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Naturally Inspired Molecules as Inhibitors in Drug Discovery

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

Deadline for manuscript submissions: 30 September 2024 | Viewed by 9534

Special Issue Editors

Department of Pharmacy and Biotechnology, Alma Mater Studiorum—University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy
Interests: flavonoids; drug design; hybrid molecules; MDR reversal; neurodegeneration
Special Issues, Collections and Topics in MDPI journals
Department of Pharmacy and Biotechnology, Alma Mater Studiorum—University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy
Interests: medicinal chemistry; natural products; curcumin; drug design; multitarget drug discovery; bioactive compounds; neurodegeneration; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Natural products (NPs) have long been regarded as precious sources of inspiration for drug design efforts. Due to their structural diversity and the broad range of valuable molecular scaffolds, they offered favored ligand-protein binding motifs. NPs have been structurally “optimized” by evolution to acquire the ability to elicit well-defined biological functions, including the modulation of different cellular pathways and the interaction with selected targets. They are also proposed as “privileged structures” to be exploited as a chemical platform for the design of analogs. Several research efforts have concentrated on developing NPs-inspired synthetic or semi-synthetic libraries of analogs to enhance their biological profile, perform structure–activity relationship (SAR) studies, and understand the molecular mechanism of action.

Besides, the synthetic methodology has significantly developed during the last century, allowing medicinal chemists to obtain naturally inspired biomimetic cores to regulate particular biological systems. This Special Issue aims to provide a broad picture of the most recent development in the field of new synthetic bioactive molecules related to NPs, with particular focus on compounds acting as inhibitors or modulators of specific enzymes/signaling pathways. Original articles, as well as reviews regarding studies on naturally inspired compounds, are welcome.

Dr. Alessandra Bisi
Dr. Federica Belluti
Guest Editors

Manuscript Submission Information

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Keywords

  • natural products
  • drug design
  • privileged structures
  • enzyme inhibition
  • bioactive compounds
  • bioinspired compounds
  • structure–activity relationship (SAR)
  • biological activity
  • organic synthesis

Published Papers (8 papers)

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Research

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22 pages, 2250 KiB  
Article
Phytochemical Profile and In Vitro Bioactivities of Wild Asparagus stipularis
by Amel Hamdi, Sara Jaramillo-Carmona, Rocío Rodríguez-Arcos, Ana Jiménez-Araujo, Najoua Karray Bouraoui and Rafael Guillén-Bejarano
Molecules 2024, 29(4), 817; https://doi.org/10.3390/molecules29040817 - 10 Feb 2024
Viewed by 568
Abstract
In this study, Asparagus stipularis was characterized concerning its phytochemical composition, antioxidant potential, cytotoxicity, and pancreatic lipase inhibitory activities. Twenty-seven compounds were identified and quantified by HPLC-DAD-MS in the leaf, stem, pericarp, and rhizome of ethanolic extracts. Seven steroidal saponins were detected, and [...] Read more.
In this study, Asparagus stipularis was characterized concerning its phytochemical composition, antioxidant potential, cytotoxicity, and pancreatic lipase inhibitory activities. Twenty-seven compounds were identified and quantified by HPLC-DAD-MS in the leaf, stem, pericarp, and rhizome of ethanolic extracts. Seven steroidal saponins were detected, and the highest content was quantified in rhizome and pericap. A. stipularis also contained significant amounts of flavonoids in the aerial part. Isorhamnetin tetra-glycoside, quercetin-3-glucosyl-rutinoside, and rutin were the main flavonoid derivatives in leaf, stem, and pericarp extracts, respectively. In addition, eleven phenolic acids were also detected; among them, caffeic acid, protocatechuic acid, p-hydroxybenzoic acid, and ferulic acid were the predominant phenolics, with these having the highest amounts quantified in the rhizome extracts. All the tested extracts possessed antioxidant capacities, with pericarp and rhizome extracts exhibiting the highest activity in DPPH, ABTS, and FRAP assays. The extracts from pericarp and rhizome were revealed to also be the strongest inhibitors of pancreatic lipase. The rhizome extracts exhibited potent cytotoxic activity against HCT-116 and HepG2 with IC50 values of 30 and 54 µg/mL after 48 h of treatment. The present study demonstrated that A. stipularis can be used as a new source of natural antioxidants and potential anticancer and antiobesity compounds. Full article
(This article belongs to the Special Issue Naturally Inspired Molecules as Inhibitors in Drug Discovery)
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13 pages, 1838 KiB  
Article
Effect of Hydroxytyrosol Derivatives of Donepezil on the Activity of Enzymes Involved in Neurodegenerative Diseases and Oxidative Damage
by Antonio D’Errico, Rosarita Nasso, Rosario Rullo, Jessica Maiuolo, Paola Costanzo, Sonia Bonacci, Manuela Oliverio, Emmanuele De Vendittis, Mariorosario Masullo and Rosaria Arcone
Molecules 2024, 29(2), 548; https://doi.org/10.3390/molecules29020548 - 22 Jan 2024
Viewed by 657
Abstract
Monoamine oxidase and xanthine oxidase inhibitors represent useful multi-target drugs for the prevention, attenuation, and treatment of oxidative damage and neurodegenerative disorders. Chimeric molecules, constituted by naturally derived compounds linked to drugs, represent lead compounds to be explored for the discovery of new [...] Read more.
Monoamine oxidase and xanthine oxidase inhibitors represent useful multi-target drugs for the prevention, attenuation, and treatment of oxidative damage and neurodegenerative disorders. Chimeric molecules, constituted by naturally derived compounds linked to drugs, represent lead compounds to be explored for the discovery of new synthetic drugs acting as enzyme inhibitors. We have previously reported that seven hydroxytyrosol-donepezil hybrid compounds play a protective role in an in vitro neuronal cell model of Alzheimer’s disease. In this work, we analyzed the effects exerted by the hybrid compounds on the activity of monoamine oxidase A (MAO-A) and B (MAO-B), as well as on xanthine oxidase (XO), enzymes involved in both neurodegenerative disorders and oxidative stress. The results pointed to the identification, among the compounds tested, of selective inhibitors between the two classes of enzymes. While the 4-hydroxy-3-methoxyphenethyl 1-benzylpiperidine-4-carboxylate- (HT3) and the 4-hydroxyphenethyl 1-benzylpiperidine-4-carboxylate- donepezil derivatives (HT4) represented the best inhibitors of MAO-A, with a scarce effect on MAO-B, they were almost ineffective on XO. On the other hand, the 4,5-dihydroxy-2-nitrophenethyl 1-benzylpiperidine-4-carboxylate donepezil derivative (HT2), the least efficient MAO inhibitor, acted like the best XO inhibitor. Therefore, the differential enzymatic targets identified among the hybrid compounds synthesized enhance the possible applications of these polyphenol-donepezil hybrids in neurodegenerative disorders and oxidative stress. Full article
(This article belongs to the Special Issue Naturally Inspired Molecules as Inhibitors in Drug Discovery)
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19 pages, 2307 KiB  
Article
Naturally Inspired Molecules for Neuropathic Pain Inhibition—Effect of Mirogabalin and Cebranopadol on Mechanical and Thermal Nociceptive Threshold in Mice
by Kinga Sałat, Paula Zaręba, Michał Awtoniuk and Robert Sałat
Molecules 2023, 28(23), 7862; https://doi.org/10.3390/molecules28237862 - 30 Nov 2023
Cited by 1 | Viewed by 738
Abstract
Background: Neuropathic pain is drug-resistant to available analgesics and therefore novel treatment options for this debilitating clinical condition are urgently needed. Recently, two drug candidates, namely mirogabalin and cebranopadol have become a subject of interest because of their potential utility as analgesics for [...] Read more.
Background: Neuropathic pain is drug-resistant to available analgesics and therefore novel treatment options for this debilitating clinical condition are urgently needed. Recently, two drug candidates, namely mirogabalin and cebranopadol have become a subject of interest because of their potential utility as analgesics for chronic pain treatment. However, they have not been investigated thoroughly in some types of neuropathic pain, both in humans and experimental animals. Methods: This study used the von Frey test, the hot plate test and the two-plate thermal place preference test supported by image analysis and machine learning to assess the effect of intraperitoneal mirogabalin and subcutaneous cebranopadol on mechanical and thermal nociceptive threshold in mouse models of neuropathic pain induced by streptozotocin, paclitaxel and oxaliplatin. Results: Mirogabalin and cebranopadol effectively attenuated tactile allodynia in models of neuropathic pain induced by streptozotocin and paclitaxel. Cebranopadol was more effective than mirogabalin in this respect. Both drugs also elevated the heat nociceptive threshold in mice. In the oxaliplatin model, cebranopadol and mirogabalin reduced cold-exacerbated pain. Conclusions: Since mirogabalin and cebranopadol are effective in animal models of neuropathic pain, they seem to be promising novel therapies for various types of neuropathic pain in patients, in particular those who are resistant to available analgesics. Full article
(This article belongs to the Special Issue Naturally Inspired Molecules as Inhibitors in Drug Discovery)
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12 pages, 1486 KiB  
Article
Enhancement of Inhibitory Activity by Combining Allosteric Inhibitors Putatively Binding to Different Allosteric Sites on Cathepsin K
by Shun Sato, Kana Yamamoto, Moeno Ito, Katsutoshi Nishino, Takanao Otsuka, Kazuhiro Irie and Masaya Nagao
Molecules 2023, 28(10), 4197; https://doi.org/10.3390/molecules28104197 - 19 May 2023
Viewed by 1129
Abstract
Background: Cathepsin K, which is involved in bone resorption, is a good target for treating osteoporosis, but no clinically approved medicine has been developed. Recently, allosteric inhibitors with high specificity and few side effects have been attracting attention for use in new medicines. [...] Read more.
Background: Cathepsin K, which is involved in bone resorption, is a good target for treating osteoporosis, but no clinically approved medicine has been developed. Recently, allosteric inhibitors with high specificity and few side effects have been attracting attention for use in new medicines. Methods: Cathepsin K inhibitors were isolated from the methanol extract of Chamaecrista nomame (Leguminosae) using cathepsin K inhibition activity-assisted multi-step chromatography. Standard kinetic analysis was employed to examine the mechanism of cathepsin K inhibition when an isolated inhibitor and its derivative were used. The allosteric binding of these cathepsin K inhibitors was supported by a docking study using AutoDock vina. Combinations of allosteric cathepsin K inhibitors expected to bind to different allosteric sites were examined by means of cathepsin K inhibition assay. Results: Two types of cathepsin K inhibitors were identified in the methanol extract of Chamaecrista nomame. One type consisted of cassiaoccidentalin B and torachrysone 8-β-gentiobioside, and inhibited both cathepsin K and B with similar inhibitory potential, while the other type of inhibitor consisted of pheophytin a, and inhibited cathepsin K but not cathepsin B, suggesting that pheophytin a binds to an allosteric site of cathepsin K. Kinetic analysis of inhibitory activity suggested that pheophytin a and its derivative, pheophorbide b, bind allosterically to cathepsin K. This possibility was supported by a docking study on cathepsin K. The cathepsin K inhibitory activity of pheophytin a and pheophorbide b was enhanced by combining them with the allosteric inhibitors NSC 13345 and NSC94914, which bind to other allosteric sites on cathepsin K. Conclusions: Different allosteric inhibitors that bind to different sites in combination, as shown in this study, may be useful for designing new allosteric inhibitory drugs with high specificity and few side effects. Full article
(This article belongs to the Special Issue Naturally Inspired Molecules as Inhibitors in Drug Discovery)
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11 pages, 1405 KiB  
Article
Isolation and LC-QToF Characterization of Secondary Metabolites from an Endemic Plant Artemisia heptapotamica Poljak
by Umit Mukatay, Mamdouh Nabil Samy, Bharathi Avula, Kumar Katragunta, Moldir Kemelbek, Azhar Zhubanova, Ikhlas A. Khan and Samir Anis Ross
Molecules 2023, 28(7), 2908; https://doi.org/10.3390/molecules28072908 - 23 Mar 2023
Cited by 1 | Viewed by 1262
Abstract
Phytochemical investigation of the aerial parts of Artemisia heptapotamica Poljak led to the isolation of ten known compounds, including four alkyl p-coumarates: octadecyl trans-p-coumarate (1), icosy trans-p-coumarate (2), docosyl trans-p [...] Read more.
Phytochemical investigation of the aerial parts of Artemisia heptapotamica Poljak led to the isolation of ten known compounds, including four alkyl p-coumarates: octadecyl trans-p-coumarate (1), icosy trans-p-coumarate (2), docosyl trans-p-coumarate (3), and tetracosyl trans-p-coumarate (4), one sesquiterpene lactone: santonin (5), four flavonoids; axillarin (6), quercetin 3-O-methyl ether (7), luteolin (8), and quercetin (9), and one phenolic acid derivative: p-coumaric acid (10). The structures of the isolated compounds were identified by various spectroscopic analyses. Additionally, the antimicrobial activity of the total extract and different fractions was screened, and they exhibited no inhibition of the growth of Candida albicans, C. neoformans, Aspergillus fumigatus, methicillin-resistant Staphylococcus aureus (MRS), E. coli, Pseudomonas aeruginosa, Klebsiella pneumonia, and Vancomycin-resistant Enterococci (VRE) at the tested concentrations ranging from 8 to 200 μg/mL. The identification and tentative characterization of the secondary metabolites were conducted using LC-QToF analysis. This method helps in the putative characterization of sesquiterpene lactones, flavonoids, coumarate derivatives, and aliphatic compounds. The developed method identified 43 compounds, of which the majority were sesquiterpene lactones, such as eudesmanolides, germacranolides, and guaianolide derivatives, followed by flavonoids. The proposed LC-QToF method helps develop dereplication strategies and understand the major class of chemicals before proceeding with the isolation of compounds. Full article
(This article belongs to the Special Issue Naturally Inspired Molecules as Inhibitors in Drug Discovery)
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13 pages, 8647 KiB  
Article
Alkaloid Profile in Wild Autumn-Flowering Daffodils and Their Acetylcholinesterase Inhibitory Activity
by Julia Lisa-Molina, Pedro Gómez-Murillo, Irene Arellano-Martín, Carles Jiménez, María L. Rodríguez-Escobar, Luciana R. Tallini, Francesc Viladomat, Laura Torras-Claveria and Jaume Bastida
Molecules 2023, 28(3), 1239; https://doi.org/10.3390/molecules28031239 - 27 Jan 2023
Cited by 2 | Viewed by 1370
Abstract
Amaryllidaceae alkaloids are secondary metabolites with interesting medicinal properties. Almost every Narcissus species can synthesize them and constitute an excellent source for their isolation and study. Several Amaryllidaceae alkaloids have shown acetylcholinesterase inhibitory activities and are a promising tool for treating cholinergic disorders [...] Read more.
Amaryllidaceae alkaloids are secondary metabolites with interesting medicinal properties. Almost every Narcissus species can synthesize them and constitute an excellent source for their isolation and study. Several Amaryllidaceae alkaloids have shown acetylcholinesterase inhibitory activities and are a promising tool for treating cholinergic disorders such as Alzheimer’s disease (AD). Indeed, three of the four palliative treatments approved for AD are acetylcholinesterase (AChE) inhibitors and one of them, galanthamine, is an Amaryllidaceae alkaloid itself. This molecule is currently isolated from natural sources. However, its production is insufficient to supply the increasing demand for the active principle. Our main aim is to discover tools to improve galanthamine production and to prospect for potential new and more efficient drugs for AD treatment. Furthermore, we seek to broaden the knowledge of plants of the genus Narcissus from a chemotaxonomic perspective. Hence, in this study, we evaluate the alkaloid content through GC–MS and the AChE inhibitory activity of ten autumn-flowering Narcissus, which have been less studied than their spring-flowering counterparts. A total of thirty Amaryllidaceae alkaloids have been found, twenty-eight properly identified. Two Narcissus contained galanthamine, and seven were able to inhibit AChE. Full article
(This article belongs to the Special Issue Naturally Inspired Molecules as Inhibitors in Drug Discovery)
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19 pages, 2759 KiB  
Article
Synthesis and Antioxidative Properties of 1,2,3,4-Tetrahydropyridine Derivatives with Different Substituents in 4-Position
by Daniele Aiello, Hendrik Jonas, Anna Carbone, Daniela Carbone, Camilla Pecoraro, Luisa Tesoriere, Jens Köhler, Bernhard Wünsch and Patrizia Diana
Molecules 2022, 27(21), 7423; https://doi.org/10.3390/molecules27217423 - 01 Nov 2022
Viewed by 1376
Abstract
Natural products are an excellent source of inspiration for the development of new drugs. Among them, betalains have been extensively studied for their antioxidant properties and potential application as natural food dyes. Herein, we describe the seven-step synthesis of new betalamic acid analogs [...] Read more.
Natural products are an excellent source of inspiration for the development of new drugs. Among them, betalains have been extensively studied for their antioxidant properties and potential application as natural food dyes. Herein, we describe the seven-step synthesis of new betalamic acid analogs without carboxy groups in the 2- and 6-position with an overall yield of ~70%. The Folin–Ciocalteu assay was used to determine the antioxidant properties of protected intermediate 21. Additionally, the five-step synthesis of betalamic acid analog 35 with three ester moieties was performed. Using NMR techniques, the stability of the obtained compounds towards oxygen was analyzed. Full article
(This article belongs to the Special Issue Naturally Inspired Molecules as Inhibitors in Drug Discovery)
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Review

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25 pages, 5726 KiB  
Review
An Overview of Cannabidiol as a Multifunctional Drug: Pharmacokinetics and Cellular Effects
by Nadia Martinez Naya, Jazmin Kelly, Giuliana Corna, Michele Golino, Ariel H. Polizio, Antonio Abbate, Stefano Toldo and Eleonora Mezzaroma
Molecules 2024, 29(2), 473; https://doi.org/10.3390/molecules29020473 - 18 Jan 2024
Cited by 1 | Viewed by 1725
Abstract
Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis Sativa, has garnered increasing attention for its diverse therapeutic potential. This comprehensive review delves into the complex pharmacokinetics of CBD, including factors such as bioavailability, distribution, safety profile, and dosage recommendations, which contribute to the [...] Read more.
Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis Sativa, has garnered increasing attention for its diverse therapeutic potential. This comprehensive review delves into the complex pharmacokinetics of CBD, including factors such as bioavailability, distribution, safety profile, and dosage recommendations, which contribute to the compound’s pharmacological profile. CBD’s role as a pharmacological inhibitor is explored, encompassing interactions with the endocannabinoid system and ion channels. The compound’s anti-inflammatory effects, influencing the Interferon-beta and NF-κB, position it as a versatile candidate for immune system regulation and interventions in inflammatory processes. The historical context of Cannabis Sativa’s use for recreational and medicinal purposes adds depth to the discussion, emphasizing CBD’s emergence as a pivotal phytocannabinoid. As research continues, CBD’s integration into clinical practice holds promise for revolutionizing treatment approaches and enhancing patient outcomes. The evolution in CBD research encourages ongoing exploration, offering the prospect of unlocking new therapeutic utility. Full article
(This article belongs to the Special Issue Naturally Inspired Molecules as Inhibitors in Drug Discovery)
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