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Journal of Basic Microbiology Dec 2022Malaria caused by Plasmodium vivax is comparatively less virulent than Plasmodium falciparum, which can also lead to severe disease and death. It shows a wide... (Review)
Review
Malaria caused by Plasmodium vivax is comparatively less virulent than Plasmodium falciparum, which can also lead to severe disease and death. It shows a wide geographical distribution. Chloroquine serves as a drug of choice, with primaquine as a radical cure. However, with the appearance of resistance to chloroquine and treatment has been shifted to artemisinin combination therapy followed by primaquine as a radical cure. Sulphadoxine-pyrimethamine, mefloquine, and atovaquone-proguanil are other drugs of choice in chloroquine-resistant areas, and later resistance was soon reported for these drugs also. The emergence of drug resistance serves as a major hurdle to controlling and eliminating malaria. The discovery of robust molecular markers and regular surveillance for the presence of mutations in malaria-endemic areas would serve as a helpful tool to combat drug resistance. Here, in this review, we will discuss the endemicity of P. vivax, a historical overview of antimalarial drugs, the appearance of drug resistance and molecular markers with their global distribution along with different measures taken to reduce malaria burden due to P. vivax infection and their resistance.
Topics: Humans; Plasmodium vivax; Primaquine; Antimalarials; Malaria, Vivax; Chloroquine; Malaria
PubMed: 36125207
DOI: 10.1002/jobm.202200316 -
Molecular Diversity Feb 2022In this paper, we report the synthesis of novel hybrids 2-14 based on itaconic acid and fluoroaniline, pyridine, indole and quinoline scaffolds. Itaconic acid is a...
In this paper, we report the synthesis of novel hybrids 2-14 based on itaconic acid and fluoroaniline, pyridine, indole and quinoline scaffolds. Itaconic acid is a naturally occurring compound with a Michael acceptor moiety, a key structural feature in several anticancer and antiviral drugs, responsible for the covalent binding of a drug to the cysteine residue of a specific protein. Aromatic parts of the hybrids also come from the substances reported as anticancer or antiviral agents. The synthetic route employed to access the amido-ester hybrids 2-13 used monomethyl itaconate or monomethyl itaconyl chloride and corresponding amines as the starting materials. Dimers 14 and 15 with two aminoindole or mefloquine moieties were prepared from itaconic acid and corresponding amino derivative, using standard coupling conditions (HATU/DIEA). All hybrids exerted anticancer effects in vitro against almost all the tumour cell lines that were evaluated (MCF-7, HCT 116, H460, LN-229, Capan-1, DND-41, HL-60, K-562, Z-138). Solid tumour cells were, in general, more responsive than the haematological cancer cells. The MCF-7 breast adenocarcinoma cell line appeared the most sensitive. Amido-ester 12 with chloroquine core and mefloquine homodimer 15 showed the highest activity with GI values between 0.7 and 8.6 µM. In addition, compound 15 also exerted antiviral activity against Zika virus and Coxsackievirus B4 in low micromolar concentrations.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Structure-Activity Relationship; Succinates; Zika Virus; Zika Virus Infection
PubMed: 33043404
DOI: 10.1007/s11030-020-10147-6 -
Viruses Feb 2022Despite the development of specific therapies against severe acute respiratory coronavirus 2 (SARS-CoV-2), the continuous investigation of the mechanism of action of...
Despite the development of specific therapies against severe acute respiratory coronavirus 2 (SARS-CoV-2), the continuous investigation of the mechanism of action of clinically approved drugs could provide new information on the druggable steps of virus-host interaction. For example, chloroquine (CQ)/hydroxychloroquine (HCQ) lacks in vitro activity against SARS-CoV-2 in TMPRSS2-expressing cells, such as human pneumocyte cell line Calu-3, and likewise, failed to show clinical benefit in the Solidarity and Recovery clinical trials. Another antimalarial drug, mefloquine, which is not a 4-aminoquinoline like CQ/HCQ, has emerged as a potential anti-SARS-CoV-2 antiviral in vitro and has also been previously repurposed for respiratory diseases. Here, we investigated the anti-SARS-CoV-2 mechanism of action of mefloquine in cells relevant for the physiopathology of COVID-19, such as Calu-3 cells (that recapitulate type II pneumocytes) and monocytes. Molecular pathways modulated by mefloquine were assessed by differential expression analysis, and confirmed by biological assays. A PBPK model was developed to assess mefloquine's optimal doses for achieving therapeutic concentrations. Mefloquine inhibited SARS-CoV-2 replication in Calu-3, with an EC of 1.2 µM and EC of 5.3 µM. It reduced SARS-CoV-2 RNA levels in monocytes and prevented virus-induced enhancement of IL-6 and TNF-α. Mefloquine reduced SARS-CoV-2 entry and synergized with Remdesivir. Mefloquine's pharmacological parameters are consistent with its plasma exposure in humans and its tissue-to-plasma predicted coefficient points suggesting that mefloquine may accumulate in the lungs. Altogether, our data indicate that mefloquine's chemical structure could represent an orally available host-acting agent to inhibit virus entry.
Topics: Adenosine Monophosphate; Alanine; Alveolar Epithelial Cells; Antiviral Agents; Cell Line; Chloroquine; Drug Repositioning; Humans; Mefloquine; SARS-CoV-2; Serine Endopeptidases; Virus Internalization; COVID-19 Drug Treatment
PubMed: 35215969
DOI: 10.3390/v14020374 -
Nature Communications Feb 2024Mutations in a Plasmodium de-ubiquitinase UBP1 have been linked to antimalarial drug resistance. However, the UBP1-mediated drug-resistant mechanism remains unknown....
Mutations in a Plasmodium de-ubiquitinase UBP1 have been linked to antimalarial drug resistance. However, the UBP1-mediated drug-resistant mechanism remains unknown. Through drug selection, genetic mapping, allelic exchange, and functional characterization, here we show that simultaneous mutations of two amino acids (I1560N and P2874T) in the Plasmodium yoelii UBP1 can mediate high-level resistance to mefloquine, lumefantrine, and piperaquine. Mechanistically, the double mutations are shown to impair UBP1 cytoplasmic aggregation and de-ubiquitinating activity, leading to increased ubiquitination levels and altered protein localization, from the parasite digestive vacuole to the plasma membrane, of the P. yoelii multidrug resistance transporter 1 (MDR1). The MDR1 on the plasma membrane enhances the efflux of substrates/drugs out of the parasite cytoplasm to confer multidrug resistance, which can be reversed by inhibition of MDR1 transport. This study reveals a previously unknown drug-resistant mechanism mediated by UBP1 through altered MDR1 localization and substrate transport direction in a mouse model, providing a new malaria treatment strategy.
Topics: Animals; Mice; Plasmodium yoelii; Malaria, Falciparum; Plasmodium falciparum; Antimalarials; Drug Resistance, Multiple; Drug Resistance; Endopeptidases
PubMed: 38413566
DOI: 10.1038/s41467-024-46006-3 -
Current Research in Pharmacology and... 2024infection is a health challenge. Although, antiplasmodial drugs kill the parasites, information on the effects of infection and drugs on the expression of some genes is...
infection is a health challenge. Although, antiplasmodial drugs kill the parasites, information on the effects of infection and drugs on the expression of some genes is limited. Malaria was induced in two different studies using NK65 (chloroquine-susceptible, study 1), and ANKA (chloroquine-resistant, study 2) strains of in 30 male Swiss mice (n = 5) in each study. Mice orally received 10 mL/kg distilled water, (infected control), Mefloquine (MF) (10 mg/kg), MF and Curcumin (CM) (25 mg/kg), MF and CM (50 mg/kg), CM (25 mg/kg) and CM (50 mg/kg). Five mice (un-infected) were used as the control. After treatment, total Ribonucleic acid (RNA) was isolated from liver and erythrocytes while Deoxyribonucleic acid (DNA)-free RNA were converted to cDNA. Polymerase Chain Reaction (PCR) amplification was performed and relative expressions of oxidoreductase, and cytochrome oxidase expressions were determined. Markers of glycolysis, toxicity and antioxidants were determined using ELISA assays. While the expression of was blunted by MF in the susceptible study, co-treatment with curcumin (25 mg/kg) yielded the same results in the chloroquine-resistant study. Similar results were obtained on in both studies. Curcumin decreased in both studies. infection decreased oxidoreductase and cytochrome oxidase but mefloquine-curcumin restored the expression of these genes. While glycolysis and toxicity were inhibited, antioxidant systems improved in the treated groups. Curcumin is needed for effective therapeutic efficacy and prevention of toxicity. infection and treatment modulate the expressions of some genes in the host. Curcumin combination with mefloquine modulates the expression of some genes in the host.
PubMed: 38725654
DOI: 10.1016/j.crphar.2024.100180 -
ACS Omega Jan 2021Toxic effects of pharmacological drugs restrict their robust application against human diseases. Although used as a drug in the combinatorial therapy to treat malaria,...
Toxic effects of pharmacological drugs restrict their robust application against human diseases. Although used as a drug in the combinatorial therapy to treat malaria, the use of mefloquine is not highly recommended because of its adverse effects in humans. Mefloquine inhibits the binding of acyl-CoAs to acyl-CoA-binding proteins of (PfACBPs) and human (hACBP). In this study, we have used molecular dynamics simulation and other computational approaches to investigate the differences of stabilities of mefloquine-PfACBP749 and mefloquine-hACBP complexes. The stability of mefloquine in the binding cavity of PfACBP749 is less than its stability in the binding pocket of hACBP. Although the essential tyrosine residues (tyrosine-30 and tyrosine-33 of PfACBP749 and tyrosine-29 and tyrosine-32 of hACBP) mediate the initial binding of mefloquine to the proteins by π-stacking interactions, additional temporally longer interactions between mefloquine and aspartate-22 and methionine-25 of hACBP result in stronger binding of mefloquine to hACBP. The higher fluctuation of mefloquine-binding residues of PfACBP749 contributes to the instability of mefloquine in the binding cavity of the protein. On the contrary, in the mefloquine-bound state, the stability of hACBP protein is less than the stability of PfACBP749. The helix-to-coil transition of the N-terminal hydrophobic region of hACBP has a destabilizing effect upon the protein's structure. This causes the induction of aggregation properties in the hACBP in the mefloquine-bound state. Taken together, we describe the mechanistic features that affect the differential dynamic stabilities of mefloquine-bound PfACBP749 and hACBP proteins.
PubMed: 33521428
DOI: 10.1021/acsomega.0c04582 -
Journal of Clinical Medicine Jan 2022Malaria is a prevalent parasitic disease that is estimated to kill between one and two million people-mostly children-every year. Here, we query PubMed for malaria drug...
Malaria is a prevalent parasitic disease that is estimated to kill between one and two million people-mostly children-every year. Here, we query PubMed for malaria drug resistance and plot the yearly citations of 14 common antimalarials. Remarkably, most antimalarial drugs display cyclic resistance patterns, rising and falling over four decades. The antimalarial drugs that exhibit cyclic resistance are quinine, chloroquine, mefloquine, amodiaquine, artesunate, artemether, sulfadoxine, doxycycline, halofantrine, piperaquine, pyrimethamine, atovaquone, artemisinin, and dihydroartemisinin. Exceptionally, the resistance of the two latter drugs can also correlate with a linear rise. Our predicted antimalarial drug resistance is consistent with clinical data reported by the Worldwide Antimalarial Resistance Network (WWARN) and validates our methodology. Notably, the cyclical resistance suggests that most antimalarial drugs are sustainable in the end. Furthermore, cyclic resistance is clinically relevant and discourages routine monotherapy, in particular, while resistance is on the rise. Finally, cyclic resistance encourages the combination of antimalarial drugs at distinct phases of resistance.
PubMed: 35160232
DOI: 10.3390/jcm11030781 -
The Journal of Organic Chemistry Aug 2021Novel 1,2-diamines based on the mefloquine scaffold prepared in enantiomerically pure forms resemble 9-amino- alkaloids. Most effectively, 11-aminomefloquine with an...
Novel 1,2-diamines based on the mefloquine scaffold prepared in enantiomerically pure forms resemble 9-amino- alkaloids. Most effectively, 11-aminomefloquine with an configuration was obtained by conversion of 11-alcohol into azide and hydrogenation. Alkylation of a secondary amine unit was needed to arrive at diastereomeric -11-aminomefloquine and to introduce diversity. Most of the substitution reactions of the hydroxyl group to azido group proceeded with net retention of the configuration and involved actual aziridine or plausible aziridinium ion intermediates. Enantiomerically pure products were obtained by the resolution of either the initial mefloquine or one of the final products. The evaluation of the efficacy of the obtained vicinal diamines in enantioselective transformations proved that -11-aminomefloquine is an effective catalyst in the asymmetric Michael addition of nitromethane to cyclohexanone (up to 96.5:3.5 er) surpassing -aminoquinine in terms of selectivity.
Topics: Amines; Diamines; Mefloquine; Molecular Structure; Stereoisomerism
PubMed: 34314190
DOI: 10.1021/acs.joc.1c01316 -
ChemMedChem Oct 2023In antimalarial drug development research, overcoming drug resistance has been a major challenge for researchers. Nowadays, several drugs like chloroquine, mefloquine,... (Review)
Review
In antimalarial drug development research, overcoming drug resistance has been a major challenge for researchers. Nowadays, several drugs like chloroquine, mefloquine, sulfadoxine, and artemisinin are used to treat malaria. But increment in drug resistance has pushed researchers to find novel drugs to tackle drug resistance problems. The idea of using transition metal complexes with pharmacophores as ligands/ligand pendants to show enhanced antimalarial activity with a novel mechanism of action has gained significant attention recently. The advantages of metal complexes include tunable chemical/physical properties, redox activity, avoiding resistance factors, etc. Several recent reports have successfully demonstrated that the metal complexation of known organic antimalarial drugs can overcome drug resistance by showing enhanced activities than the parent drugs. This review has discussed the fruitful research works done in the past few years falling into this criterion. Based on transition metal series (3d, 4d, or 5d), the antimalarial metal complexes have been divided into three broad categories (3d, 4d, or 5d metal-based), and their activities have been compared with the similar control complexes as well as the parent drugs. Furthermore, we have also commented on the potential issues and their possible solution for translating these metal-based antimalarial complexes into the clinic.
Topics: Humans; Antimalarials; Coordination Complexes; Malaria; Chloroquine; Mefloquine; Drug Resistance; Plasmodium falciparum; Malaria, Falciparum
PubMed: 37436090
DOI: 10.1002/cmdc.202300326 -
BMJ Military Health Nov 2020
Topics: Antimalarials; Humans; Malaria; Mefloquine; Military Personnel; Pre-Exposure Prophylaxis
PubMed: 32086266
DOI: 10.1136/jramc-2019-001295