Search Results (258)

In this study, we report the synthesis of three new derivatives of betulinic acid, a pentacyclic triterpenoid known for its antitumor activity. These derivatives were synthesized via amide bond formation at the C-28 position using 3-[(Ethylimino)methylidene]amino-N,N-dimethylpropan-1-amine (EDC)/Hydroxybenzotriazole (HOBt) activation and various amines as nucleophiles. The synthesized compounds were characterized by nuclear magnetic resonance (NMR) techniques, including proton (¹H), carbon-13 (¹³C), COSY, HSQC, and DEPT, as well as ultraviolet–visible (UV-VIS) spectroscopy, Fourier-transform infrared (IR) and elemental analysis. This work highlights the potential of semi-synthetic modification of betulinic acid to enhance anticancer properties while addressing challenges in solubility and bioavailability. Further structural optimization and formulation studies are warranted to improve drug-like properties and therapeutic applicability. Full article

The emergence of SARS-CoV-2 in 2019 posed significant global public health challenges. One of the most promising targets for novel antiviral drug development is the SARS-CoV-2 main protease (3CL^pro). In this study, fragment molecular orbital (FMO) calculations were conducted to provide guidance for the structural modification of natural flavonoids, identifying the pyrogallol moiety as a key candidate. Natural flavonoids were chemically modified to generate 33 semi-synthetic derivatives through the introduction of various functional groups. Our findings revealed that the incorporation of a galloyl moiety significantly enhances anti-proteolytic activity against SARS-CoV-2 3CL^pro, achieving up to a 23-fold increase compared to the activity of the parent compounds. Notably, 7-O-galloyl-DMC (40) exhibited the highest anti-proteolytic activity in an enzymatic assay. Additionally, molecular dynamics simulations provided atomic-level insights into the interactions between the galloyl moiety and 3CL^pro. All galloylated flavonoid derivatives positioned their galloyl groups within the S1′ sub-pocket, facilitating hydrogen bonding and π-interactions, particularly with Thr26 and Leu27. These findings underscore the potential of the galloyl moiety as a crucial structural element for enhancing the binding affinity of flavonoids with inhibitory activity against SARS-CoV-2 3CL^pro. Full article

Colorectal cancer (CRC) remains a major contributor to global cancer-related mortality, with rising incidence observed in several regions, including Saudi Arabia. This review compiles and critically analyzes recent preclinical research from Saudi-based institutions that investigates the anti-CRC potential of natural and synthetic compounds. Numerous natural products such as Nigella sativa, Moringa oleifera, Curcuma longa, and marine-derived metabolites have demonstrated cytotoxic effects through pathways involving apoptosis induction, reactive oxygen species (ROS) generation, and inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and cyclooxygenase-2 (COX-2). In parallel, synthetic and semi-synthetic agents, including C4–G4 (semi-synthetic hybrids designed from flavonoids and benzoxazole scaffolds that act as dual epidermal growth factor receptor (EGFR)/COX-2 inhibitors)), oxazole derivatives, and camptothecin-based nanocarriers, exhibit promising anti-tumor activity via molecular targeting of cyclin-dependent kinase 8 (CDK8), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and β-catenin pathways. Selected in vivo studies primarily utilizing xenograft and chemically induced rodent models have shown reductions in tumor volume and modulation of apoptotic and inflammatory biomarkers. Additionally, green-synthesized metallic nanoparticles (NPs) and polyethylene glycol (PEG)-modified carriers have been investigated to improve bioavailability and tumor targeting of lead compounds. While these findings are encouraging, the majority remain in preclinical phases. Limitations such as poor solubility, lack of pharmacokinetic data, and absence of clinical trials impede translational progress. This review highlights the need for standardized evaluation protocols, mechanistic validation, and region-specific clinical studies to assess efficacy and safety. Given Saudi Arabia’s rich biodiversity and growing research capacity under national strategies like Vision 2030, the country is well-positioned to contribute meaningfully to CRC drug discovery. By integrating bioactive natural products, rationally designed synthetics, and advanced delivery platforms, a pipeline of innovative CRC therapeutics tailored to local and global contexts may be realized. Full article

The inflammatory response is a defence mechanism triggered by tissue damage, aiming to eliminate harmful agents and initiate healing. Conventional anti-inflammatory drugs, such as NSAIDs and corticosteroids, are widely used but often cause severe side effects. Flavonoids, particularly flavanones, have shown significant anti-inflammatory activity with fewer adverse effects. In this study, eight analogues (1a–1d) and (2a–2d) were obtained from natural flavanones (1) and (2) using a pharmacomodulation strategy. NMR, FTIR, structurally confirmed all compounds and MS. Theoretical physicochemical analyses, including molecular orbital energies, dipole moments, and Log P, suggested favourable drug-like properties for these analogues. The anti-inflammatory activity was evaluated in vivo using a TPA-induced mouse ear edema model. Analogue (2c) exhibited the highest inhibition (98.62 ± 1.92%), followed by (2d) (76.12 ± 1.74%) and (1c) (71.64 ± 1.86%). Notably, structural modifications such as cyclization, methoxylation, and prenylation were associated with increased lipophilicity and biological activity, suggesting that tuning physicochemical properties may enhance pharmacological efficacy while preserving drug-likeness. Overall, these findings highlight semi-synthetic derivatization of flavanones as a valuable approach for developing potent and selective anti-inflammatory agents, positioning analogue (2c) as a promising lead for further pharmacological development. Full article

Background and Clinical Significance: The recreational use of semisynthetic cannabinoids (SSCs) is increasing, and SSCs account for more than 40% of all new substances reported at the European level. Although designed to mimic the effects of tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, evidence suggests that certain SSCs may elicit stronger, prolonged and unintended pharmacological effects. SSCs are easily accessible, particularly via online retailers, but in some countries, SSCs are also sold in convenience stores or specialty stores selling legal low-THC or cannabidiol (CBD) products. Often, SSCs are sold as “legal highs” and are found in various forms, including herbal mixtures (spice), vape products, and edibles such as cookies and candies, specifically targeting young users, including children. The products are frequently mislabeled and sold as souvenirs or aromatic potpourri to bypass regulations. Case Presentation: We present a case of a male in his early forties who was admitted to the Emergency Department due to noticeable deficits in alertness and responsiveness after recreational ingestion of two cannabis cookies labeled to contain 40 mg “CC9” and a bite of a gummy with unknown contents. The patient experienced vomiting and visual problems, and suffered from nine days of cognitive and physical impairment. HHC-C9, a novel SSC, was detected in blood through forensic toxicological analysis. Conclusions: Recreational use of HHC-C9 can cause vomiting, visual disturbances, and drowsiness, potentially requiring hospital treatment. Potency, clinical effects, and toxicity of SSCs can vary significantly, and in combination with easy accessibility, SSCs pose a potential risk of intoxication to unaware consumers. Full article

Chlorophyll, the green pigment essential for photosynthesis, abundantly found in green vegetables and algae, has attracted growing scientific interest for its potential therapeutic effects, particularly in diabetes management. Recent research highlighted that chlorophyll and its derivatives may beneficially influence glucose metabolism and oxidative stress, key factors in diabetes. This review examines current knowledge on how chlorophyll compounds could aid diabetes control. Chlorophyll and its derivatives appear to support glucose regulation primarily through actions in the gastrointestinal tract. They modulate gut microbiota, improve glucose tolerance, reduce inflammation, and alleviate obesity-related markers. While chlorophyll itself does not directly inhibit digestive enzymes like α-glucosidase, its derivatives such as pheophorbide a, pheophytin a, and pyropheophytin a may slow carbohydrate digestion, acting as α-amylase and α-glucosidase inhibitors, reducing postprandial glucose spikes. Additionally, chlorophyll enhances resistant starch content, further controlling glucose absorption. Beyond digestion, chlorophyll derivatives show promise in inhibiting glycation processes, improving insulin sensitivity through nuclear receptor modulation, and lowering oxidative stress. However, some compounds pose risks due to photosensitizing effects and toxicity, warranting careful consideration. Chlorophyllin, a stable semi-synthetic derivative, also shows potential in improving glucose and lipid metabolism. Notably, pheophorbide a demonstrates insulin-mimetic activity by stimulating glucose uptake via glucose transporters, offering a novel therapeutic avenue. Overall, the antioxidant, anti-inflammatory, and insulin-mimicking properties of chlorophyll derivatives suggest a multifaceted approach to diabetes management. While promising, these findings require further clinical validation to establish effective therapeutic applications. Full article

Objective: The development of natural and new P-gp modulators to reverse tumor multidrug resistance (MDR). Methods: Test compounds were prepared from the plant Metaplexis japonica, and their ability to reverse P-glycoprotein (P-gp)-mediated MDR was investigated in HepG2/Dox cells. Their effects on P-gp expression and function and their interaction modes with P-gp were also investigated. Results: Natural product 3β,12β,14β, 17β,20(S)-pentahydroxy-5α-pregnan-12β-O-(E)-cinnamate (1) and its new semisynthetic derivative 3β12β,14β,17β,20(S)-pentahydroxy-5α-pregnan-3β-O-nicotinate-12β-O-(E)-cinnamate (1a) were obtained. At non-cytotoxic concentrations of 5 or 10 μM, they significantly reversed the resistance of HepG2/Dox cells to P-gp substrate drugs doxorubicin, paclitaxel, and vinblastine, with reversal folds of 7.1, 118.5, and 198.3 (1), and 18.8, 335.8, and 140.0 (1a), respectively, at 10 μM. Cell apoptosis and expression of caspase 9 were both triggered by the combination of 10 μM of compound 1 or 1a and 500 nM of paclitaxel (p < 0.001). Compound 1 or 1a did not affect P-gp expression, but it did significantly suppress the efflux of Rhodamine 123 out of HepG2/Dox cells (p < 0.001). On the Caco-2 cell monolayer, 1 and 1a were shown to be non-substrates of P-gp, with efflux ratios of 0.83 and 0.89. Molecular docking revealed their strong binding energies (−8.2 and −8.4 kcal/mol) with P-gp, and their direct binding to P-gp was confirmed by their dissociation constants (5.53 µM for 1 and 3.72 µM for 1a), determined using surface plasmon resonance. Conclusions: Compounds 1 and 1a are potential P-gp modulators; they may reverse P-gp-MDR through interacting with P-gp to interfere with substrate binding and transporting, and have the potential to improve the efficacy of paclitaxel or vinblastine drugs for combating P-gp-mediated MDR in tumor cells. Full article

Resistance of various bacterial pathogens to the activity of clinically approved drugs currently leads to serious infections, rapid spread of difficult-to-treat diseases, and even death. Taking the threats for human health in mind, researchers are focused on the isolation and characterization of novel natural products, including plant secondary metabolites. These molecules serve as inspiration and a suitable structural platform in the design and development of novel semi-synthetic and synthetic derivatives. All considered compounds have to be adequately evaluated in silico, in vitro, and in vivo using relevant approaches. The current review paper briefly focuses on the chemical and metabolic properties of resveratrol (1), as well as its oligomeric structures, viniferins, and viniferin-based molecules. The core scaffolds of these compounds contain so-called privileged structures, which are also present in many clinically approved drugs, indicating that those natural, properly substituted semi-synthetic, and synthetic molecules can provide a notably broad spectrum of beneficial pharmacological activities, including very impressive antimicrobial efficiency. Except for spectral verification of their structures, these compounds suffer from the determination or prediction of other structural and physicochemical characteristics. Therefore, the structure–activity relationships for specific dihydrodimeric and dimeric viniferins, their bioisosteres, and derivatives with notable efficacy in vitro, especially against chosen Gram-positive bacterial strains, are summarized. In addition, a set of descriptors related to their structural, physicochemical, pharmacokinetic, and toxicological properties is generated using various computational tools. The obtained values are compared to those of clinically approved drugs. The particular relationships between these in silico parameters are also explored. Full article

Medicinal plants have been used in traditional medicines all over the world to treat human diseases throughout human history. Many of the medicinal plants have frequently become food and nutrition plants. A more sophisticated investigation resulted in discovering numbers of biologically important secondary metabolites of plants. Pentacyclic triterpenoids represent an important group of the plant secondary metabolites that have emerged as having top biological importance. While the most widespread plant triterpenoids and a majority of their semisynthetic derivatives have been reviewed quite often, other plant pentacyclic triterpenoids and their derivatives have so far been less frequently studied. Therefore, attention has been focused on selected pentacyclic triterpenoids, namely on arjunolic acid, asiatic acid, α- and β-boswellic acids, corosolic acid, maslinic acid, morolic acid, moronic acid, and the friedelane triterpenoids, and on different derivatives of the selected triterpenoids in this review article. A literature search was made in the Web of Science for the given keywords, covering the required area of secondary plant metabolites and their semisynthetic derivatives starting in 2023 and ending in February 2025. The most recently published findings on the biological activity of the selected triterpenoids, and on the structures and the biological activity of their relevant derivatives have been summarized therein. Even if cytotoxicity of the compounds has mainly been reviewed, other biological effects are mentioned if they appeared in the original articles in connection with the selected triterpenoids and their derivatives, listed above. A comparison of the effects of the parent plant products and their derivatives has also been made. Full article

A significant issue in healthcare is the growing prevalence of antibiotic-resistant strains. Therefore, it is necessary to develop strategies for discovering new antibacterial compounds, either by identifying natural products or by designing semisynthetic or synthetic compounds with this property. In this context, a great deal of research has recently been carried out on antimicrobial peptides (AMPs), which are natural, amphipathic, low-molecular-weight molecules that act by altering the cell surface and/or interfering with cellular activities essential for life. Progress is also being made in developing strategies to enhance the activity of these compounds through their association with other molecules. In addition to identifying AMPs, it is essential to ensure that they maintain their integrity after passing through the digestive tract and exhibit adequate activity against their targets. Significant advances are being made in relation to analyzing various types of conjugates and carrier systems, such as nanoparticles, vesicles, hydrogels, and carbon nanotubes, among others. In this work, we review the current knowledge of different types of AMPs, their mechanisms of action, and strategies to improve performance. Full article

Background: The natural compounds caracasine acid (1) and its methyl ester, caracasine (2), isolated from the flowers of Croton micans, are effective against several tumor cell lines. Five semi-synthetic derivatives (3–7) were synthesized based on these structures. The study aimed to evaluate the cytotoxic activity of these compounds in 2D and spheroid cultures. Methods: The assays were performed in a panel of 12 human cell lines, 8 cancer and 4 normal cell lines. The compounds were evaluated on spheroids derived from the HCT116, HCT116 p53 knockout (p53KO), A549, and U2OS cell lines, as well as mixed spheroids comprising tumor cells and normal fibroblasts. Results: The parent compound (1), the natural ester (2), and two novel derivatives, the anhydride (7) and the cyclohexanol ester (3), demonstrated cytotoxicity against different leukemic cells and HCT116, HCT116 p53 knockout (p53KO), A549, and U2OS cell lines in conventional two-dimensional cultures. Peroxide formation, however, was significantly higher in leukemic cell lines (p < 0.01) in 2D culture as compared with the other tumor cell lines. The compounds did not induce cell death in spheroid cultures; caspases 8, 9, and 3 were not activated upon treatment. Conclusions: These findings indicate potential applications in leukemia treatment, albeit with limited efficacy against solid tumors. Full article

Dye-sensitized solar cells (DSSCs) have emerged as a promising technology for converting sunlight into electricity at a low cost; however, it is still necessary to find a photostable, low-cost, and efficient photosensitizer. In this sense, the natural product bixin (Dye 1) has previously been reported as a potential photosensitizer. Thus, the present work reports the full synthesis of diester and diacid hybrids (Dyes 2 and 3, respectively, with corresponding yields of 93% and 52%) using the natural product bixin as a starting material and 1,3,4-oxadiazole ring as a connected point. The hydrolysis step of Dye 2 aims to obtain Dye 3 with a structural capacity to anchor the titanium dioxide (TiO₂) nanofilms via the carboxylic acid group. Both compounds (Dyes 1 and 3) can be adsorbed via pseudo-first order on the surface of TiO₂ nanofilms, reaching saturation after 10 and 6 min of exposure in an organic solution (1 × 10⁻⁵ M), respectively, with adsorption kinetics of the semisynthetic compound almost twofold higher than the natural product. Contrary to expectations, Dye 3 had spectral behavior similar to Dye 1, but with better frontier molecular orbital (FMO) parameters, indicating that Dye 3 will probably behave very similarly or have slightly better photovoltaic performance than Dye 1 in future DSSC measurements. Full article

One of the effective types of heat-resistant insulating products with an operating temperature of 1050 °C is made from calcium silicates or their hydrates. These materials are made from synthetic xonotlite and 1.13 nm tobermorite. Various wastes and by-products from other industries can be used for the synthesis of the latter compound. However, such raw materials often contain various impurities, especially Al-containing compounds, which strongly influence the kinetics of 1.13 nm tobermorite formation and its properties. Using XRD, DSC, TG, and SEM/EDX methods, it was found that at the beginning of the hydrothermal synthesis, the Al₂O₃ additive promotes the formation of 1.13 nm tobermorite; however, it later begins to inhibit the recrystallization of semi-crystalline C-S-H(I)-type calcium silicate hydrate and pure, high-crystallinity 1.13 nm tobermorite is more easily formed in mixtures without the aluminum additive. Aluminum oxide also influence the morphology of 1.13 nm tobermorite. When hydrothermally curing the CaO–SiO₂ mixture, long, thin fibers (needles) are formed within 24 h. Later, they thicken and form rectangular parallelepiped crystals. After adding alumina, the product produced by 24 h synthesis is dominated by agglomerates, the surface of which is partially covered with crystal plates. By extending the synthesis duration, amorphous aggregates are absent and the crystal shape becomes increasingly square. Full article

Colorectal cancer (CRC) remains one of the most prevalent malignancies of the gastrointestinal tract worldwide, with chronic inflammation recognized as a key factor in its progression. Among pro-inflammatory cytokines, interleukin 8 (IL-8) plays a pivotal role in promoting angiogenesis, tumor cell migration, and metastasis. Elevated IL-8 expression is frequently associated with advanced CRC stages. This study investigated the effects of betulin and its semi-synthetic derivatives, EB5 and ECH147, on IL-8 expression in CRC cell lines characterized by differing malignancy grades. IL-8 transcript and protein levels were quantified using real-time RT-qPCR and a proximity ligation assay, respectively, following compound exposure at 2, 8, and 24 h. Basal IL-8 levels were significantly higher in low-grade CRC cell lines. Among the compounds tested, ECH147 exerted the most pronounced, time-dependent inhibitory effect on CXCL8 expression. Furthermore, molecular docking analyses revealed that ECH147 exhibits stronger binding affinity toward the IL-8 protein compared to conventional chemotherapeutics. These findings suggest that the modification of the betulin structure via the incorporation of a propynoyl moiety enhances both its molecular interaction with CXCL8 and its anti-inflammatory potential. ECH147 and EB5 thus emerge as promising candidates for further development as immunomodulatory agents targeting the IL-8-associated pathway in CRC. Full article

Vancomycin, a cornerstone antibiotic against severe Gram-positive infections, is increasingly challenged by resistance in Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin Enterococcus spp. (VRE), necessitating the development of novel therapeutic strategies. This review examines how structural modifications to vancomycin can enhance its antibacterial activity and explores the critical role of computational approaches in designing the next generation of analogs. By analyzing the existing literature, we highlight how strategic alterations, such as the introduction of lipophilic side chains, substitutions on the sugar moieties, and modifications to the aglycone core, have yielded derivatives with improved antibacterial potency. Notably, certain analogs (e.g., Vanc-83, Dipi-Van-Zn) have demonstrated expanded activity against Gram-negative bacteria and exhibited enhanced pharmacokinetic profiles, including prolonged half-lives and improved tissue penetration, crucial for effective treatment. Semisynthetic glycopeptides like telavancin, dalbavancin, and oritavancin exemplify successful translation of structural modifications, offering sustained plasma concentrations and simplified dosing regimens that improve patient compliance. Complementing these experimental efforts, computational methods, including molecular docking and molecular dynamics simulations, provide valuable insights into drug–target interactions, guiding the rational design of more effective analogs. Furthermore, physiologically based pharmacokinetic modeling aids in predicting the in vivo behavior and optimizing the pharmacokinetic properties of these novel compounds. This review highlights a critical path forward in the fight against multidrug-resistant infections. By meticulously examining the previously carried out structural refinement of vancomycin, guided by computational predictions and validated through rigorous experimental testing, we underscore its immense potential. Full article