scholarly journals Relationship between Antimalarial Activity and Heme Alkylation for Spiro- and Dispiro-1,2,4-Trioxolane Antimalarials

2008 ◽  
Vol 52 (4) ◽  
pp. 1291-1296 ◽  
Author(s):  
Darren J. Creek ◽  
William N. Charman ◽  
Francis C. K. Chiu ◽  
Richard J. Prankerd ◽  
Yuxiang Dong ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Antimalarial Activity ◽  
Biologically Active ◽  
Radical Intermediate ◽  
Reaction Conditions ◽  
Artemisinin Derivatives ◽  
Major Reaction Product ◽  
Major Reaction ◽  
Insight Into

ABSTRACT The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism of action for this important class of antimalarials. A series of trioxolanes with various antimalarial potencies was found to be unreactive in the presence of Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. The major reaction product from the heme-mediated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate. Under standardized reaction conditions, a correlation (R 2 = 0.88) was found between the extent of heme alkylation and in vitro antimalarial activity, suggesting that heme alkylation may be related to the mechanism of action for these trioxolanes. Significantly less heme alkylation was observed for the clinically utilized artemisinin derivatives compared to the equipotent trioxolanes included in this study.

scholarly journals In vitro activities of novel catecholate siderophores against Plasmodium falciparum.

1996 ◽  
Vol 40 (9) ◽  
pp. 2094-2098 ◽  
Author(s):  
B Pradines ◽  
F Ramiandrasoa ◽  
L K Basco ◽  
L Bricard ◽  
G Kunesch ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Mechanism Of Action ◽  
Ribonucleotide Reductase ◽  
Antimalarial Activity ◽  
Iron Chelators ◽  
Resistant Clone ◽  
Iron Deprivation ◽  
Level Of Activity ◽  
Susceptible Clone

The activities of novel iron chelators, alone and in combination with chloroquine, quinine, or artemether, were evaluated in vitro against susceptible and resistant clones of Plasmodium falciparum with a semimicroassay system. N4-nonyl,N1,N8-bis(2,3-dihydroxybenzoyl) spermidine hydrobromide (compound 7) demonstrated the highest level of activity: 170 nM against a chloroquine-susceptible clone and 1 microM against a chloroquine-resistant clone (50% inhibitory concentrations). Compounds 6, 8, and 10 showed antimalarial activity with 50% inhibitory concentrations of about 1 microM. Compound 7 had no effect on the activities of chloroquine, quinine, and artemether against either clone, and compound 8 did not enhance the schizontocidal action of either chloroquine or quinine against the chloroquine-resistant clone. The incubation of compound 7 with FeCI3 suppressed or decreased the in vitro antimalarial activity of compound 7, while no effect was observed with incubation of compound 7 with CuSO4 and ZnSO4. These results suggest that iron deprivation may be the main mechanism of action of compound 7 against the malarial parasites. Chelator compounds 7 and 8 primarily affected trophozoite stages, probably by influencing the activity of ribonucleotide reductase, and thus inhibiting DNA synthesis.

In vitro antimalarial activity and molecular modeling studies of novel artemisinin derivatives

RSC Advances ◽  
2015 ◽  
Vol 5 (59) ◽  
pp. 47959-47974 ◽  
Author(s):  
Rashmi Gaur ◽  
Harveer Singh Cheema ◽  
Yogesh Kumar ◽  
Suriya Pratap Singh ◽  
Dharmendra K. Yadav ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Modeling ◽  
Cerebral Malaria ◽  
Antimalarial Activity ◽  
Anopheles Mosquito ◽  
Fatal Disease ◽  
Artemisinin Derivatives ◽  
Modeling Studies ◽  
Molecular Modeling Studies

Cerebral malaria is a serious and sometimes fatal disease caused by aPlasmodium falciparumparasite that infects a female anopheles mosquito which feeds on humans.

scholarly journals Plasmodium falciparum-Based Bioassay for Measurement of Artemisinin Derivatives in Plasma or Serum

2004 ◽  
Vol 48 (3) ◽  
pp. 954-960 ◽  
Author(s):  
Paktiya Teja-Isavadharm ◽  
James O. Peggins ◽  
Thomas G. Brewer ◽  
Nicholas J. White ◽  
H. Kyle Webster ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
High Performance ◽  
Antimalarial Activity ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Response Curves ◽  
Artemisinin Derivatives ◽  
Treatment Regimens ◽  
Limit Of Quantitation

ABSTRACT Artemisinin and its derivatives, artesunate and artemether, are rapidly acting antimalarials that are used for the treatment of severe and uncomplicated multidrug-resistant falciparum malaria. To optimize treatment regimens that use this new class of antimalarials, there is a need for readily available and reproducible assays to monitor drug levels closely in patients. A sensitive and reproducible bioassay for the measurement of the concentrations of artemisinin derivatives in plasma and serum is described. By modifying the in vitro drug susceptibility test, it was found that antimalarial activity in plasma or serum containing an unknown concentration of drug could be equated to the known concentrations of dihydroartemisinin (DHA) required to inhibit parasite growth. Dose-response curves for a Plasmodium falciparum clone (clone W2) and DHA were used as a standard for each assay. Assays with plasma or serum spiked with DHA proved to be reproducible (coefficient of variation, ≤10.9%), with a lower limit of quantitation equivalent to 2.5 ng of DHA per ml. For plasma spiked with artesunate or artemether, there was good agreement of the results obtained by the bioassay and the concentrations measured by high-performance liquid chromatography (HPLC) with electrochemical detection. The bioassay for measurement of the antimalarial activities of artemisinin derivatives in body fluids requires a smaller volume of plasma or serum and is more sensitive than the presently available HPLC methods, can provide pharmacodynamic parameters for determination of activity against the parasite, and should enhance the design of more appropriate dosage regimens for artemisinin drugs.

scholarly journals In Vitro Antimalarial Activity of Azithromycin, Artesunate, and Quinine in Combination and Correlation with Clinical Outcome

2006 ◽  
Vol 51 (2) ◽  
pp. 651-656 ◽  
Author(s):  
Harald Noedl ◽  
Srivicha Krudsood ◽  
Wattana Leowattana ◽  
Noppadon Tangpukdee ◽  
Wipa Thanachartwet ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Geometric Mean ◽  
Parasite Clearance ◽  
Drug Susceptibility ◽  
Cross Sensitivity ◽  
Artemisinin Derivatives ◽  
Synergistic Interactions ◽  
Western Border ◽  
High Level

ABSTRACT Azithromycin when used in combination with faster-acting antimalarials has proven efficacious in treating Plasmodium falciparum malaria in phase 2 clinical trials. The aim of this study was to establish optimal combination ratios for azithromycin in combination with either dihydroartemisinin or quinine, to determine the clinical correlates of in vitro drug sensitivity for these compounds, and to assess the cross-sensitivity patterns. Seventy-three fresh P. falciparum isolates originating from patients from the western border regions of Thailand were successfully tested for their drug susceptibility in a histidine-rich protein 2 (HRP2) assay. With overall mean fractional inhibitory concentrations of 0.84 (95% confidence interval [CI] = 0.77 to 1.08) and 0.78 (95% CI = 0.72 to 0.98), the interactions between azithromycin and dihydroartemisinin, as well as quinine, were classified as additive, with a tendency toward synergism. The strongest tendency toward synergy was seen with a combination ratio of 1:547 for the combination with dihydroartemisinin and 1:44 with quinine. The geometric mean 50% inhibitory concentration (IC50) of azithromycin was 2,570.3 (95% CI = 2,175.58 to 3,036.58) ng/ml. The IC50s for mefloquine, quinine, and chloroquine were 11.42, 64.4, and 54.4 ng/ml, respectively, suggesting a relatively high level of background resistance in this patient population. Distinct correlations (R = 0.53; P = 0.001) between quinine in vitro results and parasite clearance may indicate a compromised sensitivity to this drug. The correlation with dihydroartemisinin data was weaker (R = 0.34; P = 0.038), and no such correlation was observed for azithromycin. Our in vitro data confirm that azithromycin in combination with artemisinin derivatives or quinine exerts additive to synergistic interactions, shows no cross-sensitivity with traditional antimalarials, and has substantial antimalarial activity on its own.

scholarly journals Artemisinin Therapy for Malaria in Hemoglobinopathies: A Systematic Review

2018 ◽  
Vol 66 (5) ◽  
pp. 799-804 ◽  
Author(s):  
Sri Riyati Sugiarto ◽  
Brioni R Moore ◽  
Julie Makani ◽  
Timothy M E Davis
Keyword(s):  
Clinical Studies ◽  
Antimalarial Activity ◽  
Artemisinin Combination Therapy ◽  
Plasma Concentrations ◽  
Parasite Clearance ◽  
Convincing Evidence ◽  
Hemoglobin E ◽  
Artemisinin Derivatives

Abstract Artemisinin derivatives are widely used antimalarial drugs. There is some evidence from in vitro, animal and clinical studies that hemoglobinopathies may alter their disposition and antimalarial activity. This review assesses relevant data in α-thalassemia, sickle cell disease (SCD), β-thalassemia and hemoglobin E. There is no convincing evidence that the disposition of artemisinin drugs is affected by hemoglobinopathies. Although in vitro studies indicate that Plasmodium falciparum cultured in thalassemic erythrocytes is relatively resistant to the artemisinin derivatives, mean 50% inhibitory concentrations (IC50s) are much lower than in vivo plasma concentrations after recommended treatment doses. Since IC50s are not increased in P. falciparum cultures using SCD erythrocytes, delayed post-treatment parasite clearance in SCD may reflect hyposplenism. As there have been no clinical studies suggesting that hemoglobinopathies significantly attenuate the efficacy of artemisinin combination therapy (ACT) in uncomplicated malaria, recommended artemisinin doses as part of ACT remain appropriate in this patient group.

scholarly journals The soluble ectodomain of RetC634Y inhibits both the wild-type and the constitutively active Ret

2003 ◽  
Vol 372 (3) ◽  
pp. 897-903 ◽  
Author(s):  
Laura CERCHIA ◽  
Domenico LIBRI ◽  
Maria Stella CARLOMAGNO ◽  
Vittorio de FRANCISCIS
Keyword(s):  
Molecular Basis ◽  
Multiple Endocrine Neoplasia Type ◽  
Cell System ◽  
Biologically Active ◽  
Tyrosine Kinase Receptor ◽  
Wild Type ◽  
Membrane Bound ◽  
Ret Oncogene ◽  
Insight Into

Substitution of Cys-634 in the extracellular domain of the Ret tyrosine kinase receptor causes its dimerization and activation of its transforming potential. To gain further insight into the molecular basis leading to Ret activation we purified a mutant protein consisting of the entire ectodomain of the Ret carrying a Cys-634→Tyr substitution (EC-RetC634Y). The protein is glycosylated, like the native one, and is biologically active. By using an in vitro cell system we show that EC-RetC634Y inhibits the membrane-bound receptor RetC634Y, interfering with its dimerization. Furthermore, we demonstrate that EC-RetC634Y competes with the wild-type Ret receptor for ligand binding. The results presented support the notion of the possible involvment of glial cell line-derived neurotrophic factor (GDNF) with multiple endocrine neoplasia type 2A (MEN2A) tumours, and describe a useful tool for generating molecular mimetics directed towards specific mutations of the ret oncogene.

scholarly journals Co-oxidation of NADH and NADPH by a mammalian 15-lipoxygenase: inhibition of lipoxygenase activity at near-physiological NADH concentrations

1997 ◽  
Vol 327 (1) ◽  
pp. 203-208 ◽  
Author(s):  
Valerie B. O'DONNELL ◽  
Hartmut KÜHN
Keyword(s):  
Linoleic Acid ◽  
Co Oxidation ◽  
Specific Binding ◽  
Nadh Oxidation ◽  
Computer Assisted ◽  
Radical Intermediate ◽  
Sequence Alignments ◽  
Fatty Acid Binding ◽  
Major Reaction Product ◽  
Major Reaction

The purified 15-lipoxygenase from rabbit reticulocytes is capable of oxidizing NADH in the presence of linoleic acid and oxygen. This co-oxidation proceeds at a rate that amounts to approx. 7% of linoleic acid oxygenation rates. Although NADH inhibits the lipoxygenase reaction with linoleic acid as substrate (46% inhibition at 0.2 mM NADH), the reaction specificity of the enzyme was not altered since (13S)-hydroperoxy-(9Z,11E)-octadecadienoic acid was identified as the major reaction product. NADH oxidation was inhibited by NAD+ (uncompetitive with respect to linoleate and mixed/competitive with respect to NADH), and NADPH or NMNH could substitute for NADH with slightly different apparent Km values. NADH oxidation was enhanced at lower oxygen tension, but was completely prevented under anaerobic conditions. Computer-assisted modelling of 15-lipoxygenase/NADH interaction and sequence alignments of mammalian lipoxygenases with NADH-dependent enzymes suggested that there is no specific binding of the coenzyme at the putative fatty acid-binding site of lipoxygenases. These results suggest that NAD(P)H might be oxidized by a radical intermediate formed during the dioxygenase cycle of the lipoxygenase reaction but that NADH oxidation might not proceed at the active site of the enzyme. The mechanism and possible biological consequences of 15-lipoxygenase-catalysed NAD(P)H oxidation are discussed.

scholarly journals Structural and Data Science-Driven Analysis to Assess Substrate Specificity of Diketopiperazine Reverse Prenyltransferase NotF: Cascade Biocatalytic Synthesis of (–)-Eurotiumin A

2021 ◽  
Author(s):  
Samantha P. Kelly ◽  
Vikram V. Shende ◽  
Autumn R. Flynn ◽  
Qingyun Dan ◽  
Ying Ye ◽  
...  
Keyword(s):  
Data Science ◽  
Early Stage ◽  
Oxidative Cyclization ◽  
Biologically Active ◽  
Full Potential ◽  
One Pot ◽  
Unique Approach ◽  
Substrate Promiscuity ◽  
Insight Into

Prenyltransfer is an early-stage carbon–hydrogen bond (C–H) functionalization prevalent in the biosynthesis of a diverse array of biologically active bacterial, fungal, plant, and metazoan diketopiperazine (DKP) alkaloids. Towards the development of a unified strategy for biocatalytic construction of prenylated DKP indole alkaloids, we sought to identify and characterize a substrate-permissive C2 reverse prenyltransferase (PT). In the biosynthesis of cytotoxic notoamide metabolites, PT NotF is responsible for catalyzing the first tailoring event of C2 reverse prenyltransfer of brevianamide F (cyclo(L-Trp-L-Pro)). Obtaining a high-resolution crystal structure of NotF (in complex with native substrate and prenyl donor mimic dimethylallyl S-thiolodiphosphate (DMSPP)) revealed a large, solvent exposed substrate binding site, intimating NotF may possess significant substrate promiscuity. To assess the full potential of NotF’s broad substrate selectivity, we synthesized a panel of 30 tryptophanyl DKPs with a suite of sterically and electronically differentiated amino acids, which were selectively prenylated by NotF in often synthetically useful conversions (2 to >99%). Quantitative representation of this substrate library enabled the development of a descriptive statistical model that provided insight into the origins of NotF’s substrate promiscuity. Through this unique approach for understanding enzyme scope, we identified key substrate descriptors such as electrophilicity, size, and flexibility, that govern enzymatic turnover by NotF. Additionally, we demonstrated the ability to couple NotF-catalyzed prenyltransfer with oxidative cyclization using recently characterized flavin monooxygenase, BvnB, from the brevianamide biosynthetic pathway. This one-pot, in vitro biocatalytic cascade proceeds with exceptional substrate recognition, and enabled the first chemoenzymatic synthesis of the marine fungal natural product, (–)-eurotiumin A, in three steps and 60% overall yield.

Significance of Microwave Irradiation in Synthesis of Thiazolidin-4-one Bearing Pyrimidine Analogues: Their in vitro Antimicrobial, Antituberculosis and Antimalarial Studies

2020 ◽  
Vol 7 (3) ◽  
pp. 230-237
Author(s):  
Navin B. Patel ◽  
Hetal I. Soni ◽  
Rahul B. Parmar
Keyword(s):  
Plasmodium Falciparum ◽  
Microwave Irradiation ◽  
Antimalarial Activity ◽  
Biological Response ◽  
13C Nmr Spectroscopy ◽  
Biological Evaluation ◽  
Biologically Active ◽  
Microwave Irradiation Method ◽  
Tuberculosis Activity

Aim: To synthesise biologically active thiazolidin-4-one by microwave irradiation method and evaluate against different species of bacteria, fungi and Plasmodium falciparum. Background: Microwave irradiation method is serviceable for rapid and sustainable synthesis. In this present study, Thiazolidin-4-one bearing pyrimidine derivatives have been synthesized by microwave irradiation method. Objective: Thiazolidin-4-one is a valuable motif because of its broad-spectrum biological evaluation. It is famous for many types of biological profiles, mainly antimicrobial, anti-tuberculosis, anti- convulsant, antihypertensive, hypoglycemic agent and antimalarial. This biological response leads our attention towards the change of Thiazolidin-4-one skeleton to enhance potential. Present study aims to carry out a rapid synthesis of Thiazolidin-4-one derivative of pyrimidine by microwave- assisted heating. Methods: 4-(4-substituted phenyl)-6-(substituted aryl) pyrimidin-2-amine was the key intermediate required for the synthesis of 3-(4-(Substituted phenyl)-6-(substituted aryl) pyrimidin-2-yl)-2-(4-hydroxy phenyl) thiozolidin-4-one (5A-J), which was prepared by using microwave irradiation. The structures of all newly synthesized motifs were characterized by spectral analysis (IR, 1H NMR, 13C NMR spectroscopy) and screened for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pyogenes; antifungal activity against Candida albicans, Aspergillus niger, Aspergillus Clavatus; anti-tuberculosis activity against M. tuberculosis H37RV and antimalarial activity against Plasmodium falciparum. Results: Higher yield with less time-consuming method is the main advantage of Thiazolidin- 4-one bearing pyrimidine motifs synthesis. The excellent biological response of compounds 5B, 5C, 5D, 5G, 5H, 5I, and 5J was observed. Conclusion: As compared to conventional method, less time is required for the preparation of Thiazolidin- 4-one analogues by using advantageous microwave irradiation method. Thiazolidin-4-one derivatives showed improved biological activity.

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