EF24, a schistosomicidal curcumin analog: Insights from its synthesis and phenotypic, biochemical and cytotoxic activities

Badoco, Fernanda Rafacho; Paula, Lucas A.L.; Orenha, Renato Pereira; Mendes, Tiago Manuel Fernandes; Squarisi, Iara Silva; El-Sakkary, Nelly; Loiola, Messias C.; Katz, Naftale; Tavares, Denise Crispim; Sairre, Mirela Inês de; Parreira, Renato L.T.; Cabral, Fernanda Janku; Alegretti, Silmara M.; Caffrey, Conor R.; Magalhães, Lizandra Guidi

doi:10.1016/j.cbi.2022.110191

Cited by 7 publications

(5 citation statements)

References 77 publications

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“…Studies have reported that some antischistosomal compounds, such as licochalcone A, elicit mitochondrial and cellular membrane alterations in S. mansoni 57 . In addition, a wide range of natural compounds are known to generate ROS in S. mansoni , and the induction of oxidative stress has been considered an attractive treatment strategy for schistosomiasis drug discovery 57 – 59 . Accordingly, the possibility of threo -austrobailignan-6 and verrucosin causing disturbance in both ROS and the activities of enzymes associated with maintaining redox balance cannot be excluded.…”

Section: Resultsmentioning

confidence: 99%

Neolignans isolated from Saururus cernuus L. (Saururaceae) exhibit efficacy against Schistosoma mansoni

Brito

Wilairatana

Roquini

et al. 2022

Sci Rep

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Schistosomiasis, a parasitic disease caused by the blood fluke of the genus Schistosoma, affects over 230 million people, especially in developing countries. Despite the significant economic and public health consequences, only one drug is currently available for treatment of schistosomiasis, praziquantel. Thus, there is an urgent demand for new anthelmintic agents. Based on our continuous studies involving the chemical prospection of floristic biodiversity aiming to discover new bioactive compounds, this work reports the in vitro antiparasitic activity against Schistosoma mansoni adult worms of neolignans threo-austrobailignan-6 and verrucosin, both isolated from Saururus cernuus L. (Saururaceae). These neolignans showed a significant in vitro schistosomicidal activity, with EC50 values of 12.6–28.1 µM. Further analysis revealed a pronounced reduction in the number of S. mansoni eggs. Scanning electron microscopy analysis revealed morphological alterations when schistosomes were exposed to either threo-austrobailignan-6 or verrucosin. These relevant antischistosomal properties were accompanied by low cytotoxicity potential against the animal (Vero) and human (HaCaT) cell lines, resulting in a high selectivity index. Considering the promising chemical and biological properties of threo-austrobailignan-6 and verrucosin, this research should be of interest to those in the area of neglected diseases and in particular antischistosomal drug discovery.

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Section: Resultsmentioning

confidence: 99%

Neolignans isolated from Saururus cernuus L. (Saururaceae) exhibit efficacy against Schistosoma mansoni

Brito

Wilairatana

Roquini

et al. 2022

Sci Rep

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“…There is currently a large collection of clinical isolates being collated by the Natural History Museum in London. In addition to this, a number of groups in Brazil possess a variety of parasite isolates, including those less sensitive to PZQ …”

Section: Screening Cascadementioning

confidence: 99%

“…In addition to this, a number of groups in Brazil possess a variety of parasite isolates, including those less sensitive to PZQ. 33 The Hoffmann group (Aberystwyth University) use an alternative platform which enables higher throughput screening in 384-well format against S. mansoni schistosomula. Using an automated, high-content imaging platform which quantifies both schistosomula phenotype and motility, large collections of compounds can be rapidly progressed for anti-schistosomal triaging.…”

Section: ■ Screening Cascadementioning

confidence: 99%

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Perspective on Schistosomiasis Drug Discovery: Highlights from a Schistosomiasis Drug Discovery Workshop at Wellcome Collection, London, September 2022

et al. 2023

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In September 2022, the Drug Discovery Unit at the University of Dundee, UK, organised an international meeting at the Wellcome Collection in London to explore the current clinical situation and challenges associated with treating schistosomiasis. The aim of this meeting was to discuss the need for new treatments in view of the clinical situation and to ascertain what the key requirements would be for any potential new anti-schistosomals. This information will be essential to inform ongoing drug discovery efforts for schistosomiasis. We also discussed the potential drug discovery pathway and associated criteria for progressing compounds to the clinic. To date, praziquantel (PZQ) is the only drug available to treat all species causing schistosomiasis, but it is often unable to completely clear parasites from an infected patient, partially due to its inactivity against juvenile worms. PZQmediated mass drug administration campaigns conducted in endemic areas (e.g., sub-Saharan Africa, where schistosomiasis is primarily prevalent) have contributed to reducing the burden of disease but will not eliminate the disease as a public health problem. The potential for Schistosoma to develop resistance towards PZQ, as the sole treatment available, could become a concern. Consequently, new anthelmintic medications are urgently needed, and this Perspective aims to capture some of the learnings from our discussions on the key criteria for new treatments.

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“…Since the early 1980s, treatment and control of schistosomiasis has relied on one drug, praziquantel (PZQ) [4][5][6] , which is primarily delivered via mass drug administration programs that aim to reduce disease morbidity at the community level 7,8 . Although reasonably effective at the single oral dose offered [9][10][11][12] , is much less active against developing worms 9,[13][14][15][16] , which after treatment, mature and continue to generate morbidity. In addition, and apart from the ever-present threat of drug resistance 9,17,18 , PZQ has a number of pharmaceutical and pharmacological problems 5,6,9,19 that encourage the search for new drugs.…”

Section: Introductionmentioning

confidence: 99%

Development of subunit selective proteasome substrates forSchistosoma species

Jiang,

Silva,

Liu

et al. 2024

Preprint

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Schistosomiasis, or bilharzia, is a neglected tropical disease caused by Schistosoma spp. blood flukes that infects over 200 million people worldwide. Just one partially effective drug is available, and new drugs and drug targets would be welcome. The 20S proteasome is a validated drug target for many parasitic infections, including those caused by Plasmodium and Leishmania. We previously showed that anticancer proteasome inhibitors that act through the Schistosoma mansoni 20S proteasome (Sm20S) kill the parasite in vitro. To advance these initial findings, we employed Multiplex Substrate Profiling by Mass Spectrometry (MSP-MS) to define the substrate cleavage specificities of the three catalytic β subunits of purified Sm20S. The profiles in turn were used to design and synthesize subunit-specific optimized substrates that performed two to eight fold better than the equivalent substrates used to measure the activity of the constitutive human proteasome (c20S). These specific substrates also eliminated the need to purify Sm20S from parasite extracts - a single step enrichment was sufficient to accurately measure substrate hydrolysis and its inhibition with proteasome inhibitors. Finally, we show that the substrate and inhibition profiles for the 20S proteasome from the three medically important schistosome species are similar, suggesting that data arising from an inhibitor development campaign that focuses on Sm20S can be extrapolated to the other two targets with consequent time and cost savings.

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EF24, a schistosomicidal curcumin analog: Insights from its synthesis and phenotypic, biochemical and cytotoxic activities

Cited by 7 publications

References 77 publications

Neolignans isolated from Saururus cernuus L. (Saururaceae) exhibit efficacy against Schistosoma mansoni

Neolignans isolated from Saururus cernuus L. (Saururaceae) exhibit efficacy against Schistosoma mansoni

Perspective on Schistosomiasis Drug Discovery: Highlights from a Schistosomiasis Drug Discovery Workshop at Wellcome Collection, London, September 2022

Development of subunit selective proteasome substrates forSchistosoma species

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