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In this project, para‐carboxamidostilbene derivatives were synthesized using the Heck coupling reaction, confirmed through various analytical techniques such as FT‐IR, HRMS, and NMR analyses, and tested in vitro to evaluate their α‐amylase inhibitory activity. In silico molecular docking was employed to model the binding interactions of compounds with α‐amylase. Pharmacokinetic properties (ADME) and drug‐likeness were also examined. Structure activity relationship (SAR) analysis was conducted to establish the relationship between the chemical structure and α‐amylase inhibitory activity. The synthesized compounds exhibited significant α‐amylase inhibitory activity with IC50 values ranging from 15.0 to 37.5 µM in comparison with acarbose (IC50 = 30.2 ± 1.9 µM). Among them, compounds 6d–6f and 7c–7f demonstrated promising inhibitory activity. Furthermore, molecular docking studies revealed strong interactions between the studied molecules and the α‐amylase binding pocket. The drug‐likeness prediction results indicated that all synthesized compounds adhered to Lipinski's rule of five, suggesting their suitability as drug‐like molecules. Additionally, the assessment of ADMET properties indicated favorable absorption profiles, particularly in terms of human intestinal absorption (HIA). Overall, this study successfully identified several para‐carboxamidostilbene derivatives as potential α‐amylase inhibitors for the treatment of T2DM. [ABSTRACT FROM AUTHOR]

Genus Calophyllum is well-known for its phenolic constituents, especially coumarins, which have shown to have a wide range of significant biological activities. In this study, four known phenolic constituents and two triterpenoids have been isolated from the stem bark of Calophyllum lanigerum. The compounds were two pyranochromanone acids are known as caloteysmannic acid (1), isocalolongic acid (2), a simple dihydroxyxanthone, namely euxanthone (3), one coumarin named calanone (4), and two common triterpenoids, friedelin (5), and stigmasterol (6). Chromanone acids were reported for the first time in this Calophyllum species. Cytotoxic evaluations were carried out on n-hexane extract (87.14 ± 2.04 µg/mL; 81.46 ± 2.42 µg/mL) followed by the chromanone acids (1 [79.96 ± 2.39 µM; 83.41 ± 3.39 µM] & 2 [57.88 ± 2.34; 53.04 ± 3.18 µM]) against two cancerous cell lines, MDA-MB-231 and MG-63 cell lines, respectively. The results showed that all tested samples exhibited moderate cytotoxicity. [ABSTRACT FROM AUTHOR]

Genus Calophyllum from the family of Calophyllaceae is an evergreen broad-leaved tree that is endemic to Southeast Asia, especially Malaysia. They have been reported for various ethnomedicinal uses in traditional medicine. Previous studies of Malaysian Calophyllum species revealed them to be a rich source of bioactive phytoconstituents such as xanthones, coumarins, terpenoids, and chromanone acids. To date, the extracts and compounds from Malaysian Calophyllum species have shown a broad spectrum of pharmacological activities. For example, calanolide A, a coumarin isolated from Malaysian C. lanigerum, has now reached clinical development to become an anti-HIV drug. This article presents an overview of the significant phytochemical and pharmacological activities of Malaysian Calophyllum species to aid researchers in further discovery of potential benefits of various species of this genus. [ABSTRACT FROM AUTHOR]

High fructose consumption has been linked to low‐grade inflammation and insulin resistance that results in increased intracellular 11ß‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) activity. Celastrol, a pentacyclic triterpene, has been demonstrated to exhibit multifaceted targets to attenuate various metabolic diseases associated with inflammation. However, the underlying mechanisms by which celastrol exerts its attributive properties on high fructose diet (HFrD)‐induced metabolic syndrome remain elusive. Herein, the present study was aimed to elucidate the mechanistic targets of celastrol co‐administrations upon HFrD in rats and evaluate its potential to modulate 11β‐HSD1 activity. Celastrol remarkably improved glucose tolerance, lipid profiles, and insulin sensitivity along with suppression of hepatic glucose production. In rat adipose tissues, celastrol attenuated nuclear factor‐kappa B (NF‐κB)‐driven inflammation, reduced c‐Jun N‐terminal kinases (JNK) phosphorylation, and mitigated oxidative stress via upregulated genes expression involved in mitochondrial biogenesis. Furthermore, insulin signaling pathways were significantly improved through the restoration of Akt phosphorylation levels at Ser473 and Thr308 residues. Celastrol exhibited a potent, selective and specific inhibitor of intracellular 11β‐HSD1 towards oxidoreductase activity (IC50 value = 4.3 nM) in comparison to other HSD‐related enzymes. Inhibition of 11β‐HSD1 expression in rat adipose microsomes reduced the availability of its cofactor NADPH and substrate H6PDH in couple to upregulated mRNA and protein expressions of glucocorticoid receptor. In conclusion, our results underscore the most likely conceivable mechanisms exhibited by celastrol against HFrD‐induced metabolic dysregulations mainly through attenuating inflammation and insulin resistance, at least via specific inhibitions on 11β‐HSD1 activity in adipose tissues. [ABSTRACT FROM AUTHOR]

Annona muricata Linn or usually identified as soursop is a potential anticancer plant that has been widely reported to contain valuable chemopreventive agents known as annonaceous acetogenins. The antiproliferative and anticancer activities of this tropical and subtropical plant have been demonstrated in cell culture and animal studies. A. muricata L. exerts inhibition against numerous types of cancer cells, involving multiple mechanism of actions such as apoptosis, a programmed cell death that are mainly regulated by Bcl-2 family of proteins. Nonetheless, the binding mode and the molecular interactions of the plant's bioactive constituents have not yet been unveiled for most of these mechanisms. In the current study, we aim to elucidate the binding interaction of ten bioactive phytochemicals of A. muricata L. to three Bcl-2 family of antiapoptotic proteins viz. Bcl-2, Bcl-w and Mcl-1 using an in silico molecular docking analysis software, Autodock 4.2. The stability of the complex with highest affinity was evaluated using MD simulation. We compared the docking analysis of these substances with pre-clinical Bcl-2 inhibitor namely obatoclax. The study identified the potential chemopreventive agent among the bioactive compounds. We also characterized the important interacting residues of protein targets which involve in the binding interaction. Results displayed that anonaine, a benzylisoquinoline alkaloid, showed a high affinity towards the Bcl-2, thus indicating that this compound is a potent inhibitor of the Bcl-2 antiapoptotic family of proteins. [ABSTRACT FROM AUTHOR]

A growing body of evidence suggests that activation of nuclear factor kappa B (NF-κB) signaling pathways is among the inflammatory mechanism involved in the development of insulin resistance and chronic low-grade inflammation in adipose tissues derived from obese animal and human subjects. Nevertheless, little is known about the roles of NF-κB pathways in regulating mitochondrial function of the adipose tissues. In the present study, we sought to investigate the direct effects of celastrol (potent NF-κB inhibitor) upon mitochondrial dysfunction-induced insulin resistance in 3T3-L1 adipocytes. Celastrol ameliorates mitochondrial dysfunction by altering mitochondrial fusion and fission in adipocytes. The levels of oxidative DNA damage, protein carbonylation and lipid peroxidation were down-regulated. Further, the morphology and quantification of intracellular lipid droplets revealed the decrease of intracellular lipid accumulation with reduced lipolysis. Moreover, massive production of the pro-inflammatory mediators tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were markedly depleted. Insulin-stimulated glucose uptake activity was restored with the enhancement of insulin signaling pathways. This study signified that the treatments modulated towards knockdown of NF-κB transcription factor may counteract these metabolic insults exacerbated in our model of synergy between mitochondrial dysfunction and inflammation. These results demonstrate for the first time that NF-κB inhibition modulates mitochondrial dysfunction induced insulin resistance in 3T3-L1 adipocytes. [ABSTRACT FROM AUTHOR]

A series of 2-methoxypyridine-3-carbonitrile (5a–i)-bearing aryl substituents were successfully synthesized in good yields by the condensation of chalcones (4a–i) with malononitrile in basic medium. The condensation process, in most cases, offers a route to a variety of methoxypyridine derivatives (6a–g) as side products in poor yields. All new compounds were fully characterized using different spectroscopic methods. Mass ESI-HMRS measurements were also performed. Furthermore, these compounds were screened for their in vitro cytotoxicity activities against three cancer cell lines; namely, those of the liver (line HepG2), prostate (line DU145) and breast (line MBA-MB-231). The cytotoxicity assessment revealed that compounds 5d, 5g, 5h and 5i exhibit promising antiproliferative effects (IC50 1–5 µM) against those three cancer cell lines. [ABSTRACT FROM AUTHOR]