Identification of Phytochemicals and Derivatives against Infectious Diseases

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 23666

Special Issue Editors

1. Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), CESPU, Rua Central de Gandra, 1317, 4585-116 Gandra PRD, Portugal
2. LAQV-REQUIMTE, Department of Chemistry Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
Interests: organic chemistry; analytical chemistry; mass spectrometry; heterocyclic compounds
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Special Issue Information

Dear Colleagues,

Infectious diseases are a global health concern, as clearly shown by the 2019 WHO-compiled list of the top 10 health threats, of which 6 are infectious disease-related. The emergence and increase of multidrug resistance and infectious disease outbreaks (such as the coronavirus, influenza, or Ebola viruses) are the cause of significant morbidity and mortality rising worldwide for these diseases. Moreover, there is a lack of development of new candidates to tackle the huge demand related to controlling these epidemics. This demand has triggered, in recent years, a renewed interest in medicinal plants and natural products as a source of novel pharmacologically active compounds for drug discovery.

The recognition of flora biological activity importance is ancient, and the use of plants in folk medicine and its ethnomedical applications around the globe is, to date, rather significant. Plants are true manufacturing units for the production of important pharmaceuticals. The chemical diversity that can be discovered from plant-derived natural products along with the recognition of new therapeutic targets by the increasing number of genomics studies can lead to the development of new medicinal drugs able to hold the emerging era of antibiotic resistance.

This Special Issue, “Identification of Phytochemicals and Derivatives against Infectious Diseases”, invites authors to contribute with review or original research articles dedicated to the most recent advances on the discovery of plant-based bioactive compounds with anti-infectious disease properties. The contributions include the discovery of new compounds and their structural elucidation, as well as the in vitro and in vivo assessment of the biological properties against infectious diseases, namely, antibacterial, antiviral, antiparasitic, and antifungal. Studies concerning the elucidation of mechanisms of action of new phytochemicals and structural–activity studies directing toward the synthesis of more bioactive derivatives are also welcomed.

Prof. Dr. Eduarda M. P. Silva
Prof. Dr. Diana Cláudia Pinto
Guest Editors

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Keywords

  • Infectious disease
  • Natural products
  • Phytochemical
  • Biologically active

Published Papers (7 papers)

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Research

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12 pages, 1769 KiB  
Article
Extraction and Fractionation of Bioactives from Dipsacus fullonum L. Leaves and Evaluation of Their Anti-Borrelia Activity
Pharmaceuticals 2022, 15(1), 87; https://doi.org/10.3390/ph15010087 - 12 Jan 2022
Cited by 4 | Viewed by 4488
Abstract
Lyme disease (LD) is a tick-borne bacterial disease that is caused by Borrelia burgdorferi. Although acute LD is treated with antibiotics, it can develop into relapsing chronic form caused by latent forms of B. burgdorferi. This leads to the search for [...] Read more.
Lyme disease (LD) is a tick-borne bacterial disease that is caused by Borrelia burgdorferi. Although acute LD is treated with antibiotics, it can develop into relapsing chronic form caused by latent forms of B. burgdorferi. This leads to the search for phytochemicals against resistant LD. Therefore, this study aimed to evaluate the activity of Dipsacus fullonum L. leaves extract (DE) and its fractions against stationary phase B. burgdorferi in vitro. DE showed high activity against stationary phase B. burgdorferi (residual viability 19.8 ± 4.7%); however, it exhibited a noticeable cytotoxicity on NIH cells (viability 20.2 ± 5.2%). The iridoid-glycoside fraction showed a remarkable anti-Borrelia effect and reduced cytotoxicity. The iridoid-glycoside fraction was, therefore, further purified and showed to contain two main bioactives—sylvestrosides III and IV, that showed a considerable anti-Borrelia activity being the least toxic to murine fibroblast NIH/3T3 cells. Moreover, the concentration of sylvestrosides was about 15% of DE, endorsing the feasibility of purification of the compounds from D. fullonum L. leaves. Full article
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18 pages, 4138 KiB  
Article
Triphala in Traditional Ayurvedic Medicine Inhibits Dengue Virus Infection in Huh7 Hepatoma Cells
Pharmaceuticals 2021, 14(12), 1236; https://doi.org/10.3390/ph14121236 - 28 Nov 2021
Cited by 4 | Viewed by 2272
Abstract
Traditional Triphala (three fruits), consisting of Phyllanthus emblica, Terminalia chebula, and Terminalia bellirica, presents a broad range of biological activities. However, its ability to inhibit dengue virus (DENV) infection has not been reported yet. Herein, the authors investigated the efficiency of three different [...] Read more.
Traditional Triphala (three fruits), consisting of Phyllanthus emblica, Terminalia chebula, and Terminalia bellirica, presents a broad range of biological activities. However, its ability to inhibit dengue virus (DENV) infection has not been reported yet. Herein, the authors investigated the efficiency of three different Triphala formulations and its individual extract constituents to inhibit DENV infection. Treatment with T. bellirica extract or Triphala formulated with a high ratio of T. bellirica extract showed remarkable efficiency in significantly lowering DENV infection in Vero cells. Their effects were further studied in Huh7 cells, to address its potential ability in human cells. Treatment with 100 μg/mL of T. bellirica extract or Triphala resulted in an approximate 3000-fold or 1000-fold lowering of virus production, respectively. Furthermore, the treatment diminished IL-6 and CXCL-10 expressions, which are the hallmark of the cytokine storm phenomenon in DENV infection. The HPLC profiling demonstrated gallic acid as a major compound, the treatment by which showed its ability to effectively inhibit DENV infection after virus entry. Molecular docking demonstrated that gallic acid was able to interact with DENV NS5 protein, which could be one of Triphala’s antiviral mechanism. This study offers Triphala formulation and its ingredient, T. bellirica extract, as a natural based pharmaceutical to be used in DENV infection treatment. Full article
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14 pages, 3109 KiB  
Article
Investigation of the Antibacterial Activity and Efflux Pump Inhibitory Effect of Cycas thouarsii R.Br. Extract against Klebsiella pneumoniae Clinical Isolates
Pharmaceuticals 2021, 14(8), 756; https://doi.org/10.3390/ph14080756 - 01 Aug 2021
Cited by 26 | Viewed by 2349
Abstract
The vast spread of multidrug-resistant bacteria has encouraged researchers to explore new antimicrobial compounds. This study aimed to investigate the phytochemistry and antibacterial activity of Cycas thouarsii R.Br. leaves extract against Klebsiella pneumoniae clinical isolates. The minimum inhibitory concentration (MIC) values of C. [...] Read more.
The vast spread of multidrug-resistant bacteria has encouraged researchers to explore new antimicrobial compounds. This study aimed to investigate the phytochemistry and antibacterial activity of Cycas thouarsii R.Br. leaves extract against Klebsiella pneumoniae clinical isolates. The minimum inhibitory concentration (MIC) values of C. thouarsii extract ranged from 4 to 32 µg/mL. The impact of the treatment of the isolates with sub-inhibitory concentrations of C. thouarsii extract was investigated on the bacterial growth, membrane integrity, inner and outer membrane permeability, membrane depolarization, and bacterial morphology using a scanning electron microscope (SEM) and on the efflux activity using qRT-PCR. Interestingly, most K. pneumoniae isolates treated with C. thouarsii extract showed growth inhibition—a decrease in membrane integrity. In addition, we observed various morphological changes, a significant increase in inner and outer membrane permeability, a non-significant change in membrane depolarization, and a decrease in efflux activity after treatment. The phytochemical investigation of C. thouarsii extract revealed the isolation of one new biflavonoid, 5,7,7″,4‴-tetra-O-methyl-hinokiflavone (3), and five known compounds, stigmasterol (1), naringenin (2), 2,3-dihydrobilobetin (4), 4′,4‴-O-dimethyl amentoflavone (5), and hinokiflavone (6), for the first time. Moreover, the pure compounds′ MICs′ ranged from 0.25 to 2 µg/mL. Thus, C. thouarsii could be a potential source for new antimicrobials. Full article
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11 pages, 304 KiB  
Article
In Vitro Culture of Rosmarinus officinalis L. in a Temporary Immersion System: Influence of Two Phytohormones on Plant Growth and Carnosol Production
Pharmaceuticals 2021, 14(8), 747; https://doi.org/10.3390/ph14080747 - 29 Jul 2021
Cited by 8 | Viewed by 2439
Abstract
Emerging infectious diseases have become a major global problem with public health and economic consequences. It is an urgent need to develop new anti-infective therapies. The natural diterpene carnosol exhibit a wide variety of interesting antibacterial and antiviral properties, and it is considered [...] Read more.
Emerging infectious diseases have become a major global problem with public health and economic consequences. It is an urgent need to develop new anti-infective therapies. The natural diterpene carnosol exhibit a wide variety of interesting antibacterial and antiviral properties, and it is considered a theoretical inhibitor of COVID-19 Mpro. However, this compound is present in the family Lamiaceae in low quantities. To obtain carnosol in concentrations high enough to develop pharmacological studies, we evaluated the efficiency of a micropropagation protocol of Rosmarinus officinalis using a solid medium and a temporary immersion system (TIS), as well as the effect of 6-benzylaminopurine (6-BAP) and α-naphthaleneacetic acid (NAA) on the growth of shoots. Moreover, we developed and validated an analytical method to quantify carnosol using the H-point standard additions method in the high-performance liquid chromatography diode array detector (HPLC-DAD). After 30 days of culture, TIS produced the maximum number of shoots per explant (24.33 ± 1.15) on a liquid medium supplemented with 6-BAP at 5.0 mg L−1. Next, we also evaluated the effect of immersion time and frequency for TIS. After 72 days of culture, the best results were obtained with an immersion cycle of 1 min every 12 h, yielding 170.33 ± 29.40 shoots. The quantification of carnosol on the samples was performed at a flow rate of 1.2 mL min−1 using binary isocratic mobile phase system 60:40 (v/v) 10 mM formic acid (pH 3.0) (A) and acetonitrile (B) on a reverse-phase column. The content of carnosol in the in vitro cultures was around 8-fold higher than in the wild plant. The present study represents an efficient alternative method to obtain carnosol for its pre-clinical and clinical development. Full article
30 pages, 6562 KiB  
Article
Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors
Pharmaceuticals 2021, 14(6), 572; https://doi.org/10.3390/ph14060572 - 15 Jun 2021
Cited by 12 | Viewed by 3644
Abstract
The overexpression of efflux pumps is one of the causes of multidrug resistance, which leads to the inefficacy of drugs. This plays a pivotal role in antimicrobial resistance, and the most notable pumps are the AcrAB-TolC system (AcrB belongs to the resistance-nodulation-division family) [...] Read more.
The overexpression of efflux pumps is one of the causes of multidrug resistance, which leads to the inefficacy of drugs. This plays a pivotal role in antimicrobial resistance, and the most notable pumps are the AcrAB-TolC system (AcrB belongs to the resistance-nodulation-division family) and the NorA, from the major facilitator superfamily. In bacteria, these structures can also favor virulence and adaptation mechanisms, such as quorum-sensing and the formation of biofilm. In this study, the design and synthesis of a library of thioxanthones as potential efflux pump inhibitors are described. The thioxanthone derivatives were investigated for their antibacterial activity and inhibition of efflux pumps, biofilm formation, and quorum-sensing. The compounds were also studied for their potential to interact with P-glycoprotein (P-gp, ABCB1), an efflux pump present in mammalian cells, and for their cytotoxicity in both mouse fibroblasts and human Caco-2 cells. The results concerning the real-time ethidium bromide accumulation may suggest a potential bacterial efflux pump inhibition, which has not yet been reported for thioxanthones. Moreover, in vitro studies in human cells demonstrated a lack of cytotoxicity for concentrations up to 20 µM in Caco-2 cells, with some derivatives also showing potential for P-gp modulation. Full article
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18 pages, 10479 KiB  
Article
Repurposing of Some Natural Product Isolates as SARS-COV-2 Main Protease Inhibitors via In Vitro Cell Free and Cell-Based Antiviral Assessments and Molecular Modeling Approaches
Pharmaceuticals 2021, 14(3), 213; https://doi.org/10.3390/ph14030213 - 04 Mar 2021
Cited by 44 | Viewed by 4156
Abstract
The emergence of the SARS-CoV-2 pandemic has prompted scientists to search for an efficient antiviral medicine to overcome the rapid spread and the marked increase in the number of patients worldwide. In this regard natural products could be a potential source of substances [...] Read more.
The emergence of the SARS-CoV-2 pandemic has prompted scientists to search for an efficient antiviral medicine to overcome the rapid spread and the marked increase in the number of patients worldwide. In this regard natural products could be a potential source of substances active against coronavirus infections. A systematic computer-aided virtual screening approach was carried out using commercially available natural products found on the Zinc Database in addition to an in-house compound library to identify potential natural product inhibitors of SARS-CoV-2 main protease (MPRO). The top eighteen hits from the screening were selected for in vitro evaluation on the viral protease (SARS-CoV-2 MPRO). Five compounds (naringenin, 2,3′,4,5′,6-pentahydroxybenzophenone, apigenin-7-O-glucoside, sennoside B, and acetoside) displayed high activity against the viral protein. Acteoside showed similar activity to the positive control GC376. The most potent compounds were tested in vitro on SARS-CoV-2 Egyptian strain where only naringenin showed moderate anti-SARS-CoV-2 activity at non-cytotoxic micromolar concentrations in vitro with a significant selectivity index (CC50/IC50 = 178.748/28.347 = 6.3). Moreover; a common feature pharmacophore model was generated to explain the requirements for enzyme inhibition by this diverse group of active ligands. These results pave a path for future repurposing and development of natural products to aid in the battle against COVID-19. Full article
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Review

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22 pages, 12302 KiB  
Review
Evolution of Acridines and Xanthenes as a Core Structure for the Development of Antileishmanial Agents
Pharmaceuticals 2022, 15(2), 148; https://doi.org/10.3390/ph15020148 - 26 Jan 2022
Cited by 12 | Viewed by 2478
Abstract
Nowadays, leishmaniasis constitutes a public health issue in more than 88 countries, affecting mainly people from the tropics, subtropics, and the Mediterranean area. Every year, the prevalence of this infectious disease increases, with the appearance of 1.5–2 million new cases of cutaneous leishmaniasis [...] Read more.
Nowadays, leishmaniasis constitutes a public health issue in more than 88 countries, affecting mainly people from the tropics, subtropics, and the Mediterranean area. Every year, the prevalence of this infectious disease increases, with the appearance of 1.5–2 million new cases of cutaneous leishmaniasis and 500,000 cases of visceral leishmaniasis, endangering approximately 350 million people worldwide. Therefore, the absence of a vaccine or effective treatment makes the discovery and development of new antileishmanial therapies one of the focuses for the scientific community that, in association with WHO, hopes to eradicate this disease shortly. This paper is intended to highlight the relevance of nitrogen- and oxygen-containing tricyclic heterocycles, particularly acridine and xanthene derivatives, for the development of treatments against leishmaniasis. Thus, in this review, a thorough compilation of the most promising antileishmanial acridine and xanthene derivatives is performed from both natural and synthetic origins. Additionally, some structure–activity relationship studies are also depicted and discussed to provide insight into the optimal structural features responsible for these compounds’ antileishmanial activity. Full article
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