Vandetanib (Caprelsa
; VNB) is a prescription medicine that is used for the treatment of medullary thyroid cancer that has disrupted other body parts or that cannot be removed by surgery. It is ...considered a tyrosine kinase inhibitor (TKI). Fast, sensitive and validated HPLC-UV was established for VNB quantification in pure human biological fluids (urine and plasma) and human liver microsomes (HLMs). This analytical methodology was applied also to the metabolic stability assessment of VNB. This method was performed using a phenyl column (250 mm × 4.6 mm id, 5 µm particle size). A sodium dodecyl sulphate solution (0.05 M, pH 3.0 using 0.02 M orthophosphoric acid) containing 0.3% triethylamine and 10% n-butanol was used as a mobile phase and was pumped isocratically at a flow rate of 0.7 mL/min and at a 260 nm detection wavelength. The total elution time was 6 min with an injection volume of 20 μL. The linearity of the established methodology ranged from 30 to 500 ng/mL in pure form and 50 to 500 ng/mL (r
≥ 0.9994) in human biological fluids and HLMs. No significant interference from the matrix components was observed. The proposed methodology revealed the benefits of being green, reliable and economic.
How to use digitalization to support the green transformation of organizations has drawn much attention based on the rapid development of digitalization. However, digital transformation (DT) may be ...hindered by the “IT productivity paradox.” Exploring the influence of DT on green innovation, we analyze panel data encompassing A-share listed companies in Shanghai and Shenzhen spanning the period from 2010 to 2018. It tests the DT's non-linear impact, employing a random-forest and mediation effect models. The results reveal that (i) DT can promote green innovation; (ii) regarding heterogeneity, the promotion effect is mainly manifested in enterprises in non-state-owned and highly competitive industries; (iii) based on mechanism testing, DT relies on two routes to encourage green innovation: improving environmental information disclosure and reducing environmental uncertainty; and (iv) random-forest analysis shows that DT exhibits an inverted U-shaped non-linear effect on green innovation, including the “IT productivity paradox.” This study enhances the existing discourse on DT and green innovation by furnishing empirical substantiation for the non-linear influence exerted by DT on green innovation. Furthermore, it imparts insights into the mechanisms and contextual limitations governing this association.
•Digital transformation promotes green innovation.•Digital transformation exhibits an inverted U-shaped effect on green innovation.•Empirical evidence on non-linear impact and insights into mechanisms provided.•The findings have significant implications for governments.
Cancer is one of the deadliest diseases to humanity. There is significant progress in treating this disease, but developing some drugs that can fight this disease remains a challenge in the field of ...medical research. Thirteen new 1,2,3-triazole linked tetrahydrocurcumin derivatives were synthesized by click reaction, including a 1,3-dipolar cycloaddition reaction of tetrahydrocurcumin baring mono-alkyne with azides in good yields, and their in vitro anticancer activity against four cancer cell lines, including human cervical carcinoma (HeLa), human lung adenocarcinoma (A549), human hepatoma carcinoma (HepG2), and human colon carcinoma (HCT-116) were investigated using MTT(3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetraz-olium bromide) assay. The newly synthesized compounds had their structures identified using NMR HRMS and IR techniques. Some of prepared compounds, including compounds 4g and 4k, showed potent cytotoxic activity against four cancer cell lines compared to the positive control of cisplatin and tetrahydrocurcumin. Compound 4g exhibited anticancer activity with a IC50 value of 1.09 ± 0.17 μM against human colon carcinoma HCT-116 and 45.16 ± 0.92 μM against A549 cell lines compared to the positive controls of tetrahydrocurcumin and cisplatin. Moreover, further biological examination in HCT-116 cells showed that compound 4g can arrest the cell cycle at the G1 phase. A docking study revealed that the potential mechanism by which 4g exerts its anti-colon cancer effect may be through inhabiting the binding of APC–Asef. Compound 4g can be used as a promising lead for further exploration of potential anticancer agents.
In continuation of our research programs for the discovery, production, and development of the pharmacological activities of molecules for various disease treatments, Schiff bases and pyrazole ...scaffold have a broad spectrum of activities in biological applications. In this context, this manuscript aims to evaluate and study Schiff base–pyrazole molecules as a new class of antioxidant (total antioxidant capacity, iron-reducing power, scavenging activity against DPPH, and ABTS radicals), anti-diabetic (α-amylase% inhibition), anti-Alzheimer’s (acetylcholinesterase% inhibition), and anti-arthritic (protein denaturation% and proteinase enzyme% inhibitions) therapeutics. Therefore, the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were designed and synthesized for evaluation of their antioxidant, anti-diabetic, anti-Alzheimer’s, and anti-arthritic properties. The results for compound 22b demonstrated significant antioxidant, anti-diabetic (α-amylase% inhibition), and anti-Alzheimer’s (ACE%) activities, while compound 23a demonstrated significant anti-arthritic activity. Prediction of in silico bioinformatics analysis (physicochemical properties, bioavailability radar, drug-likeness, and medicinal chemistry) of the target derivatives (22a, b and 23a, b) was performed. The molecular lipophilicity potential (MLP) of the derivatives 22a, b and 23a, b was measured to determine which parts of the surface are hydrophobic and which are hydrophilic. In addition, the molecular polar surface area (PSA) was measured to determine the polar surface area and the non-polar surface area of the derivatives 22a, b and 23a, b. This study could be useful to help pharmaceutical researchers discover a new series of potent agents that may act as an antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic.
Alkaloids are a complex class of biologically active compounds with a broad spectrum of health-related applications. Particularly the alkaloids of indole, steroidal, terpenoids, isoquinoline, and ...bisbenzylisoquinoline have been extensively investigated. Ultimately, substantial advancement has been highlighted in the investigation of chemical constituents and the therapeutic benefits of plant alkaloids, particularly during the last ten years. A total of 386 alkaloids have been isolated from over 40 families, including Apocynaceae, Annonaceae, Rubiaceae, Menispermaceae, Ranunculaceae, Buxaceae, Papaveraceae, Magnoliaceae, Rutaceae and Phyllanthaceae. This paper will investigate several alkaloids that have been isolated from botanical medicines as well as offer an in-depth analysis of their cytotoxic properties.
Ethnopharmacological relevance:
Therapeutic botanicals (plants and derivatives) are in use since antiquity for various health ailments. The ethnic community is the repository of the information, the ...multifactorial therapeutic applications of which may often need scientific validation. The spreading hogweed or
Boerhaavia diffusa
L., also known as Punarnava, is a reassuring medicinal herb with diverse pharmacological benefits. It is used in Ayurveda in Asia and Africa as a rejuvenator or “Rasayan” for its excellent antiaging and antioxidant properties.
Aim:
The study aimed at compiling the state-of-art knowledge of the medicinal benefits of
Boerhaavia diffusa
L. and unraveling the unexplored commercially useful bioactive constituents by establishing their possible pharmacological benefits.
Methods:
The data from published literature, confined to pharmacological manifestations of various phytocomponents of
Boerhaavia diffusa
L. or its parts like root, leaf and stem were extracted from scientific databases, Google, Science Direct, PubMed, etc. using its antifungal, antibacterial, anticancer, anti-inflammatory, antidiabetic, hepatoprotective, cardioprotective, renoprotective, antifertility benefits and molecular docking study as search strings and keywords. Further, the reported
in silico
studies for bioactivity and bioavailability are detailed.
Results:
The botanicals possess numerous bioactive compounds, the most widely reported ones being phenolic (punarnavoside, trans-caftaric acid, boerhavic acid), rotenoid (boeravinones A-J), flavonoid (borhaavone, quercetin, kaempferol), isoflavonoid (2′-O-methyl abronisoflavone), alkaloid (punarnavine), steroid (boerhavisterol,
β
-Ecdysone), anthracenes and lignans (liriodendrin, syringaresinol mono-
β
-
D
-glucoside). Some of the reported reassuring benefits of their purified forms or even the crude extracts are antidiabetic, antimicrobial, anticancer, antioxidant, anti-inflammatory, hepatoprotective, renoprotective, cardioprotective, antifertility, etc.
Conclusion:
The article provides an extensive study on such pharmacological utility to support the ethnomedicinal use of
Boerhaavia diffusa
L. and propose possible mechanism of the various bioactive compounds in optimising metabolic dysfunctions, healing and protecting vital body organs, often related to the magnificent antioxidant property of this ayurvedic panacea. Further, establishing specific roles of its yet-to-explore bioactive constituents for diverse pharmacological applications is suggested.
Development in the fields of natural-product-derived and synthetic small molecules is in stark contrast to the ongoing demand for novel antimicrobials to treat life-threatening infections caused by ...extended-spectrum β-lactamase producing
(ESBL
). Therefore, there is an interest in the antibacterial activities of synthesized
-(4-methylpyridin-2-yl) thiophene-2-carboxamides (
-
) against ESBL-producing
ST131 strains. A blood sample was obtained from a suspected septicemia patient and processed in the Bactec Alert system. The isolate's identification and antibacterial profile were determined using the VITEK 2
compact system. Multi-locus sequence typing of
was conducted by identifying housekeeping genes, while ESBL phenotype detection was performed according to CLSI guidelines. Additionally, PCR was carried out to detect the blaCTX-M gene molecularly. Moreover, molecular docking studies of synthesized compounds (
-
) demonstrated the binding pocket residues involved in the active site of the β-lactamase receptor of
The result confirmed the detection of
ST131 from septicemia patients. The isolates were identified as ESBL producers carrying the blaCTX-M gene, which provided resistance against cephalosporins and beta-lactam inhibitors but sensitivity to carbapenems. Among the compounds tested,
and
exhibited high activity and demonstrated the best fit and interactions with the binding pocket of the β-lactamase enzyme. Interestingly, the maximum of the docking confirmations binds at a similar pocket region, further strengthening the importance of binding residues. Hence, the in vitro and molecular docking studies reflect the promising antibacterial effects of
and
compounds.
Herein, a new wave of bis(1, 2, 4triazolo)4,3-a:3',4'-cquinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their ...cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined in vitro for their VEGFR-2 inhibitory activity. The most promising derivative 23j was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional in-silico studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds 23a, 23i, 23j, 23l, and 23n displayed the highest antiproliferative activities against the two cell lines with IC
50
values ranging from 6.4 to 19.4 µM. Furthermore, compounds 23a, 23d, 23h, 23i, 23j, 23l, 23 m, and 23n showed the highest VEGFR-2 inhibitory activities with IC
50
values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC
50
= 3.12 nM). Moreover, compound 23j arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold).
Researchers are constantly searching for drugs to combat the coronavirus pandemic caused by SARS-CoV-2, which has lasted for over two years. Natural compounds such as phenolic acids are being tested ...against Mpro and AAK1, which are key players in the SARS-CoV-2 life cycle. This research work aims to study the ability of a panel of natural phenolic acids to inhibit the virus's multiplication directly through Mpro and indirectly by affecting the adaptor-associated protein kinase-1 (AAK1). Pharmacophore mapping, molecular docking, and dynamic studies were conducted over 50 ns and 100 ns on a panel of 39 natural phenolic acids. Rosmarinic acid (16) on the Mpro receptor (- 16.33 kcal/mol) and tannic acid (17) on the AAK1 receptor (- 17.15 kcal/mol) exhibited the best docking energy against both receptors. These favourable docking score values were found to be superior to those of the co-crystallized ligands. Preclinical and clinical research is required before using them simultaneously to halt the COVID-19 life cycle in a synergistic manner.
To discover anti-acetylcholinesterase agents for the treatment of Alzheimer's disease (AD), a series of novel Schiff base-coumarin hybrids was rationally designed, synthesized successfully, and ...structurally characterized using Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR), and High-Resolution Mass Spectrometry (HRMS) analyses. These hybrids were evaluated for their potential inhibitory effect on acetylcholinesterase (AChE). All of them exhibited excellent inhibitory activity against AChE. The IC
values ranged from 87.84 to 515.59 μg/mL; hybrids
and
with IC
values of 0.232 ± 0.011 and 0.190 ± 0.004 µM, respectively, showed the most potent activity as acetylcholinesterase inhibitors (AChEIs). The reference drug, Galantamine, yielded an IC
of 1.142 ± 0.027 µM. Reactivity descriptors, including chemical potential (μ), chemical hardness (η), electrophilicity (ω), condensed Fukui function, and dual descriptors are calculated at wB97XD/6-311++ G (d,p) to identify reactivity changes of the designed compounds. An in-depth investigation of the natural charge pattern of the studied compounds led to a deep understanding of the important interaction centers between these compounds and the biological receptors of AChE. The molecular electrostatic surface potential (MESP) of the most active site in these derivatives was determined using high-quality information and visualization. Molecular docking analysis was performed to predict binding sites and binding energies. The structure-activity-property relationship studies indicated that the proposed compounds exhibit good oral bioavailability properties. To explore the stability and dynamic behavior of the ligand-receptor complexes, molecular dynamics simulations (MDS) were performed for 100 ns on the two best docked derivatives,
and
, with the AChE (4EY7) receptor. A popular method for determining the free binding energies (MM/GBSA) is performed using snapshots taken from the systems' trajectories at 100 ns. These results revealed that the complex system of compound
acquired a relatively more stable conformation and exhibited better descriptors than the complex system of compound
and the Galantamine drug, suggesting its potential as an effective inhibiting drug. The binding free energy analysis revealed that the 13d-4EY7 complex exhibited greater stability with AChE receptors compared to other complexes.
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