Synthesis and evaluation of artesunate–indoloquinoline hybrids as antimalarial drug candidates

Wang, Ning; Wicht, Kathryn J.; Shaban, Elkhabiry; Ngoc, Tran Anh; Wang, Ming-Qi; Hayashi, Ikuya; Hossain, Md. Imran; Takemasa, Yoshihiko; Kaiser, Marcel; Sayed, Ibrahim El Tantawy El; Egan, Timothy J.; Inokuchi, Tsutomu

doi:10.1039/c4md00091a

Cited by 47 publications

(22 citation statements)

References 32 publications

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“…The βH activity data were sourced from previous HTS collaborations between Vanderbilt University (VU), the University of Cape Town (UCT) and Okayama University (OU), most of which are publically available. 25,26,27,28,29,30 …”

Section: Experimental and Computational Methodsmentioning

confidence: 99%

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Bayesian models trained with HTS data for predicting β-haematin inhibition and in vitro antimalarial activity

Wicht¹,

Combrinck²,

Smith³

et al. 2015

Bioorganic & Medicinal Chemistry

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A large quantity of high throughput screening (HTS) data for antimalarial activity has become available in recent years. This includes both phenotypic and target-based activity. Realising the maximum value of these data remains a challenge. In this respect, methods that allow such data to be used for virtual screening maximise efficiency and reduce costs. In this study both in vitro antimalarial activity and inhibitory data for β-haematin formation, largely obtained from publically available sources, has been used to develop Bayesian models for inhibitors of β-haematin formation and in vitro antimalarial activity. These models were used to screen two in silico compound libraries. In the first, the 1510 U.S. Food and Drug Administration approved drugs available on PubChem were ranked from highest to lowest Bayesian score based on a training set of β-haematin inhibiting compounds active against P. falciparum that did not include any of the clinical antimalarials or close analogues. The six known clinical antimalarials that inhibit β-haematin formation were ranked in the top 2.1% of compounds. Furthermore, the in vitro antimalarial hit-rate for this prioritised set of compounds was found to be 81% in the case of the subset where activity data are available in PubChem. In the second, a library of about 5,000 commercially available compounds (AldrichCPR) was virtually screened for ability to inhibit β-haematin formation and then for in vitro antimalarial activity. A selection of 34 compounds was purchased and tested, of which 24 were predicted to be β-haematin inhibitors. The hit rate for inhibition of β-haematin formation was found to be 25% and a third of these were active against P. falciparum, corresponding to enrichments estimated at about 25- and 140-fold relative to random screening, respectively.

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Section: Experimental and Computational Methodsmentioning

confidence: 99%

“…These compounds are neocryptolepine and isocryptolepine derivatives with long amine side chains for which the data is already publically available. 26,27,28,29,30 …”

Section: Introductionmentioning

confidence: 99%

Bayesian models trained with HTS data for predicting β-haematin inhibition and in vitro antimalarial activity

Wicht¹,

Combrinck²,

Smith³

et al. 2015

Bioorganic & Medicinal Chemistry

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“…The artesunate‐indoloquinoline hybrids 7 to 9 (Figure ) with IC 50 of 0.41 to 3.21 nM were more potent than the references CQ (IC 50 : 9.4 and 209.5 nM) and ART (IC 50 : 4.3 and 2.8 nM) against CQS NF54 and CQR K1 strains of P falciparum , and they also showed low cytotoxicity (IC 50 : 695‐3718 nM) toward L6 cells . Notably, the RI was ranging from 0.27 to 0.93, suggesting these hybrids have no cross‐resistance with CQ.…”

Section: Quinoline‐artemisinin (Or Its Derivatives) Hybrids (Type I)mentioning

confidence: 98%

“…For hybrids 7 , attachment of any substituents at R 1 , R 2 , and R 3 positions were disfavorable to the activity. The most active hybrid 7a (IC 50 : 0.45 and 0.42 nM) was 6.6 to 498.8 times more potent than CQ and ART against CQS NF54 and CQR K1 strains, and the SI was higher than 3641 . The excellent antiplasmodial activity and favorable selectivity profile make hybrid 7a as a foundation for further investigation.…”

Section: Quinoline‐artemisinin (Or Its Derivatives) Hybrids (Type I)mentioning

confidence: 98%

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

Feng

Chang

et al. 2019

Medicinal Research Reviews

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Malaria is a tropical disease, leading to around half a million deaths annually. Antimalarials such as quinolines are crucial to fight against malaria, but malaria control is extremely challenged by the limited pipeline of effective pharmaceuticals against drug-resistant strains of Plasmodium falciparum which are resistant toward almost all currently accessible antimalarials. To tackle the growing resistance, new antimalarial drugs are needed urgently. Hybrid molecules which contain two or more pharmacophores have the potential to overcome the drug resistance, and hybridization of quinoline privileged antimalarial building block with other antimalarial pharmacophores may provide novel molecules with enhanced in vitro and in vivo activity against drug-resistant (including multidrug-resistant) P falciparum. In recent years, numerous of quinoline hybrids were developed, and their activities against a panel of drug-resistant P falciparum strains were screened. Some of quinoline hybrids were found to possess promising in vitro and in vivo potency. This review emphasized quinoline hybrid molecules with

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“…Salinomycin was shown by Wang to rupture lung cancer ALDH-positive tumorospheres and kill CSCs. [50] Germain et al also conducted experimental studies to identify selective small-molecule inhibitors of breast CSCs using high-throughput screening. They discovered a class of acylhydrazones that are selective for breast CSCs.…”

Section: High-throughput Screening Approachesmentioning

confidence: 99%

Getting to the Source: Selective Drug Targeting of Cancer Stem Cells

Ismail

Winkler

2014

ChemMedChem

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Cancers are among the most important and most difficult to treat diseases of the 21st century. Conventional therapies include surgery, immunotherapy, and radiotherapy, as well many forms of drug treatments such as tamoxifen and Gleevec. However, these forms of treatment often do not eradicate the cancer stem cells, only managing to decrease the size of the tumor, allowing the cancer to return. The cancer stem cell hypothesis stipulates that malignancy is maintained through self-renewal of cancer stem cells (CSCs), which generate rapidly dividing progeny that comprise the tumors, and that are largely untouched by conventional therapies. Evidence for the central role of CSCs in many tumors has provided a paradigm shift in the way cancer chemotherapy may be addressed. Recent discoveries regarding the nature of the stem cell niche, and the key signaling pathways involved in stem cell self-renewal and differentiation from regenerative medicine, have provided key information that facilitates selective targeting of CSCs by small-molecule drugs. The growing body of biochemical knowledge on the nature of CSCs, and differences between them and normal adult stem cells essential for maintaining organisms, has augmented the increasing number of small molecules shown to control normal and aberrant stem cells. Here, we review small-molecule approaches to the selective targeting of CSCs.

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Synthesis and evaluation of artesunate–indoloquinoline hybrids as antimalarial drug candidates

Abstract: Hybrids of artesunate–indoloquinoline were synthesized and antiplasmodial activity was evaluated.

Cited by 47 publications

References 32 publications

Bayesian models trained with HTS data for predicting β-haematin inhibition and in vitro antimalarial activity

Bayesian models trained with HTS data for predicting β-haematin inhibition and in vitro antimalarial activity

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

Getting to the Source: Selective Drug Targeting of Cancer Stem Cells

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