The Phytochemistry and Pharmacology of Tulbaghia,Allium, Crinum and Cyrtanthus: ‘Talented’ Taxa from the Amaryllidaceae

Amaryllidaceae is a significant source of bioactive phytochemicals with a strong propensity to develop new drugs. The genera Allium, Tulbaghia, Cyrtanthus and Crinum biosynthesize novel alkaloids and other phytochemicals with traditional and pharmacological uses. Amaryllidaceae biomolecules exhibit multiple pharmacological activities such as antioxidant, antimicrobial, and immunomodulatory effects. Traditionally, natural products from Amaryllidaceae are utilized to treat non-communicable and infectious human diseases. Galanthamine, a drug from this family, is clinically relevant in treating the neurocognitive disorder, Alzheimer’s disease, which underscores the importance of the Amaryllidaceae alkaloids. Although Amaryllidaceae provide a plethora of biologically active compounds, there is tardiness in their development into clinically pliable medicines. Other genera, including Cyrtanthus and Tulbaghia, have received little attention as potential sources of promising drug candidates. Given the reciprocal relationship of the increasing burden of human diseases and limited availability of medicinal therapies, more rapid drug discovery and development are desirable. To expedite clinically relevant drug development, we present here evidence on bioactive compounds from the genera Allium, Tulgbaghia, Cyrtanthus and Crinum and describe their traditional and pharmacological applications.     

Modern Approaches in the Discovery and Development of Plant-Based Natural Products and Their Analogues as Potential Therapeutic Agents

Natural products represents an important source of new lead compounds in drug discovery research. Several drugs currently used as therapeutic agents have been developed from natural sources; plant sources are specifically important. In the past few decades, pharmaceutical companies demonstrated insignificant attention towards natural product drug discovery, mainly due to its intrinsic complexity. Recently, technological advancements greatly helped to address the challenges and resulted in the revived scientific interest in drug discovery from natural sources. This review provides a comprehensive overview of various approaches used in the selection, authentication, extraction/isolation, biological screening, and analogue development through the application of modern drug-development principles of plant-based natural products. Main focus is given to the bioactivity-guided fractionation approach along with associated challenges and major advancements. A brief outline of historical development in natural product drug discovery and a snapshot of the prominent natural drugs developed in the last few decades are also presented. The researcher’s opinions indicated that an integrated interdisciplinary approach utilizing technological advances is necessary for the successful development of natural products. These involve the application of efficient selection method, well-designed extraction/isolation procedure, advanced structure elucidation techniques, and bioassays with a high-throughput capacity to establish druggability and patentability of phyto-compounds. A number of modern approaches including molecular modeling, virtual screening, natural product library, and database mining are being used for improving natural product drug discovery research. Renewed scientific interest and recent research trends in natural product drug discovery clearly indicated that natural products will play important role in the future development of new therapeutic drugs and it is also anticipated that efficient application of new approaches will further improve the drug discovery campaign.     

Natural Products Inhibitors of Monoamine Oxidases—Potential New Drug Leads for Neuroprotection,Neurological Disorders,and Neuroblastoma

Monoamine oxidase inhibitors (MAOIs) are an important class of drugs prescribed for treatment of depression and other neurological disorders. Evidence has suggested that patients with atypical depression preferentially respond to natural product MAOIs. This review presents a comprehensive survey of the natural products, predominantly from plant sources, as potential new MAOI drug leads. The psychoactive properties of several traditionally used plants and herbal formulations were attributed to their MAOI constituents. MAO inhibitory constituents may also be responsible for neuroprotective effects of natural products. Different classes of MAOIs were identified from the natural product sources with non-selective as well as selective inhibition of MAO-A and -B. Selective reversible natural product MAOIs may be safer alternatives to the conventional MAOI drugs. Characterization of MAO inhibitory constituents of natural products traditionally used as psychoactive preparations or for treatment of neurological disorders may help in understanding the mechanism of action, optimization of these preparations for desired bioactive properties, and improvement of the therapeutic potential. Potential therapeutic application of natural product MAOIs for treatment of neuroblastoma is also discussed.     

KRAS Binders Hidden in Nature

Natural products have proven to be a rich source of molecular architectures for drugs. Here, an integrated approach to natural product screening is proposed, which uncovered eight new natural product scaffolds for KRAS—the most frequently mutated oncogenic driver in human cancers, which has remained thus far undrugged. The approach combines aspects of virtual screening, fragment-based screening, structure-activity relationships (SAR) by NMR, and structure-based drug discovery to overcome the limitations in traditional natural product approaches. By using our approach, a new “snugness of fit” scoring function and the first crystal-soaking system of the active form of KRAS^G12D, the protein–ligand X-ray structures of a tricyclic indolopyrrole fungal alkaloid and an indoloisoquinolinone have been successfully elucidated. The natural product KRAS hits discovered provide fruitful ground for the optimization of highly potent natural-product-based inhibitors of the active form of oncogenic RAS. This integrated approach for screening natural products also holds promise for other “undruggable” targets.     

Pitanga (Eugenia uniflora L.) as a source of bioactive compounds for health benefits: A review

The pitangueira (Eugenia uniflora) is a tree native to Brazil but is cultivated in several subtropical countries. A great diversity of nutrients and bioactive compounds have been found in the leaves and fruits of E. uniflora, which supports its use in folk medicine to treat diseases such as stomach and intestinal disorders, fever and general inflammation. Antimicrobial, antiviral, antifungal and antioxidant effects on metabolism have been reported for this plant. This review discusses the phytochemical profile, toxicity and pharmacological action of E. uniflora leaves and fruits and points out that gaps in the literature that need to be investigated further. This review also discusses studies developed with E. uniflora demonstrating its promising therapeutic potential for several diseases with an apparent low toxicity in mammals. The compilation of the main pharmacological and toxicological results, as well as the phytochemical characterization of the varieties and constituents of E. uniflora are general aspects that this review attempts to demonstrate in order to contribute to the new approaches and developments to plant-derived natural product drug discovery. However, further studies are required to establish the nutraceutical effects and uses of E. uniflora as an important and safe supplement for human health.     

Selective modification of oleuropein,a multifunctional bioactive natural product

Oleuropein is the major phenolic compound extracted from olive leaves and it is also present in olive fruits and virgin olive oil. It has already demonstrated a wide range of pharmacological activities, but new derivatives have to be designed in order to obtain useful Structure–Activity Relationships for this family of products, as well as new analogs with improved and/or different biological properties. However, taking into account the multiple OH groups (catechol and sugar) present in oleuropein, the selective modification of this natural product is a challenging problem. In this paper, we present an efficient strategy allowing the selective modification at the primary alcohol position of this natural product. Using appropriate protection/deprotection sequences, we prepared by hemisynthesis several triazoles linked to the oleuropein core, as representative examples for the development of such an approach.     

Resolvins,Protectins, and Maresins: DHA-Derived Specialized Pro-Resolving Mediators,Biosynthetic Pathways,Synthetic Approaches,and Their Role in Inflammation

Marine organisms are an important source of natural products with unique and diverse chemical structures that may hold the key for the development of novel drugs. Docosahexaenoic acid (DHA) is an omega-3 fatty acid marine natural product playing a crucial regulatory role in the resolution of inflammation and acting as a precursor for the biosynthesis of the anti-inflammatory specialized pro-resolving mediators (SPMs) resolvins, protectins, and maresins. These metabolites exert many beneficial actions including neuroprotection, anti-hypertension, or anti-tumorigenesis. As dysregulation of SPMs is associated with diseases of prolonged inflammation, the disclosure of their bioactivities may be correlated with anti-inflammatory and pro-resolving capabilities, offering new targets for drug design. The availability of these SPMs from natural resources is very low, but the evaluation of their pharmacological properties requires their access in larger amounts, as achieved by synthetic routes. In this report, the first review of the total organic syntheses carried out for resolvins, protectins, and maresins is presented. Recently, it was proposed that DHA-derived pro-resolving mediators play a key role in the treatment of COVID-19. In this work we also review the current evidence on the structures, biosynthesis, and functional and new-found roles of these novel lipid mediators of disease resolution.     

Phytochemistry,Food Application,and Therapeutic Potential of the Medicinal Plant (Withania coagulans): A Review

Herbal plants have been utilized to treat and cure various health-related problems since ancient times. The use of Ayurvedic medicine is very significant because of its least reported side effects and host of advantages. Withania coagulans (Family; Solanaceae), a valuable medicinal plant, has been used to cure abnormal cell growth, wasting disorders, neural as well as physical problems, diabetes mellitus, insomnia, acute and chronic hepatic ailments. This review provides critical insight regarding the phytochemistry, biological activities, and pharmacognostic properties of W. coagulans. It has been known to possess diuretic, anti-inflammatory, anti-bacterial, anti-fungal, cardio-protective, hepato-protective, hypoglycemic, anti-oxidative, and anti-mutagenic properties owing to the existence of withanolides, an active compound present in it. Apart from withanolides, W. coagulans also contains many phytochemicals such as flavonoids, tannins, and β-sterols. Several studies indicate that various parts of W. coagulans and their active constituents have numerous pharmacological and therapeutic properties and thus can be considered as a new drug therapy against multiple diseases.     

Multiple biological functions and pharmacological effects of lycorine

Lycorine is the major active component from the amaryllidaceae family plant Lycoris radiate, a represent traditional Chinese medicinal herb, and is one of the typical alkaloids with pyrrolophenanthridine nucleus core. Lycorine has drawn great interest in medicinal field due to its divergent chemical structures and multiple biological functions, as well as pharmacological effects on various diseases. Accumulated evidence shows that lycorine not only possesses strong pharmacological effects on many diseases, including anti-leukemia, anti-tumor, anti-angiogenesis, anti-virus, anti-bacteria, anti-inflammation, and antimalaria, but also exerts many other biological functions, such as inhibition of acetylcholinesterase and topoisomerase, suppression of ascorbic acid biosynthesis, and control of circadian period length. Notably, lycorine exhibits its numerous pharmacological effects on various diseases with very low toxicity and mild side effects. The divergent chemical structures, multiple biological functions, and very low toxicity of lycorine imply that the agent is a potential drug candidate that warrants for further preclinical and clinic investigation.     

Pharmacological Insights into Halophyte Bioactive Extract Action on Anti-Inflammatory,Pain Relief and Antibiotics-Type Mechanisms

The pharmacological activities in bioactive plant extracts play an increasing role in sustainable resources for valorization and biomedical applications. Bioactive phytochemicals, including natural compounds, secondary metabolites and their derivatives, have attracted significant attention for use in both medicinal products and cosmetic products. Our review highlights the pharmacological mode-of-action and current biomedical applications of key bioactive compounds applied as anti-inflammatory, bactericidal with antibiotics effects, and pain relief purposes in controlled clinical studies or preclinical studies. In this systematic review, the availability of bioactive compounds from several salt-tolerant plant species, mainly focusing on the three promising species Aster tripolium, Crithmum maritimum and Salicornia europaea, are summarized and discussed. All three of them have been widely used in natural folk medicines and are now in the focus for future nutraceutical and pharmacological applications.     

Construction of a Meroterpenoid-Like Compounds Library Based on Diversity-Enhanced Extracts

The structural diversity of natural products and their derivatives have long contributed to the development of new drugs. However, the difficulty in obtaining compounds bearing skeletally novel structures has recently led to a decline of pharmaceutical research into natural products. This paper reports the construction of a meroterpenoid-like library containing 25 compounds with diverse molecular scaffolds obtained from diversity-enhanced extracts. This method constitutes an approach for increasing the chemical diversity of natural-product-like compounds by combining natural product chemistry and diversity-oriented synthesis. Extensive pharmacological screening of the library revealed promising compounds for anti-osteoporotic and anti-lymphoma/leukemia drugs. This result indicates that the use of diversity-enhanced extracts is an effective methodology for producing chemical libraries for the purpose of drug discovery.     

Chemistry,Biosynthesis and Pharmacology of Sarsasapogenin: A Potential Natural Steroid Molecule for New Drug Design,Development and Therapy

Sarsasapogenin is a natural steroidal sapogenin molecule obtained mainly from Anemarrhena asphodeloides Bunge. Among the various phytosteroids present, sarsasapogenin has emerged as a promising molecule due to the fact of its diverse pharmacological activities. In this review, the chemistry, biosynthesis and pharmacological potentials of sarsasapogenin are summarised. Between 1996 and the present, the relevant literature regarding sarsasapogenin was obtained from scientific databases including PubMed, ScienceDirect, Scopus, and Google Scholar. Overall, sarsasapogenin is a potent molecule with anti-inflammatory, anticancer, antidiabetic, anti-osteoclastogenic and neuroprotective activities. It is also a potential molecule in the treatment for precocious puberty. This review also discusses the metabolism, pharmacokinetics and possible structural modifications as well as obstacles and opportunities for sarsasapogenin to become a drug molecule in the near future. More comprehensive preclinical studies, clinical trials, drug delivery, formulations of effective doses in pharmacokinetics studies, evaluation of adverse effects and potential synergistic effects with other drugs need to be thoroughly investigated to make sarsasapogenin a potential molecule for future drug development.     

Natural product inhibitors as potential drug candidates against Alzheimer's disease: Structural-based drug design,molecular docking,molecular dynamic simulation experiments,and ADMET predictions

Alzheimer's disease (AD) is currently an incurable ailment with complicated-mechanism that causes intellectual impairment in adults mostly from 65 years old and above. Hence, immediate effort and actions are required to prevent or cure this life-threatening disease. There are currently four medications in the market, all of which have minimal therapeutic potential and are quite hazardous. The familiar pharmacological targets and intervention principles were assessed using an in-silico technique. This strategy emphasizes the benefits of natural products operating in a polytherapeutic manner over a monotherapy approach to AD treatment. A protein target with ID code 4EY7 was utilized in this research and it was chosen based on established literature studies and reasons such as lower resolution value (2.3Å), no mutation, Homo Sapiens, and X-ray diffraction method, the protein target interacted with some natural products, with greater interactions, higher binding scores, and improved enhanced drug-like properties and drug kinetic parameters The findings of these studies can be used to design promising pharmacotherapeutic compounds for the treatment of ADNatural products were docked with protein targets, resulting in a molecule with the maximum binding energy of −19.82 kcalmol^-1. It was utilized as a template for designing natural product derivatives with lower binding energies, high stability, and improved interactions. Compound Y5 has a docking score of −26.29 kcalmol^-1. The molecular dynamics (MD) Simulation used docked protein complexes with selected ligands as standard (reference) further verified the docking results. RSMD showed that compound Y5 remain within the inhibitor binding site all through the simulation period and reached equilibrium more rapidly compared to the standard. Also, the RMSF, Rg curve, and SASA gives brilliant results which further confirmed the stability of compound Y5. Lastly, the ligand hydrogen bond was examined, compound Y5 formed more hydrogen bonds with protein during the 100ns simulation indicating that the compound Y5 complex was more stable relative to the harmine. The compounds' drug-likeness and pharmacokinetics features were also evaluated, and all showed positive results. Alzheimer's as a consequence, these designed compounds with variety of inherent endowment of therapeutic ability and support in successful research and development, leading to excellent therapeutic effects, low toxicity, and brilliant kinetic abilities, making substantial contributions to the treatment of AD.     

Research Progress in the Field of Gambogic Acid and Its Derivatives as Antineoplastic Drugs

Gambogic acid (GA) is a natural product with a wide range of pharmacological properties. It plays an important role in inhibiting tumor growth. A large number of GA derivatives have been designed and prepared to improve its shortcomings, such as poor water solubility, low bioavailability, poor stability, and adverse drug effects. So far, GA has been utilized to develop a variety of active derivatives with improved water solubility and bioavailability through structural modification. This article summarized the progress in pharmaceutical chemistry of GA derivatives to provide a reference and basis for further study on structural modifications of GA and expansion of its clinical applications.     

Photosensitization mechanisms of triplet excited state beta-lapachone. A density functional theory study

Beta-Lapachone is a natural product with multiple pharmacological activities and mechanistic studies indicated that reactive oxygen species (ROS) generated by beta-lapachone play significant roles in its pharmacological actions. As photosensitization is an important ROS-generating pathway, in the present work, the photosensitization mechanisms of beta-lapachone are explored on the basis of density functional theory estimated triplet excited state characters. Starting from triplet excited state beta-lapachone, the possible generating pathways of 1O2 and O2*- are elucidated and the solvent effects on the photosensitizing reactions are also discussed.     

The Biological Activities and Therapeutic Potentials of Baicalein Extracted from Oroxylum indicum: A Systematic Review

In Southeast Asia, traditional medicine has a longestablished history and plays an important role in the health care system. Various traditional medicinal plants have been used to treat diseases since ancient times and much of this traditional knowledge remains preserved today. Oroxylum indicum (beko plant) is one of the medicinal herb plants that is widely distributed throughout Asia. It is a versatile plant and almost every part of the plant is reported to possess a wide range of pharmacological activities. Many of the important bioactivities of this medicinal plant is related to the most abundant bioactive constituent found in this plant—the baicalein. Nonetheless, there is still no systematic review to report and vindicate the biological activities and therapeutic potential of baicalein extracted from O. indicum to treat human diseases. In this review, we aimed to systematically present in vivo and in vitro studies searched from PubMed, ScienceDirect, Scopus and Google Scholar database up to 31 March 2020 based on keywords “Oroxylum indicum” and “baicalein”. After an initial screening of titles and abstracts, followed by a full-text analysis and validation, 20 articles that fulfilled all the inclusion and exclusion criteria were included in this systematic review. The searched data comprehensively reported the biological activities and therapeutic potential of baicalein originating from the O. indicum plant for anti-cancer, antibacterial, anti-hyperglycemia, neurogenesis, cardioprotective, anti-adipogenesis, anti-inflammatory and wound healing effects. Nonetheless, we noticed that there was a scarcity of evidence on the efficacy of this natural active compound in human clinical studies. In conclusion, this systematic review article provides new insight into O. indicum and its active constituent baicalein as a prospective complementary therapy from the perspective of modern and scientific aspect. We indicate the potential of this natural product to be developed into more conscientious and judicious evidencebased medicine in the future. However, we also recommend more clinical research to confirm the efficacy and safety of baicalein as therapeutic medicine for patients.     

Coupled Chromatography for Assay of the Venom Proteome of the Snake Agkistrodon acutus: An Effective Strategy for Discovery of Active Components

Two-dimensional liquid chromatography (2D-LC) is an attractive option for proteome profiling because of its advantages in separation and analysis of proteins and peptides of extreme pH and molecular weight. Proteomics, regarded as a promising and high-throughput method for discovery of new active natural products, calls for technical progress in comprehensive separation, especially for peptides, glycoproteins, and hydrophobic proteins, etc. Here, an optimized off-line IEX-RP LC system has been used for separation of all the components of the venom of the five-pace snake (Agkistrodon acutus). Seventy-nine different natural venom components were obtained by use of this system, more than were obtained by two dimensional electrophoresis of the venom. An automated on-line IEX-RP LC system was also developed for heart-cut separation of components of interest. As a result, we discovered a new tripeptide (PGlu-Asn-Trp, MW 429.1) in the venom. This emphasizes the role of 2D-LC in drug discovery.     

Investigation of innovative synthesis of biologically active compounds on the basis of newly developed reactions

Synthesis of biologically active compounds, including natural products and pharmaceutical agents, is an important and interesting research area since the large structural diversity and complexity of bioactive compounds make them an important source of leads and scaffolds in drug discovery and development. Many structurally and also biologically interesting compounds, including marine natural products, have been isolated from nature and have also been prepared on the basis of a computational design for the purpose of developing medicinal chemistry. In order to obtain a wide variety of derivatives of biologically active compounds from the viewpoint of medicinal chemistry, it is essential to establish efficient synthetic procedures for desired targets. Newly developed reactions should also be used for efficient synthesis of desired compounds. Thus, recent progress in the synthesis of biologically active compounds by focusing on the development of new reactions is summarized in this review article.     

Natural Products in Preventing Tumor Drug Resistance and Related Signaling Pathways

Drug resistance is still an obstacle in cancer therapy, leading to the failure of tumor treatment. The emergence of tumor drug resistance has always been a main concern of oncologists. Therefore, overcoming tumor drug resistance and looking for new strategies for tumor treatment is a major focus in the field of tumor research. Natural products serve as effective substances against drug resistance because of their diverse chemical structures and pharmacological effects. We reviewed the signaling pathways involved in the development of tumor drug resistance, including Epidermal growth factor receptor (EGFR), Renin-angiotensin system (Ras), Phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), Wnt, Notch, Transforming growth factor-beta (TGF-β), and their specific signaling pathway inhibitors derived from natural products. This can provide new ideas for the prevention of drug resistance in cancer therapy.