Synthesis, Antimalarial Activity, and Intracellular Targets of MEFAS, a New Hybrid Compound Derived from Mefloquine and Artesunate

ABSTRACT A new synthetic antimalarial drug, a salt derived from two antimalarial molecules, mefloquine (MQ) and artesunate (AS), here named MEFAS, has been tested for its pharmacological activity. Combinations of AS plus MQ hydrochloride are currently being used in areas with drug-resistant Plasmodium falciparum parasites; although AS clears parasitemia in shorter time periods than any other antimalarial drug, it does not cure infected patients; in addition, MQ causes side effects and is rather expensive, important problems considering that malaria affects mostly populations in poor countries. Here, we show that MEFAS is more effective than the combination of AS and MQ, tested in parallel at different mass proportions, against P. falciparum (chloroquine-resistant clone W2 and chloroquine-sensitive clone 3D7) in vitro and in mice infected with Plasmodium berghei, promoting cure of this infection. MEFAS tested against HepG2 hepatoma cells exhibited lower toxicity than the antimalarials AS and MQ alone or combined. Possible targets of MEFAS have been studied by confocal microscopy using fluorescent probes (Fluo-4 AM and BCECF-AM) in P. falciparum synchronous culture of W2-infected red blood cells. Dynamic images show that MEFAS exhibited intracellular action increasing cytoplasmic Ca2+ at 1.0 ng/ml. This effect was also observed in the presence of tapsigargin, an inhibitor of SERCA, suggesting an intracellular target distinct from the endoplasmic reticulum. Trophozoites loaded with BCECF-AM, when treated with MEFAS, were still able to mobilize protons from the digestive vacuole (DV), altering the pH gradient. However, in the presence of bafilomycin A1, an inhibitor of the H+ pump from acidic compartments of eukaryotic cells, MEFAS had no action on the DV. In conclusion, the endoplasmic reticulum and DV are intracellular targets for MEFAS in Plasmodium sp., suggesting two modes of action of this new salt. Our data support MEFAS as a candidate for treating human malaria.

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Exploratory Analysis into the in vitro and in silico Activity of E. fusca Lour. (Fabaceae) Elucidates Substantial Antiplasmodial Activity of the Plant

10.20944/preprints202010.0576.v2 ◽

2021 ◽

Author(s):

Saiful Arefeen Sazed ◽

Ohedul Islam ◽

Sarah L. Bliese ◽

Muhammad Riadul Haque Hossainey ◽

Jakaria Shawon ◽

...

Keyword(s):

Antimalarial Drug ◽

Simulation Analysis ◽

Antimalarial Activity ◽

Dynamics Simulation ◽

Drug Candidate ◽

Phytochemical Investigation ◽

High Degree ◽

Emergence Of Resistance ◽

First Time

The exploration of alternative antimalarial therapeutics is a requisite for the emergence of resistance against Artemisinin. Considering the required cost and time length of classical small molecule drug discovery process, phytochemical screening of traditionally used medicinal plant which are repertoire of active compounds with antimalarial activity has become popular. To investigate the antimalarial property of traditionally used medicinal plants, a number of Erythrina spp have been reviewed systematically where less studied E. fusca has been selected for further analysis. Phytochemical investigation yielded five compounds namely; Phaseolin, Phytol, β-amyrin, Lupeol, and Stigmasterol. In-vitro antimalarial drug sensitivity HRP-II ELISA was carried out against chloroquine (CQ) sensitive 3D7 and CQ-resistant Dd2 strains. Extracts showed significant antimalarial activity against 3D7 and Dd2 strains (IC50 4.94 – 22 µg/mL) and these compounds have been reported here for the first time. Molecular docking analysis showed high binding energy (−9.0 ± 0.32 kcal/mole) indicating high degree of interaction between Phaseolin and 14 clinically important Plasmodium falciparum proteins at the active site. Stable interaction was also observed between ligand and protein from molecular dynamics simulation analysis with high free energy (−75.156 ± 11.459) that substantiates the potential of Phaseolin as an antimalarial drug candidate.

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Synthesis and Antimalarial Activities of Cyclen 4-Aminoquinoline Analogs

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01304-08 ◽

2009 ◽

Vol 53 (4) ◽

pp. 1320-1324 ◽

Cited By ~ 16

Author(s):

M. O. Faruk Khan ◽

Mark S. Levi ◽

Babu L. Tekwani ◽

Shabana I. Khan ◽

Eiichi Kimura ◽

...

Keyword(s):

Mammalian Cells ◽

High Selectivity ◽

Antimalarial Activity ◽

New Class ◽

Antimalarial Agents ◽

Sensitive Clone ◽

Resistant Strains ◽

Incorporation Assay

ABSTRACT In an attempt to augment the efficacy of 7-chloro 4-aminoquinoline analogs and also to overcome resistance to antimalarial agents, we synthesized three cyclen (1,4,7,10-tetraazacyclododecane) analogs of chloroquine [a bisquinoline derivative, 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline HBr, and a 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline-Zn2+ complex]. The bisquinoline displays the most potent in vitro and in vivo antimalarial activities. It displays 50% inhibitory concentrations (IC50s) of 7.5 nM against the D6 (chloroquine-sensitive) clone of Plasmodium falciparum and 19.2 nM against the W2 (chloroquine-resistant) clone, which are comparable to those of artemisinin (10.6 and 5.0 nM, respectively) and lower than those of chloroquine (10.7 and 87.2 nM, respectively), without any evidence of cytotoxicity to mammalian cells, indicating a high selectivity index (>1,333 against D6 clone and >521 against W2 clone). Potent antimalarial activities of the bisquinoline against chloroquine- and mefloquine-resistant strains of P. falciparum were also confirmed by in vitro [3H]hypoxanthine incorporation assay. The in vivo antimalarial activity of the bisquinoline, as determined in P. berghei-infected mice, is comparable to that of chloroquine (50% effective dose, ≤1.1 mg/kg when given orally); no apparent toxicity has been observed up to the highest dose tested (3 × 30 mg/kg). The bisquinoline inhibits in vitro hemozoin (β-hematin) formation with an IC50 of 1.1 μM, which is about 10-fold more potent than chloroquine (IC50 9.5 μM). Overall, this article describes the discovery of a new class of cyclen 4-aminoquinoline analogs as potent antimalarial drugs.

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4-Aminosalicylic Acid-Based Hybrid Compounds: Synthesis and In Vitro Antiplasmodial Evaluation

Letters in Drug Design & Discovery ◽

10.2174/1570180817999200802031547 ◽

2020 ◽

Vol 17 ◽

Author(s):

Siphesihle Jama ◽

Xhamla Nqoro ◽

Eric Morifi ◽

Blessing Atim Aderibigbe

Keyword(s):

Antimalarial Activity ◽

Antimalarial Drugs ◽

Aminosalicylic Acid ◽

African Region ◽

Hybrid Compound ◽

Hybrid Compounds ◽

Folate Pathway ◽

Ic50 Value ◽

Wide Range

Background: Malaria is a deadly and infectious disease responsible for millions of death worldwide mostly in the African region. The malaria parasite has developed resistance to the currently used antimalarial drugs and it has urged researchers to develop new strategies to overcome this challenge by designing different classes of antimalarials. Objectives: A class of hybrid compounds containing 4-aminosalicylic acid moiety was prepared via esterification and amidation reactions and characterized using FTIR, NMR and LC-MS. In vitro antiplasmodial evaluation was performed against asexual NF54 strain of P. falciparum parasites. Method: In this research, known 4-aminoquinoline derivatives were hybridized with 4-aminosalicylic acid to afford hybrid compounds via esterification and amidation reactions. 4-aminosalicylic acid, a dihydrofolate compound inhibits DNA synthesis in the folate pathway and is a potential pharmacophore for the development of antimalarials. Results: The LC-MS, FTIR and NMR analysis confirmed the successful synthesis of the compounds. The compounds were obtained in yields in the range of 63-80%. The hybrid compounds displayed significant antimalarial activity when compared to 4-aminosalicylic acid which exhibited poor antimalarial activity. The IC50 value of the most potent hybrid compound, 9 was 9.54±0.57 nm. Conclusion: 4-aminosalicylic has different functionalities which can be used for hybridization with a wide range of compounds. It is a potential pharmacophore that can be utilized for the design of potent antimalarial drugs. It was found to be a good potentiating agent when hybridized with 4-aminoquinoline derivatives suggesting that they can be utilized for the synthesis of a new class of antimalarials.

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In vitro antimalarial activity of some organotin(IV)2-nitrobenzoate compounds against Plasmodium falciparum

Macedonian Journal of Chemistry and Chemical Engineering ◽

10.20450/mjcce.2018.1414 ◽

2018 ◽

Vol 37 (2) ◽

Cited By ~ 3

Author(s):

Sutopo Hadi ◽

Noviany Noviany ◽

Mita Rilyanti

Keyword(s):

Plasmodium Falciparum ◽

Antimalarial Drug ◽

Antimalarial Activity ◽

Positive Control ◽

Intermediate Products ◽

Nitrobenzoic Acid ◽

The Future ◽

Ic50 Values

Antimalarial activity study of organotin(IV) derivatives with nitrobenzoic acid derivatives used as ligands has been performed. The targeted compounds were prepared from their organotin(IV) chlorides via dibutyltin(IV) oxide, diphenyltin(IV) dihydroxide, and triphenyltin(IV) hydroxide intermediate products, followed by reacting the intermediate products with 2-nitrobenzoic acid. The antimalarial activity was performed against P. falciparum. The results showed that the IC50values of dibutyiltin(IV) di-2-nitrobenzoate, diphenyltin(IV) di-2-nitrobenzoate, and triphenyltin(IV) 2-nitrobenzoate were in 8.4 × 10‑3, 5.3 × 10–2, and 9.1 × 10–3 µg/ml, respectively. The IC50 values were slightly higher than the value for chloroquine (2 × 10–3 µg/ml) used as the positive control; however, one advantage is that all prepared organotin(IV) compounds were not resistant to Plasmodium, making the use of organotin(IV) as an antimalarial is possible. The results indicated that the derivative of triphenyltin(IV) was more potent when used as an antimalarial, as expected, and has potential to be developed as an antimalarial drug in the future.

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Design, Synthesis, Antimalarial Activity and Docking Study of 7-Chloro-4- (2-(substituted benzylidene)hydrazineyl)quinolines

Medicinal Chemistry ◽

10.2174/1573406415666190806154722 ◽

2020 ◽

Vol 16 (7) ◽

pp. 928-937 ◽

Cited By ~ 1

Author(s):

Jahnabi Kalita ◽

Dipak Chetia ◽

Mithun Rudrapal

Keyword(s):

Antimalarial Drug ◽

Disease Burden ◽

Antimalarial Activity ◽

Docking Study ◽

Molecular Scaffold ◽

Design Synthesis ◽

Antimalarial Agents ◽

Drug Molecules ◽

Resistant Strains

Background: Malaria is a growing infectious disease burden due to the increasing emergence of resistant strains of Plasmodium falciparum. Because of the limited therapeutic efficacy of available antimalarial drugs, the development of potent antimalarial drug agents is therefore an urgent requirement to fight against resistant malaria. Objective: The objective of this work was to develop novel quinoline-baed antimalarial agents that would be active against resistant P. falciparum malaria. Methods: Some 7-chloro-4-(2-(substituted benzylidene)hydrazineyl)quinolines were synthesized for the evaluation of their potential as possible antimalarial agents, particularly against resistant malaria. The antimalarial activity of synthesized compounds was evaluated in vitro against bloodstage parasites of P. falciparum. Further, molecular docking and drug-likeness including ADMET (Absorption, Distribution, Metabolism, Elimination and Toxicity) studies were also carried out using in silico tools. Results: Results reveal the in vitro antimalarial activity of synthesized 7-chloro-4-(2-(substituted benzylidene)hydrazineyl)quinolines against P. falciparum. The docking study investigates the antimalarial effectiveness of synthesized quinolines as novel plasmepsin 2 inhibitors. Drug-likeness prediction exhibits acceptable drug-likeness and ADMET properties. Conclusion: Based upon our findings, it is concluded that the molecular scaffold of 7-chloro-4-(2- (substituted benzylidene)hydrazineyl)quinolines may be used as a lead structure for further modifications in the search of more potent antimalarial drug molecules.

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A systems-guided approach to discover the intracellular target of a novel evolution-drug lead

10.1101/2021.05.17.444532 ◽

2021 ◽

Author(s):

Sourav Chowdhury ◽

Daniel Craig Zielinski ◽

Christopher Dalldorf ◽

Joao V Rodrigues ◽

Bernhard Palsson ◽

...

Keyword(s):

Structural Similarity ◽

Difficult Problem ◽

E Coli ◽

Metabolic Network Analysis ◽

Drug Lead ◽

Intracellular Target ◽

Bacterial Growth Inhibition ◽

Intracellular Targets

Understanding intracellular antibiotic targeting and the associated mechanisms leading to bacterial growth inhibition has been a difficult problem. Here, we discovered the additional intracellular targets of the novelevolution-drug lead CD15-3 designed to delay the emergence of antibiotic resistance by inhibiting bacterial DHFR and its Trimethoprim resistant variants. Overexpression of DHFR only partially rescued inhibition of E. coli growth by CD15.3 suggesting that CD15.3 also inhibits a non-DHFR target in the cell. We utilized untargeted global metabolomics and the metabolic network analysis along with structural similarity search of the putative targets to identify the additional target of CD15-3. We validated in vivo and in vitro that besides DHFR CD15-3 inhibits HPPK (folK), an essential protein upstream of DHFR in bacterial folate metabolism. This bivalent cellular targeting makes CD15-3 a promising lead to develop a monotherapy analogue of combination drugs.

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Phytochemical, Biological and Computational Investigations of Erythrina fusca Lour. to Assess Antimalarial Property against Plasmodium falciparum

10.20944/preprints202010.0576.v1 ◽

2020 ◽

Author(s):

Saiful Arefeen Sazed ◽

Ohedul Islam ◽

Sarah L. Bliese ◽

Muhammad Riadul Haque Hossainey ◽

Mahfuza Afroz Soma ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Molecular Docking ◽

Antimalarial Drug ◽

Antimalarial Activity ◽

Drug Candidate ◽

Separation And Purification ◽

Membrane Stabilization ◽

Phytochemical Investigation ◽

Biological Tests

For centuries medicinal plants have been traditionally used for prophylaxis and ailment of diseases. Nowadays it’s easy to isolate, purify, and characterize bioactive compounds with high efficacy. To investigate the medicinal especially antimalarial property of traditionally used plants, a number of Erythrina spp have been reviewed systematically where Erythrina fusca has been selected for further analysis. Phytochemical investigation included chromatographic separation and purification of compounds followed by characterization using NMR. In-vitro antimalarial drug sensitivity ELISA was carried out against chloroquine (CQ) sensitive 3D7 and resistant Dd2 strains. Additional biological tests such as central and peripheral analgesic, antioxidant, anti-diarrheal, hypoglycemic, thrombolytic, and membrane stabilization activities were also investigated. Molecular docking was performed using the isolated compounds against clinically important 14 Plasmodium falciparum proteins. For the first time, Phaseolin, Phytol, β-amyrin, Lupeol, and Stigmasterol are reported here and extracts showed significant antimalarial activity against 3D7 and Dd2 strains (IC50 4.94-22 µg/mL). Potent central analgesic, antioxidant and anti-diarrheal activities (p&lt;0.05) and mild thrombolytic and membrane stabilization properties were also observed. Molecular docking of Phaseolin bolsters its potential as a new antimalarial drug candidate. This study projects significant medicinal values and necessitates further investigations to reveal its potential as a novel source of therapeutics.

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Role of the Neurotransmitter Reuptake-Blocking Activity of Antidepressants in Reversing Chloroquine Resistance In Vitro in Plasmodium falciparum

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.10.2689-2692.2000 ◽

2000 ◽

Vol 44 (10) ◽

pp. 2689-2692 ◽

Cited By ~ 10

Author(s):

Dale Taylor ◽

Jason C. Walden ◽

Ashley H. Robins ◽

Peter J. Smith

Keyword(s):

Plasmodium Falciparum ◽

Antimalarial Activity ◽

Chloroquine Resistance ◽

Resistant Isolate ◽

Significant Shift ◽

Sensitive Clone ◽

Resistance Reversal ◽

Synaptic Level

ABSTRACT Since the discovery of the chloroquine (CQ) resistance reversal properties of several different, structurally unrelated classes of compounds, including antidepressants, the way is again open to employ the aminoquinoline drugs to combat malaria effectively. In this study, CQ sensitivity was restored to varying extents in vitro in the CQ-resistant Plasmodium falciparum strain RSA11 by using the antidepressants amitriptyline, citalopram, oxaprotiline, and nomifensine. The 50% inhibitory concentrations (IC50) of CQ were reduced from 360 to as low as 11 nM when antidepressants were present. These particular antidepressants are highly specific for blocking the ATP-binding cassette transport protein-mediated reuptake of different neurotransmitters at the synaptic level. This study was aimed at determining the extent to which the neurotransmitter reuptake-blocking properties of these antidepressants play a role in the reversal process. None of the compounds or CQ-antidepressant combinations tested had innate antimalarial activity. No chemosensitizer or combination showed an increased CQ accumulation or significant shift in the IC50 in the CQ-sensitive clone D10. Of the compounds tested, citalopram, a highly specific serotonin reuptake blocker, produced the largest shift observed in the IC50 for the resistant isolate RSA11. No particular class of antidepressant was found to be better than any other at restoring CQ sensitivity. We conclude that the resistance-reversing properties of these compounds do not correlate with their activities as reuptake blockers.

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Stability of the Antimalarial Drug Dihydroartemisinin under Physiologically Relevant Conditions: Implications for Clinical Treatment and Pharmacokinetic andIn VitroAssays

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00183-15 ◽

2015 ◽

Vol 59 (7) ◽

pp. 4046-4052 ◽

Cited By ~ 25

Author(s):

Silvia Parapini ◽

Piero Olliaro ◽

Visweswaran Navaratnam ◽

Donatella Taramelli ◽

Nicoletta Basilico

Keyword(s):

Antimalarial Drug ◽

High Performance ◽

Antimalarial Activity ◽

Storage Conditions ◽

Chemosensitivity Assay ◽

Content Type ◽

Detection Analysis ◽

Different Temperatures ◽

Phosphate Buffered Saline

ABSTRACTArtemisinins are peroxidic antimalarial drugs known to be very potent but highly chemically unstable; they degrade in the presence of ferrous iron, Fe(II)-heme, or biological reductants. Less documented is how this translates into chemical stability and antimalarial activity across a range of conditions applying toin vitrotesting and clinical situations. Dihydroartemisinin (DHA) is studied here because it is an antimalarial drug on its own and the main metabolite of other artemisinins. The behaviors of DHA in phosphate-buffered saline, plasma, or erythrocyte lysate at different temperatures and pH ranges were examined. The antimalarial activity of the residual drug was evaluated using the chemosensitivity assay onPlasmodium falciparum, and the extent of decomposition of DHA was established through use of high-performance liquid chromatography with electrochemical detection analysis. The role of the Fe(II)-heme was investigated by blocking its reactivity using carbon monoxide (CO). A significant reduction in the antimalarial activity of DHA was seen after incubation in plasma and to a lesser extent in erythrocyte lysate. Activity was reduced by half after 3 h and almost completely abolished after 24 h. Serum-enriched media also affected DHA activity. Effects were temperature and pH dependent and paralleled the increased rate of decomposition of DHA from pH 7 upwards and in plasma. These results suggest that particular care should be taken in conducting and interpretingin vitrostudies, prone as their results are to experimental and drug storage conditions. Disorders such as fever, hemolysis, or acidosis associated with malaria severity may contribute to artemisinin instability and reduce their clinical efficacy.

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In Vitro Induction of Crystals of MT Protein by Vinblastine-Colcemid in Mouse Spermatids

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100050676 ◽

1974 ◽

Vol 32 ◽

pp. 132-133

Author(s):

John J. Wolosewick ◽

John H. D. Bryan

Keyword(s):

Endoplasmic Reticulum ◽

Smooth Endoplasmic Reticulum ◽

Nuclear Ring ◽

Rough Er ◽

Distal Direction ◽

In Vitro Induction

Early in spermiogenesis the manchette is rapidly assembled in a distal direction from the nuclear-ring-densities. The association of vesicles of smooth endoplasmic reticulum (SER) and the manchette microtubules (MTS) has been reported. In the mouse, osmophilic densities at the distal ends of the manchette are the organizing centers (MTOCS), and are associated with the SER. Rapid MT assembly and the lack of rough ER suggests that there is an existing pool of MT protein. Colcemid potentiates the reaction of vinblastine with tubulin and was used in this investigation to detect this protein.

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