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Microbiology Spectrum Apr 2022Due to the emergence of multidrug-resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at...
Antifungal Activity of Fibrate-Based Compounds and Substituted Pyrroles That Inhibit the Enzyme 3-Hydroxy-methyl-glutaryl-CoA Reductase of (CgHMGR), Thus Decreasing Yeast Viability and Ergosterol Synthesis.
Due to the emergence of multidrug-resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at alternative molecular targets. The aim of the current study was to evaluate the capacity of three different series of synthetic compounds to inhibit the Candida glabrata enzyme denominated 3-hydroxy-methyl-glutaryl-CoA reductase and thus affect ergosterol synthesis and yeast viability. Compounds 1c (α-asarone-related) and 5b (with a pyrrolic core) were selected as the best antifungal candidates among over 20 synthetic compounds studied. Both inhibited the growth of fluconazole-resistant and fluconazole-susceptible C. glabrata strains. A yeast growth rescue experiment based on the addition of exogenous ergosterol showed that the compounds act by inhibiting the mevalonate synthesis pathway. A greater recovery of yeast growth occurred for the C. glabrata 43 fluconazole-resistant (versus fluconazole-susceptible) strain and after treatment with 1c (versus 5b). Given that the compounds decreased the concentration of ergosterol in the yeast strains, they probably target ergosterol synthesis. According to the docking analysis, the inhibitory effect of 1c and 5b could possibly be mediated by their interaction with the amino acid residues of the catalytic site of the enzyme. Since 1c displayed higher binding energy than α-asarone and 5b, it is the best candidate for further research, which should include structural modifications to increase its specificity and potency. The derivatives could then be examined with animal models using a therapeutic dose. Within the context of the COVID-19 pandemic, there is currently an epidemiological alert in health care services due to outbreaks of Candida auris, Candida glabrata, and other fungal species multiresistant to conventional antifungals. Therefore, it is important to propose alternative molecular targets, as well as new antifungals. The three series of synthetic compounds herein designed and synthesized are inhibitors of ergosterol synthesis in yeasts. Of the more than 20 compounds studied, two were selected as the best antifungal candidates. These compounds were able to inhibit the growth and synthesis of ergosterol in C. glabrata strains, whether susceptible or resistant to fluconazole. The rational design of antifungal compounds derived from clinical drugs (statins, fibrates, etc.) has many advantages. Future studies are needed to modify the structure of the two present test compounds to obtain safer and less toxic antifungals. Moreover, it is important to carry out a more in-depth mechanistic approach.
Topics: Acyl Coenzyme A; Animals; Antifungal Agents; COVID-19; Candida glabrata; Drug Resistance, Fungal; Ergosterol; Fibric Acids; Fluconazole; Humans; Hydroxymethylglutaryl CoA Reductases; Microbial Sensitivity Tests; Pandemics; Pyrroles
PubMed: 35377226
DOI: 10.1128/spectrum.01642-21 -
Nanomedicine (London, England) Oct 2020This article is written to provide an up-to-date review of pyrrole-based biomedical materials. Porphyrins and other tetrapyrrolic molecules possess unique magnetic,... (Review)
Review
This article is written to provide an up-to-date review of pyrrole-based biomedical materials. Porphyrins and other tetrapyrrolic molecules possess unique magnetic, optical and other photophysical properties that make them useful for bioimaging and therapy. This review touches briefly on some of the synthetic strategies to obtain porphyrin- and tetrapyrrole-based nanoparticles, as well as the variety of applications in which crosslinked, self-assembled, porphyrin-coated and other nanoparticles are utilized. We explore examples of these nanoparticles' applications in photothermal therapy, drug delivery, photodynamic therapy, stimuli response, fluorescence imaging, photoacoustic imaging, magnetic resonance imaging, computed tomography and positron emission tomography. We anticipate that this review will provide a comprehensive summary of pyrrole-derived nanoparticles and provide a guideline for their further development.
Topics: Nanoparticles; Optical Imaging; Photochemotherapy; Porphyrins; Pyrroles
PubMed: 32975469
DOI: 10.2217/nnm-2020-0125 -
Journal of Natural Products May 2022Investigation of the marine sponge MeOH fractions using feature-based molecular networking, dereplication, and isolation led to the discovery of new... (Review)
Review
Investigation of the marine sponge MeOH fractions using feature-based molecular networking, dereplication, and isolation led to the discovery of new bromopyrrole-derived metabolites. An in-house library of bromopyrrole alkaloids previously isolated from and sp. was utilized, along with the investigation of an MS/MS fragmentation of these compounds. Our strategy led to the isolation and identification of the disparamides A-C (-), with a novel carbon skeleton. Additionally, new dispyrins B-F (-) and nagelamides H2 and H3 ( and ) and known nagelamide H (), citrinamine B (), ageliferin (), bromoageliferin (), and dibromoageliferin () were also isolated and identified by analysis of spectroscopic data. Analysis of MS/MS fragmentation data and molecular networking analysis indicated the presence of hymenidin (), oroidin (), dispacamide (), monobromodispacamide (), keramadine (), longamide B (), methyl ester of longamide B (), hanishin (), methyl ester of 3-debromolongamide B (), and 3-debromohanishin (). Antibacterial activity of ageliferin (), bromoageliferin (), and dibromoageliferin () was evaluated against susceptible and multi-drug-resistant ESKAPE pathogenic bacteria , , , , , and . Dibromoageliferin () displayed the most potent antimicrobial activity against all tested susceptible and MDR strains. Compounds - presented no significant hemolytic activity up to 100 μM.
Topics: Agelas; Alkaloids; Animals; Anti-Bacterial Agents; Escherichia coli; Esters; Molecular Structure; Porifera; Pyrroles; Tandem Mass Spectrometry
PubMed: 35427139
DOI: 10.1021/acs.jnatprod.2c00094 -
Molecules (Basel, Switzerland) Aug 2022Bionanocomposites based on natural bioactive entities have gained importance due to their abundance; renewable and environmentally benign nature; and outstanding... (Review)
Review
Bionanocomposites based on natural bioactive entities have gained importance due to their abundance; renewable and environmentally benign nature; and outstanding properties with applied perspective. Additionally, their formulation with biological molecules with antimicrobial, antioxidant, and anticancer activities has been produced nowadays. The present review details the state of the art and the importance of this pyrrolic compound produced by microorganisms, with interest towards , including production strategies at a laboratory level and scale-up to bioreactors. Promising results of its biological activity have been reported to date, and the advances and applications in bionanocomposites are the most recent strategy to potentiate and to obtain new carriers for the transport and controlled release of prodigiosin. Prodigiosin, a bioactive secondary metabolite, produced by , is an effective proapoptotic agent against bacterial and fungal strains as well as cancer cell lines. Furthermore, this molecule presents antioxidant activity, which makes it ideal for treating wounds and promoting the general improvement of the immune system. Likewise, some of the characteristics of prodigiosin, such as hydrophobicity, limit its use for medical and biotechnological applications; however, this can be overcome by using it as a component of a bionanocomposite. This review focuses on the chemistry and the structure of the bionanocomposites currently developed using biorenewable resources. Moreover, the work illuminates recent developments in pyrrole-based bionanocomposites, with special insight to its application in the medical area.
Topics: Anti-Bacterial Agents; Bioreactors; Nanocomposites; Prodigiosin; Serratia marcescens
PubMed: 35956931
DOI: 10.3390/molecules27154982 -
Cell Death & Disease Aug 2023Pancreatic cancer is a highly aggressive cancer, and is primarily treated with gemcitabine, with increasing resistance. SIRT6 as a member of sirtuin family plays...
Pancreatic cancer is a highly aggressive cancer, and is primarily treated with gemcitabine, with increasing resistance. SIRT6 as a member of sirtuin family plays important roles in lifespan and diverse diseases, such as cancer, diabetes, inflammation and neurodegenerative diseases. Considering the role of SIRT6 in the cytoprotective effect, it might be a potential anticancer drug target, and is associated with resistance to anticancer therapy. However, very few SIRT6 inhibitors have been reported. Here, we reported the discovery of a pyrrole-pyridinimidazole derivative, 8a, as a new non-competitive SIRT6 inhibitor, and studied its roles and mechanisms in the antitumor activity and sensitization of pancreatic cancer to gemcitabine. Firstly, we found a potent SIRT6 inhibitor compound 8a by virtual screening and identified by molecular and cellular SIRT6 activity assays. 8a could effectively inhibit SIRT6 deacetylation activity with IC values of 7.46 ± 0.79 μM in FLUOR DE LYS assay, and 8a significantly increased the acetylation levels of H3 in cells. Then, we found that 8a could inhibit the cell proliferation and induce cell apoptosis in pancreatic cancer cells. We further demonstrate that 8a sensitize pancreatic cancer cells to gemcitabine via reversing the activation of PI3K/AKT/mTOR and ERK signaling pathways induced by gemcitabine and blocking the DNA damage repair pathway. Moreover, combination of 8a and gemcitabine induces cooperative antitumor activity in pancreatic cancer xenograft model in vivo. Overall, we demonstrate that 8a, a novel SIRT6 inhibitor, could be a promising potential drug candidate for pancreatic cancer treatment.
Topics: Humans; Apoptosis; Cell Line, Tumor; Gemcitabine; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Pyrroles; Sirtuins; Xenograft Model Antitumor Assays
PubMed: 37542062
DOI: 10.1038/s41419-023-06018-1 -
The American Journal of Gastroenterology Aug 2023
Topics: Humans; Rifabutin; Cost-Benefit Analysis; Anti-Bacterial Agents; Pyrroles; Drug Therapy, Combination; Proton Pump Inhibitors; Helicobacter pylori
PubMed: 37094105
DOI: 10.14309/ajg.0000000000002248 -
Antimicrobial Agents and Chemotherapy Oct 2019The escalating burden of antibiotic drug resistance necessitates research into novel classes of antibiotics and their mechanism of action. Pyrrolomycins are a family of...
The escalating burden of antibiotic drug resistance necessitates research into novel classes of antibiotics and their mechanism of action. Pyrrolomycins are a family of potent natural product antibiotics with nanomolar activity against Gram-positive bacteria, yet with an elusive mechanism of action. In this work, we dissect the apparent Gram-positive specific activity of pyrrolomycins and show that Gram-negative bacteria are equally sensitive to pyrrolomycins when drug efflux transporters are removed and that albumin in medium plays a large role in pyrrolomycin activity. The selection of resistant mutants allowed for the characterization and validation of a number of mechanisms of resistance to pyrrolomycins in both and an Δ mutant, all of which appear to affect compound penetration rather than being target associated. Imaging of the impact of pyrrolomycin on the Δ mutant using scanning electron microscopy showed blebbing of the bacterial cell wall often at the site of bacterial division. Using potentiometric probes and an electrophysiological technique with an artificial bilayer lipid membrane, it was demonstrated that pyrrolomycins C and D are very potent membrane-depolarizing agents, an order of magnitude more active than conventional carbonyl cyanide -chlorophenylhydrazone (CCCP), specifically disturbing the proton gradient and uncoupling oxidative phosphorylation via protonophoric action. This work clearly unveils the until-now-elusive mechanism of action of pyrrolomycins and explains their antibiotic activity as well as mechanisms of innate and acquired drug resistance in bacteria.
Topics: Anti-Bacterial Agents; Escherichia coli; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Pyrroles; Staphylococcus aureus; Structure-Activity Relationship
PubMed: 31405863
DOI: 10.1128/AAC.01450-19 -
Molecules (Basel, Switzerland) May 2023Cancer is threatening the survival of human beings all over the world. Phototherapy (including photothermal therapy (PTT) and photodynamic therapy (PDT)) and bioimaging... (Review)
Review
Cancer is threatening the survival of human beings all over the world. Phototherapy (including photothermal therapy (PTT) and photodynamic therapy (PDT)) and bioimaging are important tools for imaging-mediated cancer theranostics. Diketopyrrolopyrrole (DPP) dyes have received more attention due to their high thermal and photochemical stability, efficient reactive oxygen species (ROS) generation and thermal effects, easy functionalization, and tunable photophysical properties. In this review, we outline the latest achievements of DPP derivatives in cancer therapy and imaging over the past three years. DPP-based conjugated polymers and small molecules for detection, bioimaging, PTT, photoacoustic imaging (PAI)-guided PTT, and PDT/PTT combination therapy are summarized. Their design principles and chemical structures are highlighted. The outlook, challenges, and future opportunities for the development of DPP derivatives are also presented, which will give a future perspective for cancer treatment.
Topics: Humans; Phototherapy; Pyrroles; Ketones; Neoplasms; Nanoparticles; Photochemotherapy
PubMed: 37241837
DOI: 10.3390/molecules28104097 -
Molecules (Basel, Switzerland) Dec 2022Herein, we describe the synthesis and characterization of fused pyrroles in cholestane and norcholestane side chains derived from kryptogenin and diosgenin,...
Herein, we describe the synthesis and characterization of fused pyrroles in cholestane and norcholestane side chains derived from kryptogenin and diosgenin, respectively. Both conventional and microwave heating techniques were used to synthesize the steroidal pyrroles from primary amines, with the microwave method producing the highest yields. In particular, the norcholestane pyrroles were tested as acaricides against the two-spotted spider mite ( Koch) under laboratory conditions and as plant growth promoters on habanero pepper ( Jacq) under greenhouse conditions.
Topics: Animals; Acaricides; Pyrroles; Tetranychidae; Capsicum; Cholestanes
PubMed: 36500556
DOI: 10.3390/molecules27238466 -
Molecules (Basel, Switzerland) Dec 2020The subject of the work was the synthesis of new derivatives of1-pyrrolo[3,4-c]pyridine-1,3(2)-dione with potential analgesic and sedative activity. Eight compounds...
The subject of the work was the synthesis of new derivatives of1-pyrrolo[3,4-c]pyridine-1,3(2)-dione with potential analgesic and sedative activity. Eight compounds werereceived. The analgesic activity of the new compounds was confirmed in the "hot plate" test and in the "writhing" test. All tested imides - were more active in the "writhing" test than aspirin, and two of them, and , were similar to morphine. In addition, all of the new imides inhibited the locomotor activity in mice to a statistically significant extent, and two of them also prolonged the duration of thiopental sleep.On the basis of the results obtained for the previously synthesized imides and the results presented in this paper, an attempt was madeto determine the relationship between thechemical structure of imides and their analgesic and sedativeproperties.
Topics: Analgesics; Animals; Hypnotics and Sedatives; Locomotion; Male; Mice; Pyridines; Pyrroles; Structure-Activity Relationship
PubMed: 33322767
DOI: 10.3390/molecules25245883