easily accessible organophotoredox-catalytic four-component reaction. Additionally, we report for the first time in a photoredox process the activation of alkyl boronic acid derivatives by imines, which play a dual role in the reaction as both substrate and Lewis base activator. The protocol applicability was greatly enhanced by its successful adaptation to photoflow reactors.