scholarly journals Inhibitory Activity and Docking Analysis of Antimalarial Agents from Stemona sp. toward Ferredoxin-NADP+ Reductase from Malaria Parasites

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Pratiwi Pudjiastuti ◽  
Ni Nyoman T. Puspaningsih ◽  
Imam Siswanto ◽  
Much. Z. Fanani ◽  
Yoko K. Ariga ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Plasmodium Falciparum ◽  
Inhibitory Activity ◽  
Inhibitory Effect ◽  
Malaria Parasites ◽  
Docking Analysis ◽  
Antimalarial Agent ◽  
Middle Position ◽  
Antimalarial Agents ◽  
Diaphorase Activity

Ferredoxin-NADP+ reductases (FNRs, EC 1.18.1.2) were found in the plastids of Plasmodium and have been considered as a target for the development of new antimalarial agents. Croomine, epi-croomine, tuberostemonine, javastemonine A, and isoprotostemonine are isolated alkaloids from the roots of Stemona sp. and their inhibitory effect on FNRs from Plasmodium falciparum (PfFNR) was investigated. Croomine showed the highest level of inhibition (33.9%) of electron transfer from PfFNR to PfFd, while tuberstemonine displayed the highest level of inhibition (55.4%) of diaphorase activity of PfFNR. Docking analysis represented that croomine is located at the middle position of PfFNR and PfFd. Croomine from S. tuberosa appeared to have potential as an antimalarial agent.

scholarly journals Synthesis and Antiplasmodial Activity of Novel Fosmidomycin Derivatives and Conjugates with Artemisinin and Aminochloroquinoline

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4858 ◽  
Author(s):  
Despina Palla ◽  
Antonia I. Antoniou ◽  
Michel Baltas ◽  
Christophe Menendez ◽  
Philippe Grellier ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Infectious Diseases ◽  
Antimalarial Activity ◽  
Biological Evaluation ◽  
Antiplasmodial Activity ◽  
Malaria Parasites ◽  
Antimalarial Agents ◽  
New Compounds

Malaria, despite many efforts, remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by Plasmodium falciparum. The antibiotic fosmidomycin (FSM) is also known for its antimalarial activity by targeting the non-mevalonate isoprenoid synthesis pathway, which is essential for the malaria parasites but is absent in mammalians. In this study, we synthesized and evaluated against the chloroquine-resistant P. falciparum FcB1/Colombia strain, a series of FSM analogs, derivatives, and conjugates with other antimalarial agents, such as artemisinin (ART) and aminochloroquinoline (ACQ). The biological evaluation revealed four new compounds with higher antimalarial activity than FSM: two FSM-ACQ derivatives and two FSM-ART conjugates, with 3.5–5.4 and 41.5–23.1 times more potent activities than FSM, respectively.

scholarly journals Evaluating the Time Dependent Anti-plasmodium Activity of Andrographolide and Chloroquine on Different Stages of the Intraerythrocytic Cycle of Plasmodium Falciparum 3D7 in Vitro

2020 ◽  
Author(s):  
‪ashraf Ahmad Issa alapid‬‏ ◽  
Zaid O. Ibraheem ◽  
Ramatu Omenesa Bello ◽  
Intan Safinar Ismail ◽  
Ngah Zasmy Unyah ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Activity ◽  
Drug Exposure ◽  
Inhibitory Effect ◽  
Parasite Growth ◽  
Time Dependent ◽  
Adjunctive Treatment ◽  
Pharmacologically Active ◽  
The Impact

Abstract Background: The increasing incidence of drug resistance among various strains of Plasmodium falciparum has compelled researchers to search for new improved therapeutic alternatives to current antimalarials. Consequently, the study aimed to investigate the effect of varying the duration of andrographolide exposure on its anti-plasmodial effect against intra erythrocytic stages of the P. falciparum 3D7 parasite. Although andrographolide has demonstrated prior anti-plasmodial effect against P. falciparum 3D7, its time-dependent effect subsequent to different durations of drug exposure in addition to the impact of relevant pharmacologically active concentrations on the cellular morphology of various intraerythrocytic stages of the P. falciparum 3D7 parasite cycle are limited.Methods: P. falciparum 3D7 parasites cultivated in vitro in blood cultures were individually incubated with different concentrations of andrographolide, chloroquine and drug-free parasite culture which served as the representative control. Suppression of parasite growth was determined by parasite lactate dehydrogenase (pLDH) based drug sensitivity assay. The inhibition of parasite growth and changes in morphology of intraerythrocytic parasites subsequent to treatment initiation with andrographolide or chloroquine were assessed upon commencement of a synchronized cycle at 12, 24 and 48 h respectively. Results: Andrographolide showed satisfactory growth inhibitory effect however its inhibitory activity was substantially lower when compared to that of chloroquine. Unlike chloroquine which showed maximal inhibitory activity within the first 12 h of the cycle, suppression of parasite growth by andrographolide was most prominent during the development of early trophozoites (viz the second 12 hours). Andrographolide failed to produce any effect on the morphology of ring stage parasites, it however produced a noticeable change in the morphological appearance and sizes of mature trophozoites. Whereas, with chloroquine notable changes to ring and trophozoite stages of the parasites were evident. Conclusion: The data obtained indicates the potential role of andrographolide as an adjunctive treatment in malaria subject to further clinical evaluations.

The inhibition ofPlasmodium falciparumgrowthin vitroby sera from mice infected with malaria or treated with TNF

Parasitology ◽  
1990 ◽  
Vol 101 (3) ◽  
pp. 321-326 ◽  
Author(s):  
G. A. Butcher ◽  
I. A. Clark
Keyword(s):  
Immune Response ◽  
Plasmodium Falciparum ◽  
Inhibitory Activity ◽  
Activated Macrophages ◽  
Plasmodium Chabaudi ◽  
Malaria Parasites ◽  
The Difference ◽  
Second Coming

SUMMARYDespite some years of enquiry, the mechanism that leads to intra-erythrocytic death of malarial parasites during the host's response to infection has not been elucidated. We report here that serum from mice undergoing a successful immune response toPlasmodium chabaudidoes not inhibitPlasmodium falciparumunless thePl. chabaudiis virulent enough to rise to at least 50% parasitaemia and to cause illness. This appears to be true of the 556 KA and DS strains ofPl chabaudi, and also other murine malaria parasites. In mice infected withPl. chabaudi556 KA inhibitory activity coincided with the presence of TNF in their serum. Exogenous TNF generated inhibitory activity in the serum of mice only if the animals were pretreated withProprionobacterium acnes, implying a role for activated macrophages downstream from TNF in this process. The difference in inhibitory activity againstPl. falciparumin serum from mice infected withPl. chabaudiof more or less virulence may be one of degree. Alternatively two distinct mechanisms may operate, the second coming into operation only in ill mice, with higher parasite burdens.

scholarly journals Jejucarbazoles A–C, carbazole glycosides with indoleamine 2,3-dioxygenase 1 inhibitory activity from Streptomyces sp. KCB15JA151

RSC Advances ◽  
2021 ◽  
Vol 11 (32) ◽  
pp. 19805-19812
Author(s):  
Gil Soo Kim ◽  
Jun-Pil Jang ◽  
Mincheol Kwon ◽  
Tae Hoon Oh ◽  
Kyung Taek Heo ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Structure Elucidation ◽  
Inhibitory Effect ◽  
Docking Analysis ◽  
Streptomyces Sp ◽  
Indoleamine 2,3 Dioxygenase ◽  
Molecular Docking Analysis

This study presents the isolation and structure elucidation of jejucarbazoles A–C, isolated from Streptomyces sp. KCB15JA15 and their inhibitory effect and molecular docking analysis against the IDO1 enzyme.

scholarly journals Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro

Blood ◽  
1990 ◽  
Vol 76 (6) ◽  
pp. 1250-1255 ◽  
Author(s):  
S Whitehead ◽  
TE Peto
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Antimalarial Activity ◽  
Clinical Malaria ◽  
Inhibitory Effect ◽  
Parasite Development ◽  
And Control ◽  
Speed Of Onset

Abstract Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.

scholarly journals Evaluation of Enzyme Inhibitory Activity of Flavonoids by Polydopamine-Modified Hollow Fiber-Immobilized Xanthine Oxidase

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3931
Author(s):  
Cong-Peng Zhao ◽  
Guo-Ying Chen ◽  
Yuan Wang ◽  
Hua Chen ◽  
Jia-Wen Yu ◽  
...  
Keyword(s):  
Xanthine Oxidase ◽  
Hollow Fiber ◽  
Inhibitory Activity ◽  
Ph Value ◽  
Enzymatic Reaction ◽  
Amino Acid Residues ◽  
Reaction Conditions ◽  
Docking Analysis ◽  
Dopamine Concentration ◽  
Immobilization Time

In this study, a polydopamine (PDA)-modified hollow fiber-immobilized xanthine oxidase (XOD) was prepared for screening potential XOD inhibitors from flavonoids. Several parameters for the preparation of PDA-modified hollow fiber-immobilized XOD, including the dopamine concentration, modification time, XOD concentration and immobilization time, were optimized. The results show that the optimal conditions for immobilized XOD activity were a dopamine concentration of 2.0 mg/mL in 10.0 mM Tris-HCl buffer (pH 8.5), a modification time of 3.0 h, an XOD concentration of 1000 μg/mL in 10.0 mM phosphate buffer (pH 7.5) and an immobilization time of 3.0 h. Subsequently, the enzymatic reaction conditions such as the pH value and temperature were investigated, and the enzyme kinetics and inhibition parameters were determined. The results indicate that the optimal pH value (7.5) and temperature (37 °C) of the PDA-modified hollow fiber-immobilized XOD were consistent with the free enzyme. Moreover, the PDA-modified hollow fiber-immobilized XOD could still maintain above 50% of its initial immobilized enzyme activity after seven consecutive cycles. The Michaelis–Menten constant (Km) and the half-maximal inhibitory concentration (IC50) of allopurinol on the immobilized XOD were determined as 0.25 mM and 23.2 μM, respectively. Furthermore, the PDA-modified hollow fiber-immobilized XOD was successfully applied to evaluate the inhibitory activity of eight flavonoids. Quercetin, apigenin, puerarin and epigallocatechin showed a good inhibition effect, and their percentages of inhibition were (79.86 ± 3.50)%, (80.98 ± 0.64)%, (61.15 ± 6.26)% and (54.92 ± 0.41)%, respectively. Finally, molecular docking analysis further verified that these four active compounds could bind to the amino acid residues in the XOD active site. In summary, the PDA-modified hollow fiber-immobilized XOD is an efficient method for the primary screening of XOD inhibitors from natural products.

scholarly journals Malaria parasites both repress host CXCL10 and use it as a cue for growth acceleration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yifat Ofir-Birin ◽  
Hila Ben Ami Pilo ◽  
Abel Cruz Camacho ◽  
Ariel Rudik ◽  
Anna Rivkin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Cerebral Malaria ◽  
Survival Strategy ◽  
Parasitic Disease ◽  
Malaria Parasites ◽  
Sensing System ◽  
Rich Domain ◽  
Cargo Delivery ◽  
Low Levels

AbstractPathogens are thought to use host molecular cues to control when to initiate life-cycle transitions, but these signals are mostly unknown, particularly for the parasitic disease malaria caused by Plasmodium falciparum. The chemokine CXCL10 is present at high levels in fatal cases of cerebral malaria patients, but is reduced in patients who survive and do not have complications. Here we show a Pf ‘decision-sensing-system’ controlled by CXCL10 concentration. High CXCL10 expression prompts P. falciparum to initiate a survival strategy via growth acceleration. Remarkably, P. falciparum inhibits CXCL10 synthesis in monocytes by disrupting the association of host ribosomes with CXCL10 transcripts. The underlying inhibition cascade involves RNA cargo delivery into monocytes that triggers RIG-I, which leads to HUR1 binding to an AU-rich domain of the CXCL10 3’UTR. These data indicate that when the parasite can no longer keep CXCL10 at low levels, it can exploit the chemokine as a cue to shift tactics and escape.

scholarly journals Synthesis, Molecular Docking Analysis and Biological Evaluations of Saccharide-Modified Thiadiazole Sulfonamide Derivatives

2021 ◽  
Vol 22 (11) ◽  
pp. 5482
Author(s):  
Zuo-Peng Zhang ◽  
Ye Zhong ◽  
Zhen-Bin Han ◽  
Lin Zhou ◽  
Hua-Sheng Su ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Human Cancer ◽  
Carbonic Anhydrases ◽  
Inhibitory Effects ◽  
Docking Analysis ◽  
Human Cancer Cell Lines ◽  
Hypoxic Conditions ◽  
Ca Ix ◽  
Topological Polar Surface Area ◽  
Ht 29

A series of saccharide-modified thiadiazole sulfonamide derivatives has been designed and synthesized by the “tail approach” and evaluated for inhibitory activity against carbonic anhydrases II, IX, and XII. Most of the compounds showed high topological polar surface area (TPSA) values and excellent enzyme inhibitory activity. The impacts of some compounds on the viability of HT-29, MDA-MB-231, and MG-63 human cancer cell lines were examined under both normoxic and hypoxic conditions, and they showed certain inhibitory effects on cell viability. Moreover, it was found that the series of compounds had the ability to raise the pH of the tumor cell microenvironment. All the results proved that saccharide-modified thiadiazole sulfonamides have important research prospects for the development of CA IX inhibitors.

scholarly journals Inhibitory Effects of Secondary Metabolites from the Lichen Stereocaulon evolutum on Protein Tyrosine Phosphatase 1B

Planta Medica ◽  
2021 ◽  
Author(s):  
Birgit Waltenberger ◽  
Françoise Lohézic-Le Dévéhat ◽  
Thi Huyen Vu ◽  
Olivier Delalande ◽  
Claudia Lalli ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Inhibitory Activity ◽  
Tyrosine Phosphatase ◽  
Inhibitory Effect ◽  
Positive Control ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Ic50 Values ◽  
A Cell

AbstractProtein tyrosine phosphatase 1B plays a significant role in type 2 diabetes mellitus and other diseases and is therefore considered a new drug target. Within this study, an acetone extract from the lichen Stereocaulon evolutum was identified to possess strong protein tyrosine phosphatase 1B inhibition in a cell-free assay (IC50 of 11.8 µg/mL). Fractionation of this bioactive extract led to the isolation of seven known molecules belonging to the depsidones and the related diphenylethers and one new natural product, i.e., 3-butyl-3,7-dihydroxy-5-methoxy-1(3H)-isobenzofurane. The isolated compounds were evaluated for their inhibition of protein tyrosine phosphatase 1B. Two depsidones, lobaric acid and norlobaric acid, and the diphenylether anhydrosakisacaulon A potently inhibited protein tyrosine phosphatase 1B with IC50 values of 12.9, 15.1, and 16.1 µM, respectively, which is in the range of the protein tyrosine phosphatase 1B inhibitory activity of the positive control ursolic acid (IC50 of 14.4 µM). Molecular simulations performed on the eight compounds showed that i) a contact between the molecule and the four main regions of the protein is required for inhibitory activity, ii) the relative rigidity of the depsidones lobaric acid and norlobaric acid and the reactivity related to hydrogen bond donors or acceptors, which interact with protein tyrosine phosphatase 1B key amino acids, are involved in the bioactivity on protein tyrosine phosphatase 1B, iii) the cycle opening observed for diphenylethers decreased the inhibition, except for anhydrosakisacaulon A where its double bond on C-8 offsets this loss of activity, iv) the function present at C-8 is a determinant for the inhibitory effect on protein tyrosine phosphatase 1B, and v) the more hydrogen bonds with Arg221 there are, the more anchorage is favored.

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