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Alkaloids in Future Drug Discovery

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (20 September 2021) | Viewed by 41717

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Prof. Dr. Maria José U. Ferreira

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Faculty of Pharmacy, University of Lisbon, Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal
Interests: natural products chemistry; isolation and structure elucidation; hemi-synthesis of plant-derived compounds; bioactive compounds; anticancer compounds; multidrug resistance (MDR); ABC transporter modulators; P-glycoprotein; antibacterial compounds
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Dear Colleagues,

Natural products, bearing privileged scaffolds, have been playing a crucial role in drug discovery and development. Alkaloids, biosynthesized by both marine and terrestrial organisms, are among the largest classes of natural products.

Owing to their huge chemical diversity and complexity, coupled with their broad range of biological activities, this group of secondary metabolites has long deserved a great amount of interest from natural product chemists and medicinal chemists.

This Special Issue on “Alkaloids in Future Drug Discovery” invites researchers to contribute with original research or review articles focused on biologically relevant natural alkaloids or semisynthetic derivatives.

Prof. Dr. Maria José U. Ferreira
Guest Editor

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Published Papers (12 papers)

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Editorial

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4 pages, 198 KiB

Open AccessEditorial

Alkaloids in Future Drug Discovery

by Maria-José U. Ferreira

Molecules 2022, 27(4), 1347; https://doi.org/10.3390/molecules27041347 - 16 Feb 2022

Cited by 11 | Viewed by 2035

Abstract

Alkaloids are nitrogen-containing compounds, biosynthesized by both marine and terrestrial organisms, often with strong biological properties [...] Full article

(This article belongs to the Special Issue Alkaloids in Future Drug Discovery)

Research

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13 pages, 2783 KiB

Open AccessArticle

Discovery of Guanidine Derivatives from Buthus martensii Karsch with Metal-Binding and Cholinesterase Inhibition Properties

by Yu-Ming Liu, Jing-Jing Fan and Li-Ning Wang

Molecules 2021, 26(21), 6737; https://doi.org/10.3390/molecules26216737 - 08 Nov 2021

Cited by 6 | Viewed by 1616

Abstract

Two rare guanidine-type alkaloids, Buthutin A (1) and Buthutin B (2), along with two other compounds (3, 4), were isolated from Buthus martensii Karsch, and determined using extensive spectroscopic data analysis and high resolution-mass spectrometry. Compound 1 showed the most potent inhibition on AChE and BChE with IC₅₀ values of 7.83 ± 0.06 and 47.44 ± 0.95 μM, respectively. Kinetic characterization of compound 1 confirmed a mixed-type of AChE inhibition mechanism in accordance with the docking results, which shows its interaction with both catalytic active (CAS) and peripheral anionic (PAS) sites. The specific binding of compound 1 to PAS domain of AChE was also confirmed experimentally. Moreover, compounds 1 and 3 exhibited satisfactory biometal binding abilities toward Cu²⁺, Fe²⁺, Zn²⁺ and Al³⁺ ions. These results provide a new evidence for further development and utilization of B. martensii in health and pharmaceutical products. Full article

(This article belongs to the Special Issue Alkaloids in Future Drug Discovery)

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19 pages, 5166 KiB

Open AccessArticle

Preparation of Antiproliferative Terpene-Alkaloid Hybrids by Free Radical-Mediated Modification of ent-Kauranic Derivatives

by Elena Pruteanu, Vladilena Gîrbu, Nicon Ungur, Leentje Persoons, Dirk Daelemans, Philippe Renaud and Veaceslav Kulcițki

Molecules 2021, 26(15), 4549; https://doi.org/10.3390/molecules26154549 - 28 Jul 2021

Cited by 2 | Viewed by 1802

Abstract

A convenient strategy for molecular editing of available ent-kauranic natural scaffolds has been developed based on radical mediated C–C bond formation. Iodine atom transfer radical addition (ATRA) followed by rapid ionic elimination and radical azidoalkylation were investigated. Both reactions involve radical addition to the exo-methylenic double bond of the parent substrate. Easy transformations of the obtained adducts lead to extended diterpenes of broad structural diversity and artificial diterpene-alkaloid hybrids possessing lactam and pyrrolidine pharmacophores. The cytotoxicity of selected diterpenic derivatives was examined by in vitro testing on several tumor cell lines. The terpene-alkaloid hybrids containing N-heterocycles with unprecedented spiro-junction have shown relevant cytotoxicity and promising selectivity indexes. These results represent a solid basis for following research on the synthesis of such derivatives based on available natural product templates. Full article

(This article belongs to the Special Issue Alkaloids in Future Drug Discovery)

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23 pages, 9017 KiB

Open AccessArticle

In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids of Holarrhena pubescens Wall. ex G. Don to Guanylyl Cyclase C: Implications in Designing of Novel Antidiarrheal Therapeutic Strategies

by Neha Gupta, Saurav Kumar Choudhary, Neeta Bhagat, Muthusamy Karthikeyan and Archana Chaturvedi

Molecules 2021, 26(14), 4147; https://doi.org/10.3390/molecules26144147 - 08 Jul 2021

Cited by 6 | Viewed by 3376

Abstract

The binding of heat stable enterotoxin (STa) secreted by enterotoxigenic Escherichia coli (ETEC) to the extracellular domain of guanylyl cyclase c (ECD_GC-C) causes activation of a signaling cascade, which ultimately results in watery diarrhea. We carried out this study with the objective of finding ligands that would interfere with the binding of STa on ECD_GC-C. With this view in mind, we tested the biological activity of a alkaloid rich fraction of Holarrhena pubescens against ETEC under in vitro conditions. Since this fraction showed significant antibacterial activity against ETEC, we decided to test the screen binding affinity of nine compounds of steroidal alkaloid type from Holarrhena pubescens against extracellular domain (ECD) by molecular docking and identified three compounds with significant binding energy. Molecular dynamics simulations were performed for all the three lead compounds to establish the stability of their interaction with the target protein. Pharmacokinetics and toxicity profiling of these leads demonstrated that they possessed good drug-like properties. Furthermore, the ability of these leads to inhibit the binding of STa to ECD was evaluated. This was first done by identifying amino acid residues of ECD_GC-C binding to STa by protein–protein docking. The results were matched with our molecular docking results. We report here that holadysenterine, one of the lead compounds that showed a strong affinity for the amino acid residues on ECD_GC-C, also binds to STa. This suggests that holadysenterine has the potential to inhibit binding of STa on ECD and can be considered for future study, involving its validation through in vitro assays and animal model studies. Full article

(This article belongs to the Special Issue Alkaloids in Future Drug Discovery)

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14 pages, 1948 KiB

Open AccessArticle

Neuroprotective Activities of Crossyne flava Bulbs and Amaryllidaceae Alkaloids: Implications for Parkinson’s Disease

by Sylvester I. Omoruyi, Abobaker S. Ibrakaw, Okobi E. Ekpo, James S. Boatwright, Christopher N. Cupido and Ahmed A. Hussein

Molecules 2021, 26(13), 3990; https://doi.org/10.3390/molecules26133990 - 30 Jun 2021

Cited by 8 | Viewed by 2394

Abstract

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases and affects approximately 6.3 million people worldwide. To date, the treatment of PD remains a challenge, as available treatment options are known to be associated with serious side effects; hence, the search for new treatment strategies is critical. Extracts from the Amaryllidaceae plant family as well as their alkaloids have been reported to have neuroprotective potentials. This study, therefore, investigated the biological activities of Crossyne flava and its isolated alkaloids in an in vitro MPP⁺ (1-methyl-4-phenylpyridinium) PD model using SH-SY5Y cells. The effects of the total extract as well as the four compounds isolated from Crossyne flava (i.e., pancratinine B (1), bufanidrine (2), buphanisine (3), and epibuphanisine (4)) were evaluated for cell viability, neuroprotection, levels of reactive oxygen species (ROS), adenosine triphosphate activity (ATP), and caspase 3/7 activity in SH-SY5Y cells. The results obtained showed that pre-treatment with both the extract and the isolated compounds was effective in protecting the SH-SY5Y cells from MPP⁺-induced neurotoxicity and inhibited ROS generation, ATP depletion as well as apoptosis induction in the SH-SY5Y cells. The results of this study show that the Amaryllidaceae plant family may be a source of novel compounds for the treatment of neurodegenerative diseases, which validates the reported traditional uses. Full article

(This article belongs to the Special Issue Alkaloids in Future Drug Discovery)

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19 pages, 6049 KiB

Open AccessArticle

Endophytic Fungal Community of Huperzia serrata: Diversity and Relevance to the Production of Huperzine A by the Plant Host

by Lingli Cui, Hamza Armghan Noushahi, Yipeng Zhang, Jinxin Liu, Andreea Cosoveanu, Ying Liu, Ling Yan, Jing Zhang and Shaohua Shu

Molecules 2021, 26(4), 892; https://doi.org/10.3390/molecules26040892 - 08 Feb 2021

Cited by 15 | Viewed by 4049

Abstract

As the population ages globally, there seem to be more people with Alzheimer’s disease. Unfortunately, there is currently no specific treatment for the disease. At present, Huperzine A (HupA) is one of the best drugs used for the treatment of Alzheimer’s disease and has been used in clinical trials for several years in China. HupA was first separated from Huperzia serrata, a traditional medicinal herb that is used to cure fever, contusions, strains, hematuria, schizophrenia, and snakebite for several hundreds of years in China, and has been confirmed to have acetylcholinesterase inhibitory activity. With the very slow growth of H. serrata, resources are becoming too scarce to meet the need for clinical treatment. Some endophytic fungal strains that produce HupA were isolated from H. serrate in previous studies. In this article, the diversity of the endophytic fungal community within H. serrata was observed and the relevance to the production of HupA by the host plant was further analyzed. A total of 1167 strains were obtained from the leaves of H. serrata followed by the stems (1045) and roots (824). The richness as well as diversity of endophytic fungi within the leaf and stem were higher than in the root. The endophytic fungal community was similar within stems as well as in leaves at all taxonomic levels. The 11 genera (Derxomyces, Lophiostoma, Cyphellophora, Devriesia, Serendipita, Kurtzmanomyces, Mycosphaerella, Conoideocrella, Brevicellicium, Piskurozyma, and Trichomerium) were positively correlated with HupA content. The correlation index of Derxomyces with HupA contents displayed the highest value (CI = 0.92), whereas Trichomerium showed the lowest value (CI = 0.02). Through electrospray ionization mass spectrometry (ESI-MS), it was confirmed that the HS7-1 strain could produce HupA and the total alkaloid concentration was 3.7 ug/g. This study will enable us to screen and isolate the strain that can produce HupA and to figure out the correlation between endophytic fungal diversity with HupA content in different plant organs. This can provide new insights into the screening of strains that can produce HupA more effectively. Full article

(This article belongs to the Special Issue Alkaloids in Future Drug Discovery)

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16 pages, 8435 KiB

Open AccessArticle

Alkaloids: Therapeutic Potential against Human Coronaviruses

by Burtram C. Fielding, Carlos da Silva Maia Bezerra Filho, Nasser S. M. Ismail and Damião Pergentino de Sousa

Molecules 2020, 25(23), 5496; https://doi.org/10.3390/molecules25235496 - 24 Nov 2020

Cited by 39 | Viewed by 4758

Abstract

Alkaloids are a class of natural products known to have wide pharmacological activity and have great potential for the development of new drugs to treat a wide array of pathologies. Some alkaloids have antiviral activity and/or have been used as prototypes in the development of synthetic antiviral drugs. In this study, eleven anti-coronavirus alkaloids were identified from the scientific literature and their potential therapeutic value against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is discussed. In this study, in silico studies showed an affinity of the alkaloids for binding to the receptor-binding domain of the SARS-CoV-2 spike protein, putatively preventing it from binding to the host cell. Lastly, several mechanisms for the known anti-coronavirus activity of alkaloids were discussed, showing that the alkaloids are interesting compounds with potential use as bioactive agents against SARS-CoV-2. Full article

(This article belongs to the Special Issue Alkaloids in Future Drug Discovery)

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Review

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14 pages, 1686 KiB

Open AccessReview

An Update of the Sanguinarine and Benzophenanthridine Alkaloids’ Biosynthesis and Their Applications

by José Ignacio Laines-Hidalgo, José Armando Muñoz-Sánchez, Lloyd Loza-Müller and Felipe Vázquez-Flota

Molecules 2022, 27(4), 1378; https://doi.org/10.3390/molecules27041378 - 18 Feb 2022

Cited by 24 | Viewed by 3236

Abstract

Benzophenanthridines belong to the benzylisoquinolic alkaloids, representing one of the main groups of this class. These alkaloids include over 120 different compounds, mostly in plants from the Fumariaceae, Papaveraceae, and Rutaceae families, which confer chemical protection against pathogens and herbivores. Industrial uses of BZD include the production of environmentally friendly agrochemicals and livestock food supplements. However, although mainly considered toxic compounds, plants bearing them have been used in traditional medicine and their medical applications as antimicrobials, antiprotozoals, and cytotoxic agents have been envisioned. The biosynthetic pathways for some BZD have been established in different species, allowing for the isolation of the genes and enzymes involved. This knowledge has resulted in a better understanding of the process controlling their synthesis and an opening of the gates towards their exploitation by applying modern biotechnological approaches, such as synthetic biology. This review presents the new advances on BDZ biosynthesis and physiological roles. Industrial applications, mainly with pharmacological approaches, are also revised. Full article

(This article belongs to the Special Issue Alkaloids in Future Drug Discovery)

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22 pages, 733 KiB

Open AccessReview

Natural Aporphine Alkaloids with Potential to Impact Metabolic Syndrome

by Fei-Xuan Wang, Nan Zhu, Fan Zhou and Dong-Xiang Lin

Molecules 2021, 26(20), 6117; https://doi.org/10.3390/molecules26206117 - 10 Oct 2021

Cited by 21 | Viewed by 4020

Abstract

The incidence and prevalence of metabolic syndrome has steadily increased worldwide. As a major risk factor for various diseases, metabolic syndrome has come into focus in recent years. Some natural aporphine alkaloids are very promising agents in the prevention and treatment of metabolic syndrome and its components because of their wide variety of biological activities. These natural aporphine alkaloids have protective effects on the different risk factors characterizing metabolic syndrome. In this review, we highlight the activities of bioactive aporphine alkaloids: thaliporphine, boldine, nuciferine, pronuciferine, roemerine, dicentrine, magnoflorine, anonaine, apomorphine, glaucine, predicentrine, isolaureline, xylopine, methylbulbocapnine, and crebanine. We particularly focused on their impact on metabolic syndrome and its components, including insulin resistance and type 2 diabetes mellitus, endothelial dysfunction, hypertension and cardiovascular disease, hyperlipidemia and obesity, non-alcoholic fatty liver disease, hyperuricemia and kidney damage, erectile dysfunction, central nervous system-related disorder, and intestinal microbiota dysbiosis. We also discussed the potential mechanisms of actions by aporphine alkaloids in metabolic syndrome. Full article

(This article belongs to the Special Issue Alkaloids in Future Drug Discovery)

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34 pages, 1674 KiB

Open AccessFeature PaperReview

Alkaloids in Contemporary Drug Discovery to Meet Global Disease Needs

by Sharna-kay Daley and Geoffrey A. Cordell

Molecules 2021, 26(13), 3800; https://doi.org/10.3390/molecules26133800 - 22 Jun 2021

Cited by 25 | Viewed by 4912

Abstract

An overview is presented of the well-established role of alkaloids in drug discovery, the application of more sustainable chemicals, and biological approaches, and the implementation of information systems to address the current challenges faced in meeting global disease needs. The necessity for a new international paradigm for natural product discovery and development for the treatment of multidrug resistant organisms, and rare and neglected tropical diseases in the era of the Fourth Industrial Revolution and the Quintuple Helix is discussed. Full article

(This article belongs to the Special Issue Alkaloids in Future Drug Discovery)

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47 pages, 13471 KiB

Open AccessReview

Bisindole Alkaloids from the Alstonia Species: Recent Isolation, Bioactivity, Biosynthesis, and Synthesis

by Kamal P. Pandey, Md Toufiqur Rahman and James M. Cook

Molecules 2021, 26(11), 3459; https://doi.org/10.3390/molecules26113459 - 07 Jun 2021

Cited by 11 | Viewed by 4217

Abstract

Bisindoles are structurally complex dimers and are intriguing targets for partial and total synthesis. They exhibit stronger biological activity than their corresponding monomeric units. Alkaloids, including those containing C-19 methyl-substitution in their monomeric units, their synthetic derivatives, and their mismatched pairs can be attractive targets for synthesis and may unlock better drug targets. We herein discuss the isolation of bisindoles from various Alstonia species, their bioactivity, putative biosynthesis, and synthesis. The total synthesis of macralstonidine, macralstonine, O-acetylmacralstonine, and dispegatrine, as well as the partial synthesis of alstonisidine, villalstonine, and macrocarpamine are also discussed in this review. The completion of the total synthesis of pleiocarpamine by Sato et al. completes the formal synthesis of the latter two bisindoles. Full article

(This article belongs to the Special Issue Alkaloids in Future Drug Discovery)

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13 pages, 2046 KiB

Open AccessReview

Current Knowledge and Perspectives of Pyrrolizidine Alkaloids in Pharmacological Applications: A Mini-Review

by Xianqin Wei, Weibin Ruan and Klaas Vrieling

Molecules 2021, 26(7), 1970; https://doi.org/10.3390/molecules26071970 - 31 Mar 2021

Cited by 18 | Viewed by 3219

Abstract

Pyrrolizidine alkaloids (PAs) are a widespread group of secondary metabolites in plants. PAs are notorious for their acute hepatotoxicity, genotoxicity and neurological damage to humans and animals. In recent decades, the application of PAs for beneficial biological activities to cure disease has drawn greater attention. Here, we review the current knowledge regarding the pharmacological properties of PAs and discuss PAs as promising prototypes for the development of new drugs. Full article

(This article belongs to the Special Issue Alkaloids in Future Drug Discovery)

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