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 Synthesis and Biological Evaluation of Novel Thiazole Hydrazines as Antimicrobial and Antimalarial Agents

2020 ◽  
Vol 10 (1) ◽  
pp. 1846-1855
Keyword(s):  
Plasmodium Falciparum ◽  
Spectral Analysis ◽  
Antimalarial Activity ◽  
Biological Evaluation ◽  
Phenacyl Bromide ◽  
Good Activity ◽  
E Coli ◽  
Fungal Strains ◽  
Antimalarial Agents ◽  
Synthesis And Biological Evaluation

Synthesis of some novel thiazole hydrazine derivatives from thiosemicarbazones of salicylaldehyde and 5-chlorosalicylaldehyde with phenacyl bromide in ethanol under reflux condition is reported. The synthesized compounds were characterized by spectral analysis and further screened against - S. aureus, E. coli, P. aeruginosa, S. pyogenus bacteria, and against C. albicans, A. clavatus, and A. niger fungal strains. Most of the compounds were active against E. coli and C. albicans. Antimalarial screening against Plasmodium falciparum showed moderate to the good activity of the synthesized compounds but less than the standard quinine. One of the synthesized compounds (4c) exhibited promising antimalarial activity against Plasmodium falciparum with IC50 close to the standard quinine.

scholarly journals Antimalarial Inhibitors Targeting Epigenetics or Mitochondria in Plasmodium falciparum: Recent Survey upon Synthesis and Biological Evaluation of Potential Drugs against Malaria

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5711
Author(s):  
Christina L. Koumpoura ◽  
Anne Robert ◽  
Constantinos M. Athanassopoulos ◽  
Michel Baltas
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Infectious Diseases ◽  
Dna Methyltransferases ◽  
Biological Evaluation ◽  
Dihydroorotate Dehydrogenase ◽  
Drug Candidates ◽  
The Past ◽  
Synthesis And Biological Evaluation ◽  
Epigenetic Processes

Despite many efforts, malaria remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by P. falciparum. Over the past decade, new essential pathways have been emerged to fight against malaria. Among them, epigenetic processes and mitochondrial metabolism appear to be important targets. This review will focus on recent evolutions concerning worldwide efforts to conceive, synthesize and evaluate new drug candidates interfering selectively and efficiently with these two targets and pathways. The focus will be on compounds/scaffolds that possess biological/pharmacophoric properties on DNA methyltransferases and HDAC’s for epigenetics, and on cytochrome bc1 and dihydroorotate dehydrogenase for mitochondrion.

scholarly journals Assessment of the Drug Susceptibility of Plasmodium falciparum Clinical Isolates from Africa by Using a Plasmodium Lactate Dehydrogenase Immunodetection Assay and an Inhibitory Maximum Effect Model for Precise Measurement of the 50-Percent Inhibitory Concentration

2006 ◽  
Vol 50 (10) ◽  
pp. 3343-3349 ◽  
Author(s):  
Halima Kaddouri ◽  
Serge Nakache ◽  
Sandrine Houzé ◽  
France Mentré ◽  
Jacques Le Bras
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Lactate Dehydrogenase ◽  
Active Metabolite ◽  
Inhibitory Concentration ◽  
Drug Susceptibility ◽  
Maximum Effect ◽  
Malaria Parasites ◽  
Effect Model

ABSTRACT The extension of drug resistance among malaria-causing Plasmodium falciparum parasites in Africa necessitates implementation of new combined therapeutic strategies. Drug susceptibility phenotyping requires precise measurements. Until recently, schizont maturation and isotopic in vitro assays were the only methods available, but their use was limited by technical constraints. This explains the revived interest in the development of replacement methods, such as the Plasmodium lactate dehydrogenase (pLDH) immunodetection assay. We evaluated a commercially controlled pLDH enzyme-linked immunosorbent assay (ELISA; the ELISA-Malaria antigen test; DiaMed AG, Cressier s/Morat, Switzerland) to assess drug susceptibility in a standard in vitro assay using fairly basic laboratory equipment to study the in vitro resistance of malaria parasites to major antimalarials. Five Plasmodium falciparum clones and 121 clinical African isolates collected during 2003 and 2004 were studied by the pLDH ELISA and the [8-3H]hypoxanthine isotopic assay as a reference with four antimalarials. Nonlinear regression with a maximum effect model was used to estimate the 50% inhibitory concentration (IC50) and its confidence intervals. The two methods were observed to have similar reproducibilities, but the pLDH ELISA demonstrated a higher sensitivity. The high correlation (r = 0.98) and the high phenotypic agreement (κ = 0.88) between the two methods allowed comparison by determination of the IC50s. Recently collected Plasmodium falciparum African isolates were tested by pLDH ELISA and showed drug resistance or decreased susceptibilities of 62% to chloroquine and 11.5% to the active metabolite of amodiaquine. No decreased susceptibility to lumefantrine or the active metabolite of artemisinin was detected. The availability of this simple and highly sensitive pLDH immunodetection assay will provide an easier method for drug susceptibility testing of malaria parasites.

scholarly journals Multiple Antibiotics Exert Delayed Effects against the Plasmodium falciparum Apicoplast

2007 ◽  
Vol 51 (10) ◽  
pp. 3485-3490 ◽  
Author(s):  
Erica L. Dahl ◽  
Philip J. Rosenthal
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Division ◽  
Antimalarial Activity ◽  
Mechanisms Of Action ◽  
Malaria Parasites ◽  
Delayed Effects ◽  
Delayed Death ◽  
Antimalarial Action ◽  
Multiple Antibiotics

ABSTRACT Several classes of antibiotics exert antimalarial activity. The mechanisms of action of antibiotics against malaria parasites have been unclear, and prior studies have led to conflicting results, in part because they studied antibiotics at suprapharmacological concentrations. We examined the antimalarial effects of azithromycin, ciprofloxacin, clindamycin, doxycycline, and rifampin against chloroquine-resistant (W2) and chloroquine-sensitive (3D7) Plasmodium falciparum strains. At clinically relevant concentrations, rifampin killed parasites quickly, preventing them from initiating cell division. In contrast, pharmacological concentrations of azithromycin, ciprofloxacin, clindamycin, and doxycycline were relatively inactive against parasites initially but exerted a delayed death effect, in which the progeny of treated parasites failed to complete erythrocytic development. The drugs that caused delayed death did not alter the distribution of apicoplasts into developing progeny. However, the apicoplasts inherited by the progeny of treated parasites were abnormal. The loss of apicoplast function became apparent as the progeny of antibiotic-treated parasites initiated cell division, with the failure of schizonts to fully mature or for erythrocyte rupture to take place. These findings explain the slow antimalarial action of multiple antibiotics.

scholarly journals Synthesis and Biological Evaluation of Febrifugine Analogues

2014 ◽  
Vol 9 (12) ◽  
pp. 1934578X1400901
Author(s):  
Huong Doan Thi Mai ◽  
Giang Vo Thanh ◽  
Van Hieu Tran ◽  
Van Nam Vu ◽  
Van Loi Vu ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antimalarial Activity ◽  
Biological Evaluation ◽  
Strong Inhibition ◽  
Synthetic Analogues ◽  
Synthetic Compounds ◽  
Activity Evaluation ◽  
Synthesis And Biological Evaluation

A series of febrifugine analogues were designed and synthesized. Antimalarial activity evaluation of the synthetic compounds indicated that these derivatives had a strong inhibition against both chloroquine-sensitive and -resistant Plasmodium falciparum parasites. Many of them were found to be more active than febrifugine hydrochloride. The tested analogues had also a significant cytotoxicity against four cancer cell lines (KB, MCF7, LU1 and HepG2). Among the synthetic analogues, two compounds 17b and 17h displayed a moderate cytotoxicity while they exhibited a remarkable antimalarial activity.

scholarly journals Synthesis and Antimalarial Activity of 1,4-Disubstituted Piperidine Derivatives

Molecules ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 299 ◽  
Author(s):  
Rokhyatou Seck ◽  
Abdoulaye Gassama ◽  
Sandrine Cojean ◽  
Christian Cavé
Keyword(s):  
Plasmodium Falciparum ◽  
Side Effects ◽  
Antimalarial Activity ◽  
Low Cost ◽  
Compound Library ◽  
New Compounds

In order to prepare, at low cost, new compounds active against Plasmodium falciparum, and with a less side-effects, we have designed and synthesized a library of 1,4-disubstituted piperidine derivatives from 4-aminopiperidine derivatives 6. The resulting compound library has been evaluated against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. The most active molecules—compounds 12d (13.64 nM (3D7)), 13b (4.19 nM (3D7) and 13.30 nM (W2)), and 12a (11.6 nM (W2))—were comparable to chloroquine (22.38 nM (3D7) and 134.12 nM (W2)).

scholarly journals A Single-Dose Combination Study with the Experimental Antimalarials Artefenomel and DSM265 To Determine Safety and Antimalarial Activity against Blood-Stage Plasmodium falciparum in Healthy Volunteers

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
James S. McCarthy ◽  
Thomas Rückle ◽  
Suzanne L. Elliott ◽  
Emma Ballard ◽  
Katharine A. Collins ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Plasma Concentrations ◽  
Parasite Clearance ◽  
Blood Stage ◽  
Content Type ◽  
Dose Combination ◽  
Combination Study ◽  
Study Support ◽  
New Compounds

ABSTRACT Artefenomel and DSM265 are two new compounds that have been shown to be well tolerated and effective when administered as monotherapy malaria treatment. This study aimed to determine the safety, pharmacokinetics, and pharmacodynamics of artefenomel and DSM265 administered in combination to healthy subjects in a volunteer infection study using the Plasmodium falciparum-induced blood-stage malaria model. Thirteen subjects were inoculated with parasite-infected erythrocytes on day 0 and received a single oral dose of artefenomel and DSM265 on day 7. Cohort 1 (n = 8) received 200 mg artefenomel plus 100 mg DSM265, and cohort 2 (n = 5) received 200 mg artefenomel plus 50 mg DSM265. Blood samples were collected to measure parasitemia, gametocytemia, and artefenomel-DSM265 plasma concentrations. There were no treatment-related adverse events. The pharmacokinetic profiles of artefenomel and DSM265 were similar to those of the compounds when administered as monotherapy, suggesting no pharmacokinetic interactions. A reduction in parasitemia occurred in all subjects following treatment (log10 parasite reduction ratios over 48 h [PRR48] of 2.80 for cohort 1 and 2.71 for cohort 2; parasite clearance half-lives of 5.17 h for cohort 1 and 5.33 h for cohort 2). Recrudescence occurred in 5/8 subjects in cohort 1 between days 19 and 28 and in 5/5 subjects in cohort 2 between days 15 and 22. Low-level gametocytemia (1 to 330 female gametocytes/ml) was detected in all subjects from day 14. The results of this single-dosing combination study support the further clinical development of the use of artefenomel and DSM265 in combination as a treatment for falciparum malaria. (This study has been registered at ClinicalTrials.gov under identifier NCT02389348.)

scholarly journals Nanopore sequencing of drug-resistance-associated genes in malaria parasites, Plasmodium falciparum

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Lucky R. Runtuwene ◽  
Josef S. B. Tuda ◽  
Arthur E. Mongan ◽  
Wojciech Makalowski ◽  
Martin C. Frith ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Nanopore Sequencing ◽  
Malaria Parasites

scholarly journals Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Hangjun Ke ◽  
Joanne M. Morrisey ◽  
Shiwei Qu ◽  
Oraphin Chantarasriwong ◽  
Michael W. Mather ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Morphological Changes ◽  
Biological Activities ◽  
Hek293 Cells ◽  
Therapeutic Window ◽  
Malaria Parasites ◽  
Content Type ◽  
Lead Compounds ◽  
Antimalarial Agents ◽  
Transport Chain

ABSTRACT Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia. CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ∼10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents.

scholarly journals Andrographolide: A Novel Antimalarial Diterpene Lactone Compound fromAndrographis paniculataand Its Interaction with Curcumin and Artesunate

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Kirti Mishra ◽  
Aditya P. Dash ◽  
Nrisingha Dey
Keyword(s):  
Plasmodium Falciparum ◽  
Life Span ◽  
Plasmodium Berghei ◽  
Antimalarial Activity ◽  
Andrographis Paniculata ◽  
Antiplasmodial Activity ◽  
Template Molecule

Andrographolide (AND), the diterpene lactone compound, was purified by HPLC from the methanolic fraction of the plantAndrographis paniculata. The compound was found to have potent antiplasmodial activity when tested in isolation and in combination with curcumin and artesunate against the erythrocytic stages ofPlasmodium falciparum in vitroandPlasmodium bergheiANKAin vivo. IC50s for artesunate (AS), andrographolide (AND), and curcumin (CUR) were found to be 0.05, 9.1 and 17.4 μM, respectively. The compound (AND) was found synergistic with curcumin (CUR) and addictively interactive with artesunate (AS).In vivo, andrographolide-curcumin exhibited better antimalarial activity, not only by reducing parasitemia (29%), compared to the control (81%), but also by extending the life span by 2-3 folds. Being nontoxic to thein vivosystem this agent can be used as template molecule for designing new derivatives with improved antimalarial properties.

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