Anti-Schistosomal Activity of Cinnamic Acid Esters: Eugenyl and Thymyl Cinnamate Induce Cytoplasmic Vacuoles and Death in Schistosomula of Schistosoma mansoni

Glaser, Jan; Schurigt, Uta; Suzuki, Brian M.; Caffrey, Connor R.; Holzgrabe, Ulrike

doi:10.3390/molecules200610873

Cited by 23 publications

(24 citation statements)

References 31 publications

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“…The presence of 4‐methoxy, 3,4‐methylenedioxy or the 4‐nitro group on the benzene ring of the cinnamoyl moiety did not enhance insecticidal activity. Although the biological activities of thymyl cinnamate such as antischistosomal and antifungal activities, have been addressed, no reports have identified this compound as an active insecticide. Thus, thymyl cinnamate was first reported in the current study to have insecticidal activity against S. litura .…”

Section: Discussionmentioning

confidence: 99%

Synthesis of thymyl esters and their insecticidal activity against Spodoptera litura (Lepidoptera: Noctuidae)

Tharamak

Yooboon

Pengsook

et al. 2019

Pest Management Science

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BACKGROUND Thymol, a natural phenolic monoterpene originating from Thymus vulgaris, is recognized as a safe and potent botanical insecticide to many insects. The structural modification of thymol into thymyl esters is a potential approach for the development of novel insecticides, which showed more toxicity than thymol. However, there are no reports on the insecticidal activity of thymyl esters to control Spodoptera litura. RESULTS Thymol was structurally modified into ten thymyl esters by esterification using a new reagent, PPh3/Br3CSO2Ph. The insecticidal activity of these compounds was examined against the second instars of Spodoptera litura using a topical application. Among the ten thymyl esters evaluated, thymyl cinnamate was the most toxic with LD50 = 0.41 and 0.34 μg/larva after 24 and 48 h posttreatment, respectively. In addition, thymyl cinnamate‐treated larvae showed increasing carboxylesterase and acetylcholinesterase activities in vivo experiment, whereas glutathione S‐transferase activity showed no significant difference. CONCLUSION Thymyl cinnamate were first reported to exhibit toxicity against S. litura 2.41–2.46 fold more efficient than thymol. However, the detailed biochemical interactions are necessary for further development of novel insecticides. © 2019 Society of Chemical Industry

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Section: Discussionmentioning

confidence: 99%

Synthesis of thymyl esters and their insecticidal activity against Spodoptera litura (Lepidoptera: Noctuidae)

Tharamak

Yooboon

Pengsook

et al. 2019

Pest Management Science

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“…Somules and adults were cultured in the presence of compounds over five concentrations (0.625, 1.25, 2.5, 5, and 10 µM) for up to 48 h and 24 h, respectively. As reported previously, simple descriptors were employed to describe the observable effects of compounds on parasites (changes in shape, motility and density; see legend to Table 2 ) 58 , 61 using an inverted microscope at 18 and 48 h post-exposure (somules) or 11 and 24 h post-exposure (adults). To convert these observations into a partially quantitative output for comparing drug effects, each descriptor was awarded a score of 1 and these were summed to a maximum score of 4 62 – 64 .…”

Section: Methodsmentioning

confidence: 99%

Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing

Weeks

Roberts

Leasure

et al. 2018

Sci Rep

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Parasitic helminths infect over 1 billion people worldwide, while current treatments rely on a limited arsenal of drugs. To expedite drug discovery, we screened a small-molecule library of compounds with histories of use in human clinical trials for anthelmintic activity against the soil nematode Caenorhabditis elegans. From this screen, we found that the neuromodulatory drugs sertraline, paroxetine, and chlorpromazine kill C. elegans at multiple life stages including embryos, developing larvae and gravid adults. These drugs act rapidly to inhibit C. elegans feeding within minutes of exposure. Sertraline, paroxetine, and chlorpromazine also decrease motility of adult Trichuris muris whipworms, prevent hatching and development of Ancylostoma caninum hookworms and kill Schistosoma mansoni flatworms, three widely divergent parasitic helminth species. C. elegans mutants with resistance to known anthelmintic drugs such as ivermectin are equally or more susceptible to these three drugs, suggesting that they may act on novel targets to kill worms. Sertraline, paroxetine, and chlorpromazine have long histories of use clinically as antidepressant or antipsychotic medicines. They may represent new classes of anthelmintic drug that could be used in combination with existing front-line drugs to boost effectiveness of anti-parasite treatment as well as offset the development of parasite drug resistance.

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“…The ‘traditional’ approach to adjudicating the many phenotypic responses possible for this parasite involves microscopical observation. We use simple ‘descriptors’ to record changes in movement, shape, translucence, surface integrity and, for adults specifically, the ability of the parasite to adhere to the culture dish surface (see S1 File and [ 20 , 55 , 70 ]). To convert these observations into an ordinal numeric output and thus facilitate relative comparisons of compound effects, each descriptor was awarded a ‘severity score’ of one up to a maximum score of four.…”

Section: Methodsmentioning

confidence: 99%

Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni

et al. 2016

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BackgroundSchistosoma flatworm parasites cause schistosomiasis, a chronic and debilitating disease of poverty in developing countries. Praziquantel is employed for treatment and disease control. However, its efficacy spectrum is incomplete (less active or inactive against immature stages of the parasite) and there is a concern of drug resistance. Thus, there is a need to identify new drugs and drug targets.Methodology/Principal FindingsWe show that RNA interference (RNAi) of the Schistosoma mansoni ortholog of human polo-like kinase (huPLK)1 elicits a deleterious phenotypic alteration in post-infective larvae (schistosomula or somules). Phenotypic screening and analysis of schistosomula and adult S. mansoni with small molecule inhibitors of huPLK1 identified a number of potent anti-schistosomals. Among these was a GlaxoSmithKline (GSK) benzimidazole thiophene inhibitor that has completed Phase I clinical trials for treatment of solid tumor malignancies. We then obtained GSKs Published Kinase Inhibitor Sets (PKIS) 1 and 2, and phenotypically screened an expanded series of 38 benzimidazole thiophene PLK1 inhibitors. Computational analysis of controls and PLK1 inhibitor-treated populations of somules demonstrated a distinctive phenotype distribution. Using principal component analysis (PCA), the phenotypes exhibited by these populations were mapped, visualized and analyzed through projection to a low-dimensional space. The phenotype distribution was found to have a distinct shape and topology, which could be elicited using cluster analysis. A structure-activity relationship (SAR) was identified for the benzimidazole thiophenes that held for both somules and adult parasites. The most potent inhibitors produced marked phenotypic alterations at 1–2 μM within 1 h. Among these were compounds previously characterized as potent inhibitors of huPLK1 in cell assays.Conclusions/SignificanceThe reverse genetic and chemical SAR data support a continued investigation of SmPLK1 as a possible drug target and/or the prosecution of the benzimidazole thiophene chemotype as a source of novel anti-schistosomals.

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Anti-Schistosomal Activity of Cinnamic Acid Esters: Eugenyl and Thymyl Cinnamate Induce Cytoplasmic Vacuoles and Death in Schistosomula of Schistosoma mansoni

Cited by 23 publications

References 31 publications

Synthesis of thymyl esters and their insecticidal activity against Spodoptera litura (Lepidoptera: Noctuidae)

Synthesis of thymyl esters and their insecticidal activity against Spodoptera litura (Lepidoptera: Noctuidae)

Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing

Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni

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