Synthesis and Antimalarial Activities of New Hybrid Atokel Molecules

Li, Youzhi; Loureiro, Anthony; Nguyen, Michel; Laurent, Marion; Bijani, Christian; Benoit‐Vical, Françoise; Robert, Anne; Liu, Yan; Meunier, Bernard

doi:10.1002/open.202200064

Cited by 4 publications

(3 citation statements)

References 35 publications

(87 reference statements)

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Section: Introductionmentioning

confidence: 99%

“…Among them, Plasmodium falciparum is the deadliest malaria-causing parasite. The parasite resistance to many existing antimalarial drugs such as chloroquine and pyrimethamine is exacerbating disease 1 2 3 4 5 6 Resistance to commonly used malaria drugs is spreading and new drugs are required urgently. Development of low-grade drug resistance in malaria parasites results in delays in the immediate therapeutic response and increasing recrudescence rates.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Docking Studies of Rifampicin – rpoB complex: Repurposing Drug Design Implications for against Plasmodium falciparum Malaria through a Computational Approach

Yadav

Pandey

2023

Drug Res (Stuttg)

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Malaria is one of the world’s most devastating diseases, infecting well over 300 million people annually and killing between 2 and 3 million worldwide. Increasing parasite resistance to many existing drugs is exacerbating disease. Resistance to commonly used malarial drugs is increasing the need to develop new drugs urgently. Due to the slow pace and substantial costs of new drug development, repurposing of old drugs which is recently increasingly becoming an attractive proposition of highly efficient and effective way of drug discovery led us to study the drug rifampicin for this purpose. The present paper aims to investigate the route of Plasmodium falciparum apicoplast-targeted proteins that putatively encode β subunits of RNA polymerase with an objective to develop an effective antimalarial drug. Homology searching for conserved binding site to the rifampicin drug and the functional analysis of rpoB gene were done. Multiple Sequence alignment analysis of rpoB was compared with that in E.coli – rpoB and M. tuberculosis – rpoB. Docking studies of Rifampicin – rpoB complex was also done for finding binding affinity. The results of computational studies showed that rifampicin is a potential drug for malaria.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Docking Studies of Rifampicin – rpoB complex: Repurposing Drug Design Implications for against Plasmodium falciparum Malaria through a Computational Approach

Yadav

Pandey

2023

Drug Res (Stuttg)

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“…Moreover, the risk of noncompatibility of drugs in combination therapy is avoided by using hybrid drugs . The recent interest to develop chimeric hybrids incorporating the chloroquine − or aminoquinoline − scaffold was not restricted to increasing the arsenal to fight malaria. In fact, some hybrid analogues showed interesting antileukemia activity as multitarget drugs .…”

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confidence: 99%

Squaramide Tethered Clindamycin, Chloroquine, and Mortiamide Hybrids: Design, Synthesis, and Antimalarial Activity

Tremblay

Bergeron

Gagnon

et al. 2023

ACS Med. Chem. Lett.

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Malaria remains one of the major health problems in the world. In this work, a series of squaramide tethered chloroquine, clindamycin, and mortiamide D hybrids have been synthesized to assess their in vitro antiplasmodial activity against 3D7 (chloroquine-sensitive) and Dd2 strains of Plasmodium falciparum. The most active compound, a simple chloroquine analogue, displayed low nanomolar IC 50 value against both strains (3 nM for 3D7 strain and 18 nM for Dd2 strain). Moreover, all molecular hybrids incorporating the hydroxychloroquine scaffold showed the most potent activities, exemplified with a chloroquine dimer, IC 50 = 31 nM and 81 nM against 3D7 and Dd2 strains, respectively. These results highlight the first time use of clindamycin and mortiamide D as antimalarial molecular hybrids and establish these valuable hits for future optimization.

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Synthesis and Antimalarial Activities of New Hybrid Atokel Molecules

Loureiro

Nguyen

et al. 2022

ChemistryOpen

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The currently spreading resistance of the malaria parasite Plasmodium falciparum to artemisinin‐based combination therapies makes an urgent need for new efficient drugs. Aiming to kill artemisinin‐resistant Plasmodium , a series of novel hybrid drugs named Atokels were synthesized and characterized. Atokels are based on an 8‐amino‐ or 8‐hydroxyquinoline entity covalently bound to a 1,4‐naphthoquinone through a polyamine linker. These drugs have been designed to target the parasite mitochondrion by their naphthoquinone moiety reminiscent of the antimalarial drug atovaquone, and to trigger a damaging oxidative stress due to their ability to chelate metal ions in order to generate redox active complexes in situ. The most effective Atokel drug shown a promising antimalarial activity (IC 50 =622 n m on an artemisinin‐resistant P. falciparum strain) and no cytotoxicity at 50 μ m indicating a specific antiplasmodial mode of action.

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Synthesis and Antimalarial Activities of New Hybrid Atokel Molecules

Cited by 4 publications

References 35 publications

Molecular Docking Studies of Rifampicin – rpoB complex: Repurposing Drug Design Implications for against Plasmodium falciparum Malaria through a Computational Approach

Molecular Docking Studies of Rifampicin – rpoB complex: Repurposing Drug Design Implications for against Plasmodium falciparum Malaria through a Computational Approach

Squaramide Tethered Clindamycin, Chloroquine, and Mortiamide Hybrids: Design, Synthesis, and Antimalarial Activity

Synthesis and Antimalarial Activities of New Hybrid Atokel Molecules

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