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Biologically Active Small Molecules Inspired by Plant Secondary Metabolites
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Biologically Active Small Molecules Inspired by Plant Secondary Metabolites

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

Deadline for manuscript submissions: 30 September 2024 | Viewed by 30019

Special Issue Editors

Dr. Giovanni Lentini

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Guest Editor
Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Bari, Italy
Interests: medicinal chemistry; drug discovery; chirality
Special Issues, Collections and Topics in MDPI journals
Dr. Maria Maddalena Cavalluzzi

E-Mail Website
Guest Editor
Department of Pharmacy - Pharmaceutical Sciences, University of Bari Aldo Moro, Bari, Italy
Interests: biologically active compounds; chirality; antimyotonic agents; antiarrhythmics; antimicrobials; anticancers; α-glucosidase inhibitors; synthesis and extraction of antioxidant agents
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Solomon Habtemariam

E-Mail Website
Guest Editor
Herbal Analysis Services UK, Greenwich, University of Greenwich, London, UK
Interests: natural products chemistry; pharmacology; drug discovery; pharmacognosy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It would seem that more than 500 centuries ago, our closest human relatives―the Neanderthals―used to place Ephedra plant flowers into graves. This might be the most ancient example of paleoethnobotany. As questionable as this statement might be, undoubtedly, the Plant Kingdom has been the most prodigal source of medicines for over 20 centuries.

The last four decades have witnessed a resurgence of interest in plant product research. Numerous and varied are the reasons for this:

  • Ever-increasing difficulty in developing new drugs;
  • The success of the natural product approach;
  • The uniqueness of plant secondary metabolites;
  • The impact of new screening methods and analytic techniques.

Unfortunately, plant secondary metabolites are not necessarily the best compounds for pharmaceutical uses, for the following reasons:

  • Limitations may exist that prevent the acquisition of sufficient biomass;
  • Isolation procedures may be long and expensive;
  • The structure of the secondary metabolites may be too complex to allow total synthesis;
  • The pharmacological profile may be promiscuous;
  • Toxicological aspects may cause concern;
  • Oral bioavailability can be too low.

For all of the above reasons, medicinal chemists use to prepare analogues of the starting secondary metabolites in order to unveil sound structure–activity relationships (SAR) and possibly overcome the above limitations.

This Special Issue is designed to scrutinize recent developments in the medicinal chemistry of biologically relevant compounds that were inspired by plant-derived compounds.

Between 1980 and 2013, 20% of the new drugs introduced into the market were either natural products or natural products derivatives, with the latter being highly predominant (18%). The contribution of natural product derivatives to the physician panoply is expected to rise in the next decade. The colleagues that would like to share their valuable work in the field by contributing to this Special Issue of Molecules will give shine to the issue, of course, and would possibly confer higher chances to this prophecy.


Dr. Giovanni Lentini
Dr. Maria Maddalena Cavalluzzi
Prof. Dr. Solomon Habtemariam
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Drug discovery
  • Secondary metabolites
  • Natural product scaffolds
  • Structure–activity relationships
  • Pharmacophore

Published Papers (8 papers)

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Research

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20 pages, 4046 KiB  
Article
Role of Stereochemistry on the Biological Activity of Nature-Inspired 3-Br-Acivicin Isomers and Derivatives
by Andrea Galbiati, Aureliano Zana, Chiara Borsari, Marco Persico, Stefania Bova, Oleh Tkachuk, Alexandra Ioana Corfu, Lucia Tamborini, Nicoletta Basilico, Caterina Fattorusso, Stefano Bruno, Silvia Parapini and Paola Conti
Molecules 2023, 28(7), 3172; https://doi.org/10.3390/molecules28073172 - 03 Apr 2023
Cited by 2 | Viewed by 1980
Abstract
Chiral natural compounds are often biosynthesized in an enantiomerically pure fashion, and stereochemistry plays a pivotal role in biological activity. Herein, we investigated the significance of chirality for nature-inspired 3-Br-acivicin (3-BA) and its derivatives. The three unnatural isomers of 3-BA and its ester [...] Read more.
Chiral natural compounds are often biosynthesized in an enantiomerically pure fashion, and stereochemistry plays a pivotal role in biological activity. Herein, we investigated the significance of chirality for nature-inspired 3-Br-acivicin (3-BA) and its derivatives. The three unnatural isomers of 3-BA and its ester and amide derivatives were prepared and characterized for their antimalarial activity. Only the (5S, αS) isomers displayed significant antiplasmodial activity, revealing that their uptake might be mediated by the L-amino acid transport system, which is known to mediate the acivicin membrane’s permeability. In addition, we investigated the inhibitory activity towards Plasmodium falciparum glyceraldehyde 3-phosphate dehydrogenase (PfGAPDH) since it is involved in the multitarget mechanism of action of 3-BA. Molecular modeling has shed light on the structural and stereochemical requirements for an efficient interaction with PfGAPDH, leading to covalent irreversible binding and enzyme inactivation. While stereochemistry affects the target binding only for two subclasses (1a–d and 4a–d), it leads to significant differences in the antimalarial activity for all subclasses, suggesting that a stereoselective uptake might be responsible for the enhanced biological activity of the (5S, αS) isomers. Full article
(This article belongs to the Special Issue Biologically Active Small Molecules Inspired by Plant Secondary Metabolites)
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11 pages, 8299 KiB  
Article
Furanocoumarins from Ruta chalepensis with Amebicide Activity
by Aldo Fabio Bazaldúa-Rodríguez, Ramiro Quintanilla-Licea, María Julia Verde-Star, Magda Elizabeth Hernández-García, Javier Vargas-Villarreal and Jesús Norberto Garza-González
Molecules 2021, 26(12), 3684; https://doi.org/10.3390/molecules26123684 - 16 Jun 2021
Cited by 9 | Viewed by 2111
Abstract
Entamoeba histolytica (protozoan; family Endomoebidae) is the cause of amoebiasis, a disease related to high morbidity and mortality. Nowadays, this illness is considered a significant public health issue in developing countries. In addition, parasite resistance to conventional medicinal treatment has increased in recent [...] Read more.
Entamoeba histolytica (protozoan; family Endomoebidae) is the cause of amoebiasis, a disease related to high morbidity and mortality. Nowadays, this illness is considered a significant public health issue in developing countries. In addition, parasite resistance to conventional medicinal treatment has increased in recent years. Traditional medicine around the world represents a valuable source of alternative treatment for many parasite diseases. In a previous paper, we communicated about the antiprotozoal activity in vitro of the methanolic (MeOH) extract of Ruta chalepensis (Rutaceae) against E. histolytica. The plant is extensively employed in Mexican traditional medicine. The following workup of the MeOH extract of R. chalepensis afforded the furocoumarins rutamarin (1) and chalepin (2), which showed high antiprotozoal activity on Entamoeba histolytica trophozoites employing in vitro tests (IC50 values of 6.52 and 28.95 µg/mL, respectively). Therefore, we offer a full scientific report about the bioguided isolation and the amebicide activity of chalepin and rutamarin. Full article
(This article belongs to the Special Issue Biologically Active Small Molecules Inspired by Plant Secondary Metabolites)
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11 pages, 1143 KiB  
Article
Synthesis and In Vitro Growth Inhibition of 2-Allylphenol Derivatives Against Phythopthora cinnamomi Rands
by Andrés F. Olea, Luis Espinoza, Claudia Sedan, Mario Thomas, Rolando Martínez, Marco Mellado, Héctor Carrasco and Katy Díaz
Molecules 2019, 24(22), 4196; https://doi.org/10.3390/molecules24224196 - 19 Nov 2019
Cited by 8 | Viewed by 3035
Abstract
Phytophthora cinnamomi is a phytopathogen that causes extensive damage in different crops, and therefore, produces important economic losses all around the world. Chemical fungicides are a key factor for the control of this disease. However, ecological and environmental considerations, as well as the [...] Read more.
Phytophthora cinnamomi is a phytopathogen that causes extensive damage in different crops, and therefore, produces important economic losses all around the world. Chemical fungicides are a key factor for the control of this disease. However, ecological and environmental considerations, as well as the appearance of strains that are resistant to commercial fungicides, have prompted the quest for new antifungal agents which are of low ecological impact. In this work, a series of new 2-allylphenol derivatives was synthesized, and their structures were confirmed by FT-IR, NMR, and MS. Some of the synthesized compounds, more specifically nitro derivatives, exhibit strong growth inhibition of P. cinnamomi with EC50 as low as 10.0 µg/mL. This level of activity is similar to that exhibited by METALAXYL MZ 58 WP, a commonly-used commercial fungicide; therefore, these compounds might be of agricultural interest due to their potential use as fungicides against P. cinnamomi. The results indicate that this activity depends on the chemical structures of the 2-allylphenol derivatives, and that it is strongly enhanced in molecules where nitro and hydroxyl groups adopt a -para configuration. These effects are discussed in terms of the electronic distribution of the aromatic ring induced by substituent groups. Full article
(This article belongs to the Special Issue Biologically Active Small Molecules Inspired by Plant Secondary Metabolites)
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Review

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19 pages, 596 KiB  
Review
Pharmacological Properties of Four Plant Species of the Genus Anabasis, Amaranthaceae
by Zhanybek Shegebayev, Aknur Turgumbayeva, Ubaidilla Datkhayev, Kairat Zhakipbekov, Assem Kalykova, Elmira Kartbayeva, Ahmet Beyatli, Kuanysh Tastambek, Gulmira Altynbayeva, Bassymbek Dilbarkhanov, Aiman Akhelova, Rabiga Anarbayeva and Kulpan Orynbassarova
Molecules 2023, 28(11), 4454; https://doi.org/10.3390/molecules28114454 - 31 May 2023
Cited by 4 | Viewed by 1621
Abstract
The genus Anabasis is a member of the family Amaranthaceae (former name: Chenopodiaceae) and includes approximately 102 genera and 1400 species. The genus Anabasis is one of the most significant families in salt marshes, semi-deserts, and other harsh environments. They are also [...] Read more.
The genus Anabasis is a member of the family Amaranthaceae (former name: Chenopodiaceae) and includes approximately 102 genera and 1400 species. The genus Anabasis is one of the most significant families in salt marshes, semi-deserts, and other harsh environments. They are also renowned for their abundance in bioactive compounds, including sesquiterpenes, diterpenes, triterpenes, saponins, phenolic acids, flavonoids, and betalain pigments. Since ancient times, these plants have been used to treat various diseases of the gastrointestinal tract, diabetes, hypertension, and cardiovascular diseases and are used as an antirheumatic and diuretic. At the same time, the genus Anabasis is very rich in biologically active secondary metabolites that exhibit great pharmacological properties such as antioxidant, antibacterial, antiangiogenic, antiulcer, hypoglycemic, hepatoprotective, antidiabetic, etc. All of the listed pharmacological activities have been studied in practice by scientists from different countries and are presented in this review article to familiarize the entire scientific community with the results of these studies, as well as to explore the possibilities of using four plant species of the genus Anabasis as medicinal raw materials and developing medicines based on them. Full article
(This article belongs to the Special Issue Biologically Active Small Molecules Inspired by Plant Secondary Metabolites)
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29 pages, 1539 KiB  
Review
Antibacterial and Antifungal Terpenes from the Medicinal Angiosperms of Asia and the Pacific: Haystacks and Gold Needles
by Christophe Wiart, Geethanjali Kathirvalu, Chandramathi Samudi Raju, Veeranoot Nissapatorn, Mohammed Rahmatullah, Alok K. Paul, Mogana Rajagopal, Jaya Seelan Sathiya Seelan, Nor Azizun Rusdi, Scholastica Lanting and Mazdida Sulaiman
Molecules 2023, 28(9), 3873; https://doi.org/10.3390/molecules28093873 - 04 May 2023
Cited by 6 | Viewed by 2341
Abstract
This review identifies terpenes isolated from the medicinal Angiosperms of Asia and the Pacific with antibacterial and/or antifungal activities and analyses their distribution, molecular mass, solubility, and modes of action. All data in this review were compiled from Google Scholar, PubMed, Science Direct, [...] Read more.
This review identifies terpenes isolated from the medicinal Angiosperms of Asia and the Pacific with antibacterial and/or antifungal activities and analyses their distribution, molecular mass, solubility, and modes of action. All data in this review were compiled from Google Scholar, PubMed, Science Direct, Web of Science, ChemSpider, PubChem, and library searches from 1968 to 2022. About 300 antibacterial and/or antifungal terpenes were identified during this period. Terpenes with a MIC ≤ 2 µg/mL are mostly amphiphilic and active against Gram-positive bacteria, with a molecular mass ranging from about 150 to 550 g/mol, and a polar surface area around 20 Ų. Carvacrol, celastrol, cuminol, dysoxyhainic acid I, ent-1β,14β-diacetoxy-7α-hydroxykaur-16-en-15-one, ergosterol-5,8-endoperoxide, geranylgeraniol, gossypol, 16α-hydroxy-cleroda-3,13 (14)Z-diene-15,16-olide, 7-hydroxycadalene, 17-hydroxyjolkinolide B, (20R)-3β-hydroxy-24,25,26,27-tetranor-5α cycloartan-23,21-olide, mansonone F, (+)-6,6′-methoxygossypol, polygodial, pristimerin, terpinen-4-ol, and α-terpineol are chemical frameworks that could be candidates for the further development of lead antibacterial or antifungal drugs. Full article
(This article belongs to the Special Issue Biologically Active Small Molecules Inspired by Plant Secondary Metabolites)
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21 pages, 2458 KiB  
Review
Papaverine: A Miraculous Alkaloid from Opium and Its Multimedicinal Application
by Sania Ashrafi, Safaet Alam, Arifa Sultana, Asef Raj, Nazim Uddin Emon, Fahmida Tasnim Richi, Tasnuva Sharmin, Myunghan Moon, Moon Nyeo Park and Bonglee Kim
Molecules 2023, 28(7), 3149; https://doi.org/10.3390/molecules28073149 - 31 Mar 2023
Cited by 5 | Viewed by 4662
Abstract
The pharmacological actions of benzylisoquinoline alkaloids are quite substantial, and have recently attracted much attention. One of the principle benzylisoquinoline alkaloids has been found in the unripe seed capsules of Papaver somniferum L. Although it lacks analgesic effects and is unrelated to the [...] Read more.
The pharmacological actions of benzylisoquinoline alkaloids are quite substantial, and have recently attracted much attention. One of the principle benzylisoquinoline alkaloids has been found in the unripe seed capsules of Papaver somniferum L. Although it lacks analgesic effects and is unrelated to the compounds in the morphine class, it is a peripheral vasodilator and has a direct effect on vessels. It is reported to inhibit the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) phosphodiesterase in smooth muscles, and it has been observed to increase intracellular levels of cAMP and cGMP. It induces coronary, cerebral, and pulmonary artery dilatation and helps to lower cerebral vascular resistance and enhance cerebral blood flow. Current pharmacological research has revealed that papaverine demonstrates a variety of biological activities, including activity against erectile dysfunction, postoperative vasospasms, and pulmonary vasoconstriction, as well as antiviral, cardioprotective, anti-inflammatory, anticancer, neuroprotective, and gestational actions. It was recently demonstrated that papaverine has the potential to control SARS-CoV-2 by preventing its cytopathic effect. These experiments were carried out both in vitro and in vivo and require an extensive understanding of the mechanisms of action. With its multiple mechanisms, papaverine can be considered as a natural compound that is used to develop therapeutic drugs. To validate its applications, additional research is required into its precise therapeutic mechanisms as well as its acute and chronic toxicities. Therefore, the goal of this review is to discuss the major studies and reported clinical studies looking into the pharmacological effects of papaverine and the mechanisms of action underneath these effects. Additionally, it is recommended to conduct further research via significant pharmacodynamic and pharmacokinetic studies. Full article
(This article belongs to the Special Issue Biologically Active Small Molecules Inspired by Plant Secondary Metabolites)
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24 pages, 15461 KiB  
Review
Role of Phenylpropanoids and Flavonoids in Plant Resistance to Pests and Diseases
by Marie-Louisa Ramaroson, Claude Koutouan, Jean-Jacques Helesbeux, Valérie Le Clerc, Latifa Hamama, Emmanuel Geoffriau and Mathilde Briard
Molecules 2022, 27(23), 8371; https://doi.org/10.3390/molecules27238371 - 30 Nov 2022
Cited by 38 | Viewed by 4323
Abstract
Phenylpropanoids and flavonoids are specialized metabolites frequently reported as involved in plant defense to biotic or abiotic stresses. Their biosynthetic accumulation may be constitutive and/or induced in response to external stimuli. They may participate in plant signaling driving plant defense responses, act as [...] Read more.
Phenylpropanoids and flavonoids are specialized metabolites frequently reported as involved in plant defense to biotic or abiotic stresses. Their biosynthetic accumulation may be constitutive and/or induced in response to external stimuli. They may participate in plant signaling driving plant defense responses, act as a physical or chemical barrier to prevent invasion, or as a direct toxic weapon against microbial or insect targets. Their protective action is described as the combinatory effect of their localization during the host’s interaction with aggressors, their sustained availability, and the predominance of specific compounds or synergy with others. Their biosynthesis and regulation are partly deciphered; however, a lot of gaps in knowledge remain to be filled. Their mode of action on microorganisms and insects probably arises from an interference with important cellular machineries and structures, yet this is not fully understood for all type of pests and pathogens. We present here an overview of advances in the state of the art for both phenylpropanoids and flavonoids with the objective of paving the way for plant breeders looking for natural sources of resistance to improve plant varieties. Examples are provided for all types of microorganisms and insects that are targeted in crop protection. For this purpose, fields of phytopathology, phytochemistry, and human health were explored. Full article
(This article belongs to the Special Issue Biologically Active Small Molecules Inspired by Plant Secondary Metabolites)
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Other

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4 pages, 361 KiB  
Commentary
COVID-19, Chloroquine Repurposing, and Cardiac Safety Concern: Chirality Might Help
by Giovanni Lentini, Maria Maddalena Cavalluzzi and Solomon Habtemariam
Molecules 2020, 25(8), 1834; https://doi.org/10.3390/molecules25081834 - 16 Apr 2020
Cited by 41 | Viewed by 8340
Abstract
The desperate need to find drugs for COVID-19 has indicated repurposing strategies as our quickest way to obtain efficacious medicines. One of the options under investigation is the old antimalarial drug, chloroquine, and its analog, hydroxychloroquine. Developed as synthetic succedanea of cinchona alkaloids, [...] Read more.
The desperate need to find drugs for COVID-19 has indicated repurposing strategies as our quickest way to obtain efficacious medicines. One of the options under investigation is the old antimalarial drug, chloroquine, and its analog, hydroxychloroquine. Developed as synthetic succedanea of cinchona alkaloids, these chiral antimalarials are currently in use as the racemate. Besides the ethical concern related to accelerated large-scale clinical trials of drugs with unproven efficacy, the known potential detrimental cardiac effects of these drugs should also be considered. In principle, the safety profile might be ameliorated by using chloroquine/hydroxychloroquine single enantiomers in place of the racemate. Full article
(This article belongs to the Special Issue Biologically Active Small Molecules Inspired by Plant Secondary Metabolites)
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