Search Results (99)

Background: Among the alkaloids from Cassia siamea, cassiarin A has outstanding antiprotozoal activity, but structure–activity relationships for this chemotype were only poorly understood until now. Methods: We worked out efficient approaches to hitherto underexplored analogs (12 examples) on three synthesis routes which mainly comprised variations in the methyl groups at C-2 and C-5. The new compounds were tested for antiprotozoal and cytotoxic activities. Results: Introduction of a (substituted) benzene ring at C-2 led to a significant enhancement of activity against Plasmodium falciparum, while modifications of the methyl group at C-5 and the phenolic group had detrimental effects. Two of the 2-phenyl analogs further showed a resistance index comparable to the one of the reference drug chloroquine. Although the novel derivatives did not show hemolytic effects, investigation on human endothelial (HUVEC) cells at relevant concentrations indicated strong cytotoxic effects on human cells. Conclusions: Systematic structure modifications of cassiarin A led to a significant enhancement of antiplasmodial activity, but the observed strong cytotoxicity to human cells renders this library of cassiarin A derivatives inadequate for drug development. Full article

Colon cancer is the second leading cause of cancer-related deaths in the world. This is commonly observed among older adults, and the occurrence of colon cancer is mainly influenced by unhealthy lifestyle factors. Edible medicinal mushrooms have been demonstrated to have anti-colon cancer effects both individually and in combination with conventional therapies, including synergistically enhancing the efficacy of chemotherapy medications such as 5-fluorouracil in preclinical models. Medicinal mushrooms such as Lentinus edodes, Phellinus linteus, Ganoderma lucidum, Inonotus obliquus, Pleurotus ostreatus, Hericium erinaceus, Pleurotus eryngii, Gloeostereum incarnatum, and Termitomyces heimii are emerging as promising candidates, not only because conventional treatments for colon cancer face significant limitations, including side effects, psychological impacts on patients, high cost, limited specificity toward cancer and healthy cells, and the development of drug resistance, but also due to the diverse array of bioactive compounds present within them. Therefore, there is a strong demand for innovative, affordable, and minimally invasive treatments such as medicinal mushrooms. Their bioactive compounds, including terpenoids, sterols, phenols, polysaccharides, acids, sesquiterpenes, alkaloids, lactones, metal-chelating agents, nucleotide analogs, glycoproteins, β-glucan, cerebrosides, steroids, terpenes, quinolones, anthraquinones, benzoic acid derivatives, linoleic acid, ascorbic acid, glycosides, organic acids, flavonoids, grifolin, tocopherols, proteins, indoles, lectin, and laccases, exert anti-colon cancer activities through various mechanisms, including anti-proliferative effects, cell cycle arrest, anti-inflammatory effects, antioxidant effects, induction of apoptosis, cytotoxic effects, and antimigratory effects. Further research is needed to elucidate the molecular mechanisms and confirm the safety and efficacy of medicinal mushrooms as a holistic anti-colon cancer treatment. Full article

Alkaloids are nitrogen-containing compounds naturally occurring in plants, microorganisms, and marine organisms. Potent biological activities have been reported to date, ranging from neuroprotective to antioxidant and anticancer effects. Alkaloids have recently gained attention as potential antifungal agents for crop protection due to their broad spectrum of activity, eco-friendly nature, and ability to overcome some of the issues associated with synthetic fungicides, such as resistance development and environmental contamination. Several efforts have been made to obtain natural and nature-derived alkaloids endowed with significant activity against numerous pathogenic fungal strains. In this review, we collect synthetic strategies developed over the past decade to produce alkaloid fungicides for crop protection. Special emphasis is given to recent advancements in obtaining pure natural compounds and more potent analogs endowed with tailored and optimized properties. Full article

Polycarpine, a diimidazolyl disulfan alkaloid isolated from the ascidian Polycarpa aurata, showed high cytotoxic activity in vitro. However, in vivo experiments have shown that polycarpine has a high acute toxicity. At the same time, its synthetic thiazolyl analog, thiacarpine, showed less acute toxicity and had a greater therapeutic index, which makes its derivatives promising for further drug development. We assume that due to the presence of a disulfide bond in the molecules of polycarpine and thiacarpine and the possibility of its reduction in a living cell, the mercapto derivatives formed are responsible for the high activity of the original compounds. Based on this assumption, and to increase the selectivity of action, glycosyl disulfide conjugates of thiacarpine derivatives with thioglucose and thioxylose were synthesized and screened for their cytotoxic and antimicrobial activities. The target compounds did not show hemolytic activity at concentrations of up to 25 μM. Some of them exhibited moderate cytotoxic activity, blocked colony growth and migration of HeLa tumor cells, high antimicrobial activity, and inhibited biofilm formation comparable to or higher than that of a standard antibiotic (gentamicin) and antimycotic (nitrofungin). Full article

Fascaplysins form a group of marine natural products with unique cationic five-ring coplanar backbone. Native fascaplysin exhibits a broad spectrum of bioactivities, among which the cytotoxic activity has been the most investigated. Several fascaplysin derivatives have more selective biological effects and are promising as lead compounds. Thus, the introduction of a substituent at C-9 of fascaplysin leads to a strong increase in its antimicrobial properties. Here, a comparative assessment of the antimicrobial activity of synthetic analogs of the marine alkaloids 3-bromofascaplysin, 10-bromofascaplysin, and 3,10-dibromofascaplysin, along with some of their isomers and analogs, was carried out against a panel of Gram-positive bacteria in vitro. For the first time, a significant increase in the antimicrobial activity of fascaplysin was observed when a substituent was introduced at C-3. The introduction of two bromine atoms at C-2 and C-9 enhances the antimicrobial properties by 4 to 16 times, depending on the tested strain. Evaluation of the antimicrobial potential in vivo showed that fascaplysin and 3,10-dibromofascaplysin had comparable efficacy in the mouse staphylococcal sepsis model. Additionally, 3,10-dibromofascaplysin demonstrated a strong and reliable antitumor effect in vivo on the Ehrlich carcinoma inoculated subcutaneously, with a value of tumor growth inhibition by 49.2% 20 days after treatment. However, further studies on alternative chemical modifications of fascaplysin are needed to improve its chemotherapeutic properties. Full article

Berberine is a natural substance obtained from the roots of common barberry which, due to its strong pharmacological activity, is a commonly tested ingredient of dietary supplements. However, ornamental barberries, which are widely available, have not been considered as a source of berberine so far. The research aimed to check whether the ornamental barberry leaves and twigs could be used as an easily accessible raw material for obtaining natural berberine-rich extract with biological activity. Twigs and leaves of seven cultivars of ornamental barberry extracts were assessed for their polyphenol content, antioxidant potential (FRAP and DPPH), and berberine content using high-performance thin layer chromatography (HPTLC). As a reference, commercially available roots of Berberis vulgaris were used. For the next step, selected extracts (two with high and two with low berberine content) were tested on three cell lines (HaCaT, A375, Caco-2) using neutral red assay, and pure berberine sulfate (1–100 μg mL⁻¹) was used as a control. Although the antioxidant potential of aqueous–methanol extracts of tested barberry was higher for the leaves than for the twigs, the berberine content was determined only in the twig extracts (from 42 to 676 mg 100 g⁻¹). Studies on cell lines have shown the general toxicity of barberry extracts, but the observed effect was not directly correlated with the content of the alkaloid. However, the extract showed greater activity compared to an analogous dose of pure berberine, suggesting a significant effect of the matrix composition. For the first time, it was shown that the twigs of selected cultivars of ornamental barberry can be considered as a promising berberine source for the pharmaceutical industry to develop new effective formulations. However, these findings require further studies. Full article

Flavonoid alkaloids represent an interesting subgroup of the alkaloid family. Several plants containing flavonoid alkaloids are used in folk medicine for the treatment of various diseases. The interesting biological properties of flavonoid alkaloids make them attractive candidates for lead compounds in drug discovery. Capitavine, or 5,7-dihydroxy-6-(1-methylpiperidin-2-yl)flavone, and related compounds, belong to piperidine–flavonoid alkaloids, possessing a piperidine ring connected to the C6-position of flavonoid skeleton, while buchenavianine is C8 piperidine-bonded analog. Capitavine derivatives were isolated mainly from Buchenavia capitata, while buchenavianine derivatives are present mainly in B. macrophylla. It was found that the chloroform extract of the leaves of B. capitata showed anti-HIV activity. The biological activity of capitavine and buchenavianine derivatives needs to be investigated in terms of their pharmacokinetic properties and toxicity, which are important factors in finding potential drug candidates. The present in silico study using SwissADME, Osiris, and Molinspiration software shows that studied capitavine-derived flavonoid alkaloids exhibit considerable bioactivity for the GPCR ligand (0.12 to 0.20), as enzyme inhibitors (0.17 to 0.22) and as nuclear receptor ligands (0.07 to 0.28). All compounds exhibit good gastrointestinal absorption and low risks of being irritants, tumorigenic, or having a reproductive effect. The risk of mutagenicity was calculated for two compounds related to buchenavianine, and at this point the role of 5-methoxy group appears to be crucial for the low risk of mutagenicity. Full article

The use of chiral organic ligands as linkers and metal ion nodes with specific coordination geometry is an effective strategy for creating homochiral structures with potential ferroelectric properties. Natural Cinchona alkaloids, e.g., quinine and cinchonine, as compounds with a polar quinuclidine fragment and aromatic quinoline ring, are suitable candidates for the construction of molecular ferroelectrics. In this work, the compounds [CnZnCl₃]·MeOH and [CnZnBr₃]·MeOH, which crystallize in the ferroelectric polar space group P2₁, were prepared by reacting the cinchoninium cation (Cn) with zinc(II) chloride or zinc(II) bromide. The structure of [CnZnBr₃]·MeOH was determined from single-crystal X-ray diffraction analysis and was isostructural with the previously reported chloride analog [CnZnCl₃]·MeOH. The compounds were characterized by infrared spectroscopy, and their thermal stability was determined by thermogravimetric analysis and temperature-modulated powder X-ray diffraction experiments. The intermolecular interactions of the different cinchoninium halogenometalate complexes were evaluated and compared. Full article

Mitragynine is an “atypic opioid” analgesic with an alternative mechanism of action and a favorable side-effect profile. Our aim was to optimize the alkaloid extraction procedure from kratom leaves and to determine and isolate the most relevant compounds capable of penetrating the central nervous system. The PAMPA-BBB study revealed that mitragynine and its coalkaloids, speciociliatine, speciogynine, and paynantheine, possess excellent in vitro BBB permeability. An optimized sequence of CPC, flash chromatography, and preparative HPLC methods was used to isolate the four identified BBB+ alkaloids. To improve the bioavailability of the isolated alkaloids, their cyclodextrin (CD) complexation behavior was investigated via affinity capillary electrophoresis using almost 40 CD derivatives. The apparent alkaloid–CD complex stability constants were determined and compared, and the most relevant CDs phase-solubility studies were also performed. Both the neutral and negatively charged derivatives were able to form complexes with all four kratom alkaloids. It was found that cavity size, substituent type, and degree of substitution also influenced complex formation. The negatively charged Sugammadex, Subetadex, and the sufoalkylated-beta-CD analogs were able to form the most stable complexes, exceeding 1000 M⁻¹. These results serve as a good basis for further solubility and stability enhancement studies of kratom alkaloids. Full article

Sesquiterpene pyridine alkaloids (SPAs), as a main class of components in Tripterygium wilfordii Hook. f., possess a variety of bioactivities, such as immunosuppressive, insecticidal, and anti-tumor activities. SPAs can be structurally classed into four subtypes: wilfordate-, evoninate-, iso-wilfordate-, and iso-evoninate types. Our previous study unveiled ten new wilfordate-type SPAs, named wilfordatine A–J, isolated from the roots of Tripterygium wilfordii Hook. f., several of which exhibited significant immunosuppressive activities. As an extension and augmentation of the previous findings, we have now isolated one new iso-wilfordate-type SPA, wilfordatine K (1), alongside three new iso-evoninate-type SPAs, wilfordatines L–N (3–5), and six known analogs. Their structures were characterized by the extensive use of 1D and 2D NMR spectroscopic analysis, as well as HRMS data. Interestingly, compounds 4 and 6 were found to exhibit potent inhibitory effects on the nuclear factor-kappa B (NF-κB) pathway in lipopolysaccharide (LPS)-induced HEK293/NF-κB-Luc cells, with IC₅₀ values of 1.64 μM and 9.05 μM, respectively. Notably, these two compounds had no influence on the cell viability at a concentration of 100 μM. Consequently, they hold significant promise as potential anti-inflammatory candidates for further exploration and development. Full article

The skin, as the body’s largest organ, is vital for protecting against environmental stressors, regulating temperature, and preventing water loss. Here, we examined the potential of a mixture of five traditional Korean herbal extracts—Cimicifuga racemosa, Paeonia lactiflora, Phellodendron amurense, Rheum rhaponticum, and Scutellaria baicalensis—referred to as herbal medicine composite 5 (HRMC5) for enhancing skin health and managing menopausal symptoms. High-performance liquid chromatography identified 14 bioactive compounds, including flavonoids, phenolic acids, anthraquinones, and alkaloids. In vitro studies revealed an optimal concentration of 0.625 g/L for cell survival and UV protection, with the mixture demonstrating significant wound-healing properties comparable to epidermal growth factor. HRMC5 exhibited anti-inflammatory effects by downregulating COX2 expression and upregulating the key skin barrier proteins. A 4-week clinical trial involving 20 postmenopausal women showed significant improvements in skin redness, hemoglobin concentration, and skin moisture content. Visual analog scale assessments indicated substantial reductions in facial flushing severity and the associated sweating. The topical application of HRMC5 cream offered potential advantages over ingested phytoestrogens by reducing the systemic side effects. These findings suggest that HRMC5 is a promising non-invasive treatment for vasomotor symptoms in menopausal women and overall skin health, warranting further research on its long-term efficacy and safety in larger populations. Full article

Four new alkaloids, vibripyrrolidine A (1), vibripiperazine A (2), and vibridiazinane A, B (3, 4), comprising one pyrrolidine, one piperazine, and two diazinane alkaloids, along with two known analogs (5, 6), were isolated from the marine bacterium Vibrio ruber ZXR-93 cultured in ISP2 medium. Their chemical structures were elucidated by analysis of their 1D and 2D NMR, mass spectra, and electronic circular dichroism (ECD) calculations. Compounds 1 and 3–6 showed vigorous antibacterial activity against Staphylococcus aureus, with MIC values ranging from 0.96 to 7.81 μg/mL. Moreover, compound 1 exhibited robust anti-inflammatory activity in vitro using the LPS-induced RAW264.7 macrophage model. All compounds also showed moderate antineoplastic activity against cervical cancer cells (HeLa) and gastric cancer cells (SGC-7901). Full article

COVID-19 continues to spread around the world. This is mainly because new variants of the SARS-CoV-2 virus emerge due to genomic mutations, evade the immune system and result in the effectiveness of current therapeutics being reduced. We previously established a series of detection platforms, comprising computational docking analysis, S-protein-based ELISA, pseudovirus entry, and 3CL protease activity assays, which allow us to screen a large library of phytochemicals from natural products and to determine their potential in blocking the entry of SARS-CoV-2. In this new screen, rutaecarpine (an alkaloid from Evodia rutaecarpa) was identified as exhibiting anti-SARS-CoV-2 activity. Therefore, we conducted multiple rounds of structure-activity-relationship (SAR) studies around this phytochemical and generated several rutaecarpine analogs that were subjected to in vitro evaluations. Among these derivatives, RU-75 and RU-184 displayed remarkable inhibitory activity when tested in the 3CL protease assay, S-protein-based ELISA, and pseudovirus entry assay (for both wild-type and omicron variants), and they attenuated the inflammatory response induced by SARS-CoV-2. Interestingly, RU-75 and RU-184 both appeared to be more potent than rutaecarpine itself, and this suggests that they might be considered as lead candidates for future pharmacological elaboration. Full article

Previously, we analyzed 316 herbal extracts to evaluate their potential nematocidal properties in Caenorhabditis elegans. In this study, our attention was directed towards Torenia sp., resulting in reduced survival and heightened larval arrest/lethality, alongside a noticeable decrease in DAPI-stained bivalent structures and disrupted meiotic progression, thus disrupting developmental processes. Notably, Torenia sp. extracts activated a DNA damage checkpoint response via the ATM/ATR and CHK-1 pathways, hindering germline development. LC–MS analysis revealed 13 compounds in the Torenia sp. extracts, including flavonoids, terpenoids, tanshinones, an analog of resveratrol, iridoids, carotenoids, fatty acids, and alkaloids. Of these, 10 are known for their antitumor activity, suggesting the potential of Torenia species beyond traditional gardening, extending into pharmaceutical and therapeutic applications. Full article

In this study, Antarctic Latrunculia sponge-derived discorhabdin G was considered a hit for developing potential lead compounds acting as cholinesterase inhibitors. The hypothesis on the pharmacophore moiety suggested through molecular docking allowed us to simplify the structure of the metabolite. ADME prediction and drug-likeness consideration provided valuable support in selecting 5-methyl-2H-benzo[h]imidazo[1,5,4-de]quinoxalin-7(3H)-one as a candidate molecule. It was synthesized in a four-step sequence starting from 2,3-dichloronaphthalene-1,4-dione and evaluated as an inhibitor of electric eel acetylcholinesterase (eeAChE), human recombinant AChE (hAChE), and horse serum butyrylcholinesterase (BChE), together with other analogs obtained by the same synthesis. The candidate molecule showed a slightly lower inhibitory potential against eeAChE but better inhibitory activity against hAChE than discorhabdin G, with a higher selectivity for AChEs than for BChE. It acted as a reversible competitive inhibitor, as previously observed for the natural alkaloid. The findings from the in vitro assay were relatively consistent with the data available from the AutoDock Vina and Protein-Ligand ANTSystem (PLANTS) calculations. Full article