scholarly journals Flavopereirine—An Alkaloid Derived from Geissospermum vellosii—Presents Leishmanicidal Activity In Vitro

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 785 ◽  
Author(s):  
João Victor da Silva e Silva ◽  
Heliton Patrick Cordovil Brigido ◽  
Kelly Cristina Oliveira de Albuquerque ◽  
Josiwander Miranda Carvalho ◽  
Jordano Ferreira Reis ◽  
...  
Keyword(s):  
Physicochemical Characteristics ◽  
Inhibitory Effect ◽  
Antileishmanial Activity ◽  
Lipinski’S Rule ◽  
Oligopeptidase B ◽  
Mechanism Of Interaction ◽  
Low Toxicity ◽  
Alkaloid Fraction ◽  
Dynamics Simulations

Chemotherapy is limited in the treatment of leishmaniasis due to the toxic effects of drugs, low efficacy of alternative treatments, and resistance of the parasite. This work assesses the in vitro activity of flavopereirine on promastigote cultures of Leishmania amazonensis. In addition, an in silico evaluation of the physicochemical characteristics of this alkaloid is performed. The extract and fractions were characterized by thin-layer chromatography and HPLC-DAD, yielding an alkaloid identified by NMR. The antileishmanial activity and cytotoxicity were assayed by cell viability test (MTT). The theoretical molecular properties were calculated on the Molinspiration website. The fractionation made it possible to isolate a beta-carboline alkaloid (flavopereirine) in the alkaloid fraction. Moreover, it led to obtaining a fraction with greater antileishmanial activity, since flavopereirine is very active. Regarding the exposure time, a greater inhibitory effect of flavopereirine was observed at 24 h and 72 h (IC50 of 0.23 and 0.15 μg/mL, respectively). The extract, fractions, and flavopereirine presented low toxicity, with high selectivity for the alkaloid. Furthermore, flavopereirine showed no violation of Lipinski’s rule of five, showing even better results than the known inhibitor of oligopeptidase B, antipain, with three violations. Flavopereirine also interacted with residue Tyr-499 of oligopeptidase B during the molecular dynamics simulations, giving a few insights of a possible favorable mechanism of interaction and a possible inhibitory pathway. Flavopereirine proved to be a promising molecule for its antileishmanial activity.

Effect of different types of sesquiterpene lactones on the maturation of Rhinella arenarum oocytes

Zygote ◽  
2014 ◽  
Vol 23 (3) ◽  
pp. 406-411
Author(s):  
G. Sánchez-Toranzo ◽  
J. Zapata-Martínez ◽  
C. Catalán ◽  
M.I. Bühler
Keyword(s):  
Sesquiterpene Lactones ◽  
Plant Secondary Metabolites ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Different Types ◽  
Low Toxicity ◽  
Rhinella Arenarum ◽  
High Degree ◽  
Asteraceae Family

SummaryThe sesquiterpene lactones (STLs) are a large class of plant secondary metabolites that are generally found in the Asteraceae family and that have high diversity with respect to chemical structure as well as biological activity. STLs have been classified into different groups, such as guaianolides, germacranolides, and melampolides etc., based on their carboxylic skeleton. In amphibians, fully grown ovarian oocytes are arrested at the beginning of meiosis I. Under the stimulus of progesterone, this meiotic arrest is released and meiosis progresses to metaphase II, a process known as oocyte maturation. The purpose of this work was to determine whether sesquiterpene lactones from the germacranolide and melampolide groups act as inhibitor agents on the meiosis of amphibian oocytes in vitro. Results for germacranolides indicated that the addition of deoxyelephantopins caused a high degree of inhibition and that minimolide showed a moderate inhibitory effect, whereas glaucolide A was inactive. Furthermore, the addition of melampolides (uvedalin, enhydrin, polymatin A and polymatin B) showed inhibitory effects. For enhydrin and uvedalin, inhibitory effects were observed at the higher concentrations assayed. The results of this study suggest that the inhibitory activity of the tested sesquiterpene lactones on the meiosis of Rhinella arenarum oocytes is not dependent on the group to which they belong, i.e. not on the carboxylic skeleton, but probably due to the arrangement and type of function groups present in the molecules. All assayed lactones in the germacranolide group showed low toxicity. In contrast, important differences in toxicity were observed for lactones from the melampolide group: enhydrin and uvedalin showed low toxicity, but polymatin A and B were highly toxic.

Novel Strobilurin Derivatives Containing Carboxylate Unit as Potential Antifungal Agents

2020 ◽  
Vol 17 (3) ◽  
pp. 300-311
Author(s):  
Longzhu Bao ◽  
Shuangshuang Wang ◽  
Di Song ◽  
Jingjing Wang ◽  
Xiali Yue ◽  
...  
Keyword(s):  
Fungicidal Activity ◽  
Pathogenic Fungi ◽  
Inhibitory Effect ◽  
Phytopathogenic Fungi ◽  
Side Chain ◽  
Test Results ◽  
Strobilurin Fungicide ◽  
Low Toxicity ◽  
Control Failures

Background: Due to the extensive use of a single fungicide to control crop diseases, the increase of resistant individuals leads to control failures. The search for molecules with fungicidal activity is still ongoing. Strobilurin is one of the most popularly used fungicides in the agrochemical field. A large number of strobilurin derivatives with both high activity and low toxicity have been developed. Methods: In the present study, a series of novel ortho-substituted benzyl carboxylates were efficiently synthesized by the reaction of (E)-methyl 2-(2-(bromom-ethyl)phenyl)-2-methox-yiminoaceta with various carboxylic acids. Their structures were confirmed and characterized by 1H NMR, 13C NMR, and ESI-MS analysis. Their fungicidal activities against common phytopathogenic fungi from six major cash crops were screened based on the pesticides guidelines for the laboratory bioactivity tests. Results: The primary fungicidal activity test results indicate that all compounds showed a certain inhibitory effect on the growth of 13 plants pathogenic fungi at a concentration of 100 ppm, and Compd. 3 has the most obvious inhibitory effect on all fungi. Further fungicidal activity studies indicate that some of these novel strobilurin derivatives containing carboxylate unit exhibited potential in vitro fungicidal activities at the dosage of 6.25 mg/L-1. Conclusion: A series of the ortho-substituted benzyl carboxylates derivatives containing β- methoxyacrylate moiety were designed and synthesized by modifying the side chain of traditional strobilurin fungicide. Compd. 3, Compd. 2 and Compd. 16 were identified as the most promising candidates for further study.

American Leishmania spp: Formycin B treatment of cutaneous leishmaniasis in mice

Parasitology ◽  
1987 ◽  
Vol 94 (3) ◽  
pp. 467-474 ◽  
Author(s):  
Tamara Rojas ◽  
J. L. Avila
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Optimal Dose ◽  
Dose Schedule ◽  
Inhibitory Effect ◽  
American Cutaneous Leishmaniasis ◽  
Leishmania Spp ◽  
Low Toxicity ◽  
Foot Pad

Using foot-pad infection of female C57BL/6, DBA/2J and NMRI-IVIC mice as an animal model for American cutaneous leishmaniasis (ACL), we evaluated the inhibitory effect of Formycin B (FoB) on the infection produced by 7 different Leishmania isolates. When treatment was initiated some days, or even some weeks, after infection a significant leishmanistatic effect was detected on mice infected with all Leishmania isolates, which reached 30–55 weeks for some isolates. The optimal dose schedule was 1·25 mg/kg body weight/day, injected intraperitoneally for 20 consecutive days. Significant differences in the sensitivity of various Leishmania spp. to FoB were found, either in vivo, or in vitro where a high [3H]FoB incorporation rate was found only for certain Leishmania isolates. The low toxicity of this drug and the sensitivity of the 7 Leishmania isolates tested suggest that FoB could be useful in the treatment of ACL.

scholarly journals Bio-guided isolation of anti-leishmanial natural products from Diospyros gracilescens L. (Ebenaceae)

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Cyrille Armel N. Njanpa ◽  
Steven Collins N. Wouamba ◽  
Lauve Rachel T. Yamthe ◽  
Darline Dize ◽  
Brice Mariscal T. Tchatat ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Colorimetric Assay ◽  
Exposure Period ◽  
2D Nmr ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Antileishmanial Activity ◽  
Hexane Fraction ◽  
Raw 264.7 Cells

Abstract Background Plants represent an intricate and innovative source for the discovery of novel therapeutic remedies for the management of infectious diseases. The current study aimed at discovering new inhibitors of Leishmania spp., using anti-leishmanial activity-guided investigation approach of extracts from Diospyros gracilescens Gürke (1911) (Ebenaceae), targeting the extracellular (promastigotes) and intracellular (amastigotes) forms of Leishmania donovani. Methods The plant extracts were prepared by maceration using H20: EtOH (30:70, v/v) and further fractionated using a bio-guided approach. Different concentrations of D. gracilescens extracts, fractions and isolated compounds were tested in triplicate against L. donovani promastigotes and amastigotes in vitro. The antileishmanial potency and cytotoxicity on RAW 264.7 cells were determined using the resazurin colorimetric assay. The time kill kinetic profile of the most active sample was also investigated. The structures of all compounds were elucidated on the basis of extensive spectroscopic analyses, including 1D and 2D NMR, and HR-ESI-MS and by comparison of their data with those reported in the literature. Results The hydroethanolic crude extract of D. gracilescens trunk showed the most potent antileishmanial activity (IC50 = 5.84 μg/mL). Further fractionation of this extract led to four (4) fractions of which, the hexane fraction showed the most potent activity (IC50 = 0.79 μg/mL), and seven (07) compounds that exhibited moderate potency (IC50 = 13.69–241.71 μM) against L. donovani. Compound 1-deoxyinositol (7) inhibited the promastigote and amastigote forms of L. donovani with IC50 values of 241.71 μM and 120 μM respectively and also showed the highest selectivity against L. donovani promastigotes (SI > 5.04). To the best of our knowledge, the antileishmanial activity of this compound is being reported here for the first time. The promising hexane fraction showed significant inhibition of parasites growth at different concentrations, but with no evidence of cidal effect over an exposure period of 120 h. Conclusions The results obtained indicated that the hydroethanolic extract from the D. gracilescens trunk and the derived hexane fraction have very potent inhibitory effect on cultivated promastigotes and amastigotes of L. donovani parasite. The isolated compounds showed a lesser extent of potency and selectivity. However, further structure-activity-relationship studies of 1-deoxyinositol could lead to more potent and selective hit derivatives of interest for detailed drug discovery program against visceral leishmaniasis.

scholarly journals In silico study on anti-Chikungunya virus activity of hesperetin

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2602 ◽  
Author(s):  
Adrian Oo ◽  
Pouya Hassandarvish ◽  
Sek Peng Chin ◽  
Vannajan Sanghiran Lee ◽  
Sazaly Abu Bakar ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Chikungunya Virus ◽  
Md Simulations ◽  
Inhibitory Effect ◽  
Structural Proteins ◽  
In Vitro Screening ◽  
Intracellular Replication ◽  
Lipinski’S Rule ◽  
Lipinski’S Rule Of Five

BackgroundThe re-emerging,Aedes spp.transmitted Chikungunya virus (CHIKV) has recently caused large outbreaks in a wide geographical distribution of the world including countries in Europe and America. Though fatalities associated with this self-remitting disease were rarely reported, quality of patients’ lives have been severely diminished by polyarthralgia recurrence. Neither effective antiviral treatment nor vaccines are available for CHIKV. Our previous in vitro screening showed that hesperetin, a bioflavonoid exhibits inhibitory effect on the virus intracellular replication. Here, we present a study using the computational approach to identify possible target proteins for future mechanistic studies of hesperetin.Methods3D structures of CHIKV nsP2 (3TRK) and nsP3 (3GPG) were retrieved from Protein Data Bank (PDB), whereas nsP1, nsP4 and cellular factor SPK2 were modeled using Iterative Threading Assembly Refinement (I-TASSER) server based on respective amino acids sequence. We performed molecular docking on hesperetin against all four CHIKV non-structural proteins and SPK2. Proteins preparation and subsequent molecular docking were performed using Discovery Studio 2.5 and AutoDock Vina 1.5.6. The Lipinski’s values of the ligand were computed and compared with the available data from PubChem. Two non-structural proteins with crystal structures 3GPG and 3TRK in complexed with hesperetin, demonstrated favorable free energy of binding from the docking study, were further explored using molecular dynamics (MD) simulations.ResultsWe observed that hesperetin interacts with different types of proteins involving hydrogen bonds, pi-pi effects, pi-cation bonding and pi-sigma interactions with varying binding energies. Among all five tested proteins, our compound has the highest binding affinity with 3GPG at −8.5 kcal/mol. The ligand used in this study also matches the Lipinski’s rule of five in addition to exhibiting closely similar properties with that of in PubChem. The docking simulation was performed to obtain a first guess of the binding structure of hesperetin complex and subsequently analysed by MD simulations to assess the reliability of the docking results. Root mean square deviation (RMSD) of the simulated systems from MD simulations indicated that the hesperetin complex remains stable within the simulation timescale.DiscussionThe ligand’s tendencies of binding to the important proteins for CHIKV replication were consistent with our previous in vitro screening which showed its efficacy in blocking the virus intracellular replication. NsP3 serves as the highest potential target protein for the compound’s inhibitory effect, while it is interesting to highlight the possibility of interrupting CHIKV replication via interaction with host cellular factor. By complying the Lipinski’s rule of five, hesperetin exhibits drug-like properties which projects its potential as a therapeutic option for CHIKV infection.

scholarly journals In Vitro Cellular Uptake and Transfection of Oligoarginine-Conjugated Glycol Chitosan/siRNA Nanoparticles

Polymers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 4219
Author(s):  
Eun-Ju Jeong ◽  
Jangwook Lee ◽  
Hyun-Seung Kim ◽  
Kuen-Yong Lee
Keyword(s):  
Transfection Efficiency ◽  
Physicochemical Characteristics ◽  
Gene Carrier ◽  
Glycol Chitosan ◽  
Arginine Residues ◽  
Low Toxicity ◽  
Low Cytotoxicity ◽  
Low Solubility ◽  
Positively Charged

Chitosan and its derivatives have been extensively utilized in gene delivery applications because of their low toxicity and positively charged characteristics. However, their low solubility under physiological conditions often limits their application. Glycol chitosan (GC) is a derivative of chitosan that exhibits excellent solubility in physiological buffer solutions. However, it lacks the positive characteristics of a gene carrier. Thus, we hypothesized that the introduction of oligoarginine peptide to GC could improve the formation of complexes with siRNA, resulting in enhanced uptake by cells and increased transfection efficiency in vitro. A peptide with nine arginine residues and 10 glycine units (R9G10) was successfully conjugated to GC, which was confirmed by infrared spectroscopy, 1H NMR spectroscopy, and elemental analysis. The physicochemical characteristics of R9G10-GC/siRNA complexes were also investigated. The size and surface charge of the R9G10-GC/siRNA nanoparticles depended on the amount of R9G10 coupled to the GC. In addition, the R9G10-GC/siRNA nanoparticles showed improved uptake in HeLa cells and enhanced in vitro transfection efficiency while maintaining low cytotoxicity determined by the MTT assay. Oligoarginine-modified glycol chitosan may be useful as a potential gene carrier in many therapeutic applications.

scholarly journals In Vitro Evaluation of Antileishmanial Activity of Computationally Screened Compounds against Ascorbate Peroxidase To Combat Amphotericin B Drug Resistance

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Rani Mansuri ◽  
Ashish Kumar ◽  
Sindhuprava Rana ◽  
Bhavana Panthi ◽  
M. Yousuf Ansari ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Ascorbate Peroxidase ◽  
Leishmania Donovani ◽  
Harmful Effect ◽  
Annexin V ◽  
Antileishmanial Activity ◽  
New Drugs ◽  
Content Type ◽  
Lipinski’S Rule

ABSTRACT In visceral leishmaniasis (VL), the host macrophages generate oxidative stress to destroy the pathogen, while Leishmania combats the harmful effect of radicals by redox homeostasis through its unique trypanothione cascade. Leishmania donovani ascorbate peroxidase (LdAPx) is a redox enzyme that regulates the trypanothione cascade and detoxifies the effect of H2O2. The absence of an LdAPx homologue in humans makes it an excellent drug target. In this study, the homology model of LdAPx was built, including heme, and diverse compounds were prefiltered (PAINS, ADMET, and Lipinski's rule of five) and thereafter screened against the LdAPx model. Compounds having good affinity in terms of the Glide XP (extra precision) score were clustered to select diverse compounds for experimental validation. A total of 26 cluster representatives were procured and tested on promastigote culture, yielding 12 compounds with good antileishmanial activity. Out of them, six compounds were safer on the BALB/c peritoneal macrophages and were also effective against disease-causing intracellular amastigotes. Three out of six compounds inhibited recombinant LdAPx in a noncompetitive manner and also demonstrated partial reversion of the resistance property in an amphotericin B (AmB)-resistant strain, which may be due to an increased level of reactive oxygen species (ROS) and decrease of glutathione (GSH) content. However, inhibition of LdAPx in resistant parasites enhanced annexin V staining and activation of metacaspase-like protease activity, which may help in DNA fragmentation and apoptosis-like cell death. Thus, the present study will help in the search for specific hits and templates of potential therapeutic interest and therefore may facilitate the development of new drugs for combination therapy against VL.

scholarly journals Chemical Chaperones Modulate the Formation of Metabolite Assemblies

2021 ◽  
Vol 22 (17) ◽  
pp. 9172
Author(s):  
Hanaa Adsi ◽  
Shon A. Levkovich ◽  
Elvira Haimov ◽  
Topaz Kreiser ◽  
Massimiliano Meli ◽  
...  
Keyword(s):  
Self Assembly ◽  
Rational Design ◽  
Inhibitory Effect ◽  
Amyloid Formation ◽  
Inborn Errors ◽  
Chemical Chaperones ◽  
Dynamics Simulations ◽  
Fibril Morphology

The formation of amyloid-like structures by metabolites is associated with several inborn errors of metabolism (IEMs). These structures display most of the biological, chemical and physical properties of protein amyloids. However, the molecular interactions underlying the assembly remain elusive, and so far, no modulating therapeutic agents are available for clinical use. Chemical chaperones are known to inhibit protein and peptide amyloid formation and stabilize misfolded enzymes. Here, we provide an in-depth characterization of the inhibitory effect of osmolytes and hydrophobic chemical chaperones on metabolite assemblies, thus extending their functional repertoire. We applied a combined in vivo-in vitro-in silico approach and show their ability to inhibit metabolite amyloid-induced toxicity and reduce cellular amyloid content in yeast. We further used various biophysical techniques demonstrating direct inhibition of adenine self-assembly and alteration of fibril morphology by chemical chaperones. Using a scaffold-based approach, we analyzed the physiochemical properties of various dimethyl sulfoxide derivatives and their role in inhibiting metabolite self-assembly. Lastly, we employed whole-atom molecular dynamics simulations to elucidate the role of hydrogen bonds in osmolyte inhibition. Our results imply a dual mode of action of chemical chaperones as IEMs therapeutics, that could be implemented in the rational design of novel lead-like molecules.

scholarly journals Minor sequence modifications in temporin B cause drastic changes in antibacterial potency and selectivity by fundamentally altering membrane activity

2018 ◽  
Author(s):  
Giorgia Manzo ◽  
Philip M. Ferguson ◽  
V. Benjamin Gustilo ◽  
Tam T. Bui ◽  
Alex F. Drake ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Activity ◽  
Gram Positive Bacteria ◽  
C Terminus ◽  
N Terminus ◽  
Mechanism Of Interaction ◽  
Minor Sequence ◽  
Dynamics Simulations ◽  
Effective Translation

ABSTRACTAntimicrobial peptides (AMPs) are a potential source of new molecules to counter the increase in antimicrobial resistant infections but a better understanding of their properties is required to understand their native function and for effective translation as therapeutics. Details of the mechanism of their interaction with the bacterial plasma membrane are desired since damage or penetration of this structure is considered essential for AMP activity. Relatively modest modifications to AMP primary sequence can induce substantial changes in potency and/or spectrum of activity but, hitherto, have not been predicted to substantially alter the mechanism of interaction with the bacterial plasma membrane. Here we use a combination of molecular dynamics simulations, circular dichroism, solid-state NMR and patch clamp to investigate the extent to which temporin B and its analogues can be distinguished both in vitro and in silico on the basis of their interactions with model membranes. Enhancing the hydrophobicity of the N-terminus and cationicity of the C-terminus in temporin B improves its membrane activity and potency against both Gram-negative and Gram-positive bacteria. In contrast, enhancing the cationicity of the N-terminus abrogates its ability to trigger channel conductance and renders it ineffective against Staphylococcus aureus while nevertheless enhancing its potency against Escherichia coli. Our findings suggest even closely related AMPs may target the same bacterium with fundamentally differing mechanisms of action.

A Systematic Literature Review of Curcumin With Promising Antileishmanial Activity

2020 ◽  
Vol 20 ◽  
Author(s):  
Reza Saberi ◽  
Mahdi Fakhar ◽  
Shabnam Asfaram ◽  
Javad Akhtari ◽  
Maryam Nakhaei ◽  
...  
Keyword(s):  
Systematic Review ◽  
Literature Review ◽  
Bioactive Compounds ◽  
Leishmania Species ◽  
Inhibitory Effect ◽  
Antileishmanial Activity ◽  
Eligibility Criteria ◽  
Intracellular Amastigote ◽  
Leishmania Parasites

Background: Curcumin (CUR) is a bright yellow chemical and it is used as an additive in foods. Recently CUR and its associated bioactive compounds have received much attention in the literature review. The aim of this systematic review is to overview antileishmanial properties of CUR and its mechanism, perhaps the results of this study will be used for therapeutic and preventive purposes. Methods: Following the PRISMA guidelines, international databases were systematically searched for studies published until September 2019. Articles related to the subject were selected and included in this systematic review. Results: A total of 15 articles met our eligibility criteria. Then, the effect of CUR and its associated bioactive compounds on Leishmania species was evaluated. In most studies CUR/derivatives were tested on L. major and in vitro condition. Most investigations were conducted on the promastigote rather than the more relevant intracellular amastigote stage. Our results showed that CUR overcomes the inhibitory effect of nitric oxide (NO) on Leishmania parasites. Conclusions: This review indicated that CUR derivatives instead of alone CUR showed a high potential to serve as an effective herbal drug against leishmaniasis. Moreover, we concluded that the antileishmanial activity of CUR/bioactive compounds is mostly due to increasing oxidative stress and inducing apoptosis.

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