Advancement of chimeric hybrid drugs to cure malaria infection: An overview with special emphasis on endoperoxide pharmacophores

Sharma, Bhawana; Singh, Preeti; Singh, Ankita; Awasthi, Satish Kumar

doi:10.1016/j.ejmech.2021.113408

Cited by 18 publications

(10 citation statements)

References 164 publications

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“…The high potency of artemisinin and the recognized clinical efficacy of artemisinin combination therapy, which is recommended by the World Health Organization, contribute to promoting the design and development of novel compounds with a cyclic endoperoxide core. A huge diversity of compounds has been synthesized, including second and third generations of artemisinin derivatives (monomer, dimer, trimer), trioxolanes, tri- and tetra-oxanes, and a variety of non-artemisinin-derived synthetic endoperoxide-containing molecules [ 129 , 130 , 131 , 132 , 133 ]. Novel artemisinin derivatives are regularly proposed [ 134 ].…”

Section: Discussionmentioning

confidence: 99%

Advocacy for the Medicinal Plant Artabotrys hexapetalus (Yingzhao) and Antimalarial Yingzhaosu Endoperoxides

Bailly

Hénichart

2022

Molecules

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The medicinal plant Artabotrys hexapetalus (synonyms: A. uncinatus and A. odoratissimus) is known as yingzhao in Chinese. Extracts of the plant have long been used in Asian folk medicine to treat various symptoms and diseases, including fevers, microbial infections, ulcers, hepatic disorders and other health problems. In particular, extracts from the roots and fruits of the plant are used for treating malaria. Numerous bioactive natural products have been isolated from the plant, mainly aporphine (artabonatines, artacinatine) and benzylisoquinoline (hexapetalines) alkaloids, terpenoids (artaboterpenoids), flavonoids (artabotrysides), butanolides (uncinine, artapetalins) and a small series of endoperoxides known as yingzhaosu A-to-D. These natural products confer antioxidant, anti-inflammatory and antiproliferative properties to the plant extracts. The lead compound yingzhaosu A displays marked activities against the malaria parasites Plasmodium falciparum and P. berghei. Total syntheses have been developed to access yingzhaosu compounds and analogues, such as the potent compound C14-epi-yingzhaosu A and simpler molecules with a dioxane unit. The mechanism of action of yingzhaosu A points to an iron(II)-induced degradation leading to the formation of two alkylating species, an unsaturated ketone and a cyclohexyl radical, which can then react with vital parasitic proteins. A bioreductive activation of yingzhaosu A endoperoxide can also occur with the heme iron complex. The mechanism of action of yingzhaosu endoperoxides is discussed, to promote further chemical and pharmacological studies of these neglected, but highly interesting bioactive compounds. Yingzhaosu A/C represent useful templates for designing novel antimalarial drugs.

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Section: Discussionmentioning

confidence: 99%

Advocacy for the Medicinal Plant Artabotrys hexapetalus (Yingzhao) and Antimalarial Yingzhaosu Endoperoxides

Bailly

Hénichart

2022

Molecules

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“…To deal with the complex lifecycle of the malaria parasite, it is important to develop a drug with multiple modes of action targeting both exoerythrocytic (sexual and liver stages) and erythrocytic (blood asexual stage) stages and which can combat drug resistance as well. 25,26 Hybridization plays a crucial role in resolving this issue as it enables the possibility of multiple modes of action. Hybridization basically is the process of combining two different molecules with the help of some linkers.…”

Section: Hybridizationmentioning

confidence: 99%

Is structural hybridization invoking new dimensions for antimalarial drug discovery research?

2023

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“…This approach aims to increase effectiveness through a synergistic effect and to delay resistance selection. The linker between the pharmacophoric moieties can be tailored to adjust the drug’s pharmacokinetic performance and bioavailability [ 22 , 23 ]. Given the potential of endoperoxides and pyrazoles as tools against parasitic diseases, namely malaria and leishmaniases, we propose to explore endoperoxide–pyrazole hybrids.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids

et al. 2022

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Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against Leishmania parasites. This study reports the synthesis and structure of trioxolane–pyrazole (OZ1, OZ2) and tetraoxane–pyrazole (T1, T2) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for in vitro antileishmanial activity against promastigotes of L. tropica and L. infantum, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of L. infantum. Trioxolane–pyrazole hybrids OZ1 and OZ2 exhibited some activity against Leishmania promastigotes, while tetraoxane–pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound OZ1•HCl was the most active against both strains of Leishmania. Such finding was corroborated by the results obtained in assessments of the L. infantum amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide–pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of Leishmania. Our preliminary biological findings encourage further optimization of peroxide–pyrazole hybrids to identify a promising antileishmanial lead.

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Advancement of chimeric hybrid drugs to cure malaria infection: An overview with special emphasis on endoperoxide pharmacophores

Cited by 18 publications

References 164 publications

Advocacy for the Medicinal Plant Artabotrys hexapetalus (Yingzhao) and Antimalarial Yingzhaosu Endoperoxides

Advocacy for the Medicinal Plant Artabotrys hexapetalus (Yingzhao) and Antimalarial Yingzhaosu Endoperoxides

Is structural hybridization invoking new dimensions for antimalarial drug discovery research?

Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids

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