Synonym name: beta-Febrifugine
Catalogue No.: BP0264
Cas No.: 24159-07-7
Formula: C₁₆H₁₉N₃O₃
Mol Weight: 301.346
Botanical Source: Alkaloid from Root and leaves of the Chinese drug Ch'ang Shan (Dichroa febrifuga) and from Hydrangea spp. (Hydrangeaceae)

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle
Can be supplied from milligrams to grams.

For Reference Standard and R&D, Not for Human Use Directly.
Inquire for bulk scale.

HPLC of Febrifugine

Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃

Introduction/Overview

Malaria, a serious infectious disease caused by Plasmodium falciparum, has long been a major challenge in global public health. With the emergence of antimalarial drug resistance, the development of new, efficient, and low-toxicity antimalarial drugs is urgently needed. Natural products, as an important source of drug discovery, provide a rich array of chemical structures and bioactive molecules. Febrifugine, a typical quinazolinone alkaloid, was isolated from the traditional Chinese medicinal material Dichroa febrifuga in the early 20th century and has attracted significant attention for its remarkable antimalarial activity.

In recent years, in addition to traditional antimalarial effects, Changshan alkaloid has also shown potential pharmacological value in the field of anti-tumors, especially in inhibiting bladder cancer, demonstrating the ability to induce apoptosis and regulate steroid metabolism. This paper aims to systematically review the chemical structure, origin, pharmacological activity, mechanism of action, and druggability of Changshan alkaloid 乙, explore its clinical application prospects, and provide a theoretical basis for subsequent drug development and clinical translation.

Chemical structure and physicochemical properties

Febrifugine has the molecular formula C_16H_19N_3O_2 and a molecular weight of 301.34, belonging to the quinazolinone alkaloids. Its structural core is a polycyclic heterocyclic framework containing quinazolinone rings, containing multiple hydrogen bond acceptors (5), moderate molecular polarity, topopole surface area (TPSA) of 85.8 Ų, and LogP value of 0.19, indicating good balance between water and lipid solubility.

Structurally, the quinazolinone group of Changshan alkaloid E provides a key binding site for its biological activity, enabling stable interactions with various biomacromolecules. Additionally, its molecules have high blood-brain barrier permeability, suggesting potential applications in central nervous system diseases. However, its safety indicators such as hepatotoxicity, cardiotoxicity, and hERG channel inhibition remain unclear and require further systematic evaluation.

Plant Origins and Extraction Methods

Changshan alkaloid was originally isolated from the traditional Chinese medicinal herb Changshan (Dichroa febrifuga Lour.). Changshan is a member of the Ranunculaceae family, widely distributed in southern China and Southeast Asia, traditionally used to treat malaria, fever, and other symptoms. As one of the main active components of Changshan, alkaloid B in Changshan may not be high in content, but it possesses significant biological activity.

The extraction process typically uses organic solvent extraction combined with acid-base extraction. The specific steps include: crushing the dried Changshan rhizome, reflux extraction using methanol or ethanol, concentrating the filtrate and adjusting the pH to acidity with hydrochloric acid solution, then extracting the alkaline components with organic solvents (such as ethyl acetate), and finally separating and purifying Changshan alkali ethyl by column chromatography. In modern research, the application of ultrasound-assisted extraction and high-performance liquid chromatography (HPLC) technology has improved extraction efficiency and purity.

Pharmacological activity research

Antimalarial activity

Changshan alkaloid is best known for its pharmacological effect of inhibiting Plasmodium falciparum. Both in vitro and in vivo experiments showed significant inhibitory effects on Plasmodium falciparum and good activity against various drug-resistant strains. Its antimalarial mechanism involves multiple biological targets, including the DNA synthetase, membrane transporter, and metabolic enzyme systems of the malaria parasite.

Antitumor activity

Recent studies have found that Changshan-methyl acid can exert anti-tumor effects in bladder cancer cells by inhibiting DNA synthesis and inducing apoptosis. In addition, it can lower intracellular steroid levels, disrupt endocrine regulation in tumor cells, thereby inhibiting tumor growth. Cell experiments showed that after treatment with Changshan alkaloid ethyl, the proliferative capacity of bladder cancer cells significantly decreased and apoptosis rate increased, suggesting its potential for anticancer drug development.

Other pharmacological effects

In addition to antimalarial and antitumor effects, Changshan alkaloid also shows a certain inhibitory effect on the inflammatory responses induced by certain bacterial lipopolysaccharides (LPS), suggesting possible anti-inflammatory activity. However, related research is still in its early stages and requires further in-depth exploration.

Mechanism of action and molecular targets

The pharmacological mechanism of Changshan alkaloid B is complex, involving multiple signaling pathways and multiple molecular targets.

Antimalarial mechanisms

For malaria, Changshan Ethyl mainly acts through the following targets:

• PPARG (Peroxisome Proliferator-Activated Receptor γ): Regulates host immune responses and influences the living environment of malaria parasites.
• GPX1 (glutathione peroxidase 1): participates in oxidative stress responses and alleviates cell damage induced by malaria parasites.
• PFCRT (malaria chloroquine transporter) and PFMDR1 (multidrug resistance protein 1): affect the uptake and excretion of drugs by malaria parasites, and Changshanjie B may reverse resistance by inhibiting these transporters.
• PFDHFR (Plasmodium dihydrofolate reductase) and DHFR: Block folic acid metabolism in Plasmodium and inhibit DNA synthesis.
• PFK13 (Plasmodium potassium channel protein) and PFATP6 (Plasmodium calcium ATPase): regulate the ion balance and energy metabolism of the parasite.
• PFCYT (Plasmodium cytochrome): Interferes with the respiratory chain function of the malaria parasite.

Through multi-target synergistic action, Changshan alkaloid effectively inhibits the growth and reproduction of malaria parasites.

Antitumor mechanism

In bladder cancer, Changshan alkaloid acts through the following pathways:

• Inhibits DNA synthesis: Blocks the proliferation cycle of cancer cells and induces cell stagnation.
• Induction of apoptosis: activates endogenous apoptosis signaling pathways, including mitochondrial pathways and death receptor pathways.
• Lowering steroid levels: Interferes with hormone-dependent growth of tumor cells and suppresses the supportive role of the tumor microenvironment.

Additionally, Changshan alkaloid ethyl may indirectly affect tumor cell survival and metastasis by regulating inflammatory factors and oxidative stress states.

Druggability evaluation and pharmacokinetics

Druggability parameters

The molecular weight of Changshan alkaloid B (301.34) is within the ideal molecular range for drugs, and the LogP value (0.19) indicates strong hydrophilicity, which is beneficial for distribution in the body. TPSA was 85.8 Ų, indicating good cell membrane penetration and oral bioavailability. The number of hydrogen bond receptors is 5, which complies with Lipinski's rule and facilitates stable binding to target proteins.

The high permeability of the blood-brain barrier suggests it may affect the central nervous system, but potential neurotoxicity risks should also be watched for. Safety indicators such as hepatotoxicity, cardiotoxicity, and hERG channel inhibition remain unclear and require focused attention in subsequent pharmacological and toxicological studies.

Pharmacokinetics

Currently, pharmacokinetic research on Changshan-alkaloid B is relatively limited. Animal experiments have shown that it is absorbed orally quickly, has a moderate plasma half-life, and is mainly metabolized by the liver; the metabolites have not yet been fully identified. Given its structural characteristics, it is speculated that it may be metabolized via the CYP450 enzyme system, posing potential risks of drug interactions.

In the future, systematic studies on absorption, distribution, metabolism, and excretion (ADME) and toxicology are needed to clarify its in vivo behavior and safety window, providing a basis for clinical development.

Prospects and outlooks for clinical applications

Changshan alkaloid ethyl, as a natural quinazolinone alkaloid, has broad clinical application prospects due to its remarkable antimalarial activity and potential antitumor effects. In the field of malarial treatment, facing increasingly severe resistance issues, Changshanjie B and its derivatives are expected to become candidates for the next generation of antimalarial drugs. By optimizing structure and designing drugs to enhance its selectivity and safety, it will further drive its clinical translation.

In the field of anti-tumor treatment, especially for bladder cancer, Changshan alkaloid B has demonstrated a unique mechanism of action and good pharmacological activity. In the future, targeted drugs and immunotherapy strategies can be combined to explore the synergistic effects of their combination therapy. Moreover, due to its high blood-brain barrier permeability, Changshanjie E-Binh has potential applications in central nervous system diseases and is also worth in-depth study.

However, the safety evaluation of Changshan alkaloid B is still incomplete, and key indicators such as hepatotoxicity, cardiotoxicity, and genotoxicity require systematic evaluation. Pharmacokinetic characteristics and formulation development are also key bottlenecks in clinical application. In the future, multidisciplinary collaboration should be strengthened, utilizing modern medicinal chemistry, pharmacology, and pharmacokinetic technologies to promote the conversion of Changshanjil B into clinical drugs.

Conclusion

As a natural product with a unique structure and multiple biological activities, Changshan alkali ethylide demonstrates dual potential for antimalarial and anti-tumor properties. Its multi-target mechanism of action offers new ideas for antimalarial and anticancer treatments. Although there are still many challenges in druggability, safety, and pharmacokinetics, with deeper research and technological advancements, Changshan alkaloid B is expected to become an important breakthrough in the development of natural product drugs. Future research should focus on structural optimization, safety evaluation, and preclinical studies to promote early clinical application and benefit a broad range of patients.