Synthetic Kavalactone Analogues with Increased Potency and Selective Anthelmintic Activity against Larvae of <em>Haemonchus contortus</em> In Vitro
Kava extract, an aqueous rhizome emulsion of the plant <i>Piper methysticum</i>, has been used for centuries by Pacific Islanders as a ceremonial beverage, and has been sold as an anxiolytic agent for some decades. Kavalactones are a major constituent of kava extract. In a previous inves...
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MDPI AG
2020-04-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/8/2004 |
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| author | H.M.P. Dilrukshi Herath Aya C. Taki Nghi Nguyen José Garcia-Bustos Andreas Hofmann Tao Wang Guangxu Ma Bill C.H. Chang Abdul Jabbar Brad E. Sleebs Robin B. Gasser |
| author_facet | H.M.P. Dilrukshi Herath Aya C. Taki Nghi Nguyen José Garcia-Bustos Andreas Hofmann Tao Wang Guangxu Ma Bill C.H. Chang Abdul Jabbar Brad E. Sleebs Robin B. Gasser |
| author_sort | H.M.P. Dilrukshi Herath |
| collection | DOAJ |
| description | Kava extract, an aqueous rhizome emulsion of the plant <i>Piper methysticum</i>, has been used for centuries by Pacific Islanders as a ceremonial beverage, and has been sold as an anxiolytic agent for some decades. Kavalactones are a major constituent of kava extract. In a previous investigation, we had identified three kavalactones that inhibit larval development of <i>Haemonchus contortus</i> in an in vitro-bioassay. In the present study, we synthesized two kavalactones, desmethoxyyangonin and yangonin, as well as 17 analogues thereof, and evaluated their anthelmintic activities using the same bioassay as employed previously. Structure activity relationship (SAR) studies showed that a 4-substituent on the pendant aryl ring was required for activity. In particular, compounds with 4-trifluoromethoxy, 4-difluoromethoxy, 4-phenoxy, and 4-<i>N</i>-morpholine substitutions had anthelmintic activities (IC<sub>50</sub> values in the range of 1.9 to 8.9 µM) that were greater than either of the parent natural products—desmethoxyyangonin (IC<sub>50</sub> of 37.1 µM) and yangonin (IC<sub>50</sub> of 15.0 µM). The synthesized analogues did not exhibit toxicity on HepG2 human hepatoma cells in vitro at concentrations of up to 40 µM. These findings confirm the previously-identified kavalactone scaffold as a promising chemotype for new anthelmintics and provide a basis for a detailed SAR investigation focused on developing a novel anthelmintic agent. |
| first_indexed | 2024-03-10T20:15:41Z |
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| id | doaj.art-a1fa4607c627436d84244c91f929fa20 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T20:15:41Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a1fa4607c627436d84244c91f929fa202023-11-19T22:38:29ZengMDPI AGMolecules1420-30492020-04-01258200410.3390/molecules25082004Synthetic Kavalactone Analogues with Increased Potency and Selective Anthelmintic Activity against Larvae of <em>Haemonchus contortus</em> In VitroH.M.P. Dilrukshi Herath0Aya C. Taki1Nghi Nguyen2José Garcia-Bustos3Andreas Hofmann4Tao Wang5Guangxu Ma6Bill C.H. Chang7Abdul Jabbar8Brad E. Sleebs9Robin B. Gasser10Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaFaculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaWalter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, AustraliaFaculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaFaculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaFaculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaFaculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaFaculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaFaculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaWalter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, AustraliaFaculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaKava extract, an aqueous rhizome emulsion of the plant <i>Piper methysticum</i>, has been used for centuries by Pacific Islanders as a ceremonial beverage, and has been sold as an anxiolytic agent for some decades. Kavalactones are a major constituent of kava extract. In a previous investigation, we had identified three kavalactones that inhibit larval development of <i>Haemonchus contortus</i> in an in vitro-bioassay. In the present study, we synthesized two kavalactones, desmethoxyyangonin and yangonin, as well as 17 analogues thereof, and evaluated their anthelmintic activities using the same bioassay as employed previously. Structure activity relationship (SAR) studies showed that a 4-substituent on the pendant aryl ring was required for activity. In particular, compounds with 4-trifluoromethoxy, 4-difluoromethoxy, 4-phenoxy, and 4-<i>N</i>-morpholine substitutions had anthelmintic activities (IC<sub>50</sub> values in the range of 1.9 to 8.9 µM) that were greater than either of the parent natural products—desmethoxyyangonin (IC<sub>50</sub> of 37.1 µM) and yangonin (IC<sub>50</sub> of 15.0 µM). The synthesized analogues did not exhibit toxicity on HepG2 human hepatoma cells in vitro at concentrations of up to 40 µM. These findings confirm the previously-identified kavalactone scaffold as a promising chemotype for new anthelmintics and provide a basis for a detailed SAR investigation focused on developing a novel anthelmintic agent.https://www.mdpi.com/1420-3049/25/8/2004kavalactonesynthetic analoguesanthelminticin vitro-activity<i>Haemonchus contortus</i> |
| spellingShingle | H.M.P. Dilrukshi Herath Aya C. Taki Nghi Nguyen José Garcia-Bustos Andreas Hofmann Tao Wang Guangxu Ma Bill C.H. Chang Abdul Jabbar Brad E. Sleebs Robin B. Gasser Synthetic Kavalactone Analogues with Increased Potency and Selective Anthelmintic Activity against Larvae of <em>Haemonchus contortus</em> In Vitro Molecules kavalactone synthetic analogues anthelmintic in vitro-activity <i>Haemonchus contortus</i> |
| title | Synthetic Kavalactone Analogues with Increased Potency and Selective Anthelmintic Activity against Larvae of <em>Haemonchus contortus</em> In Vitro |
| title_full | Synthetic Kavalactone Analogues with Increased Potency and Selective Anthelmintic Activity against Larvae of <em>Haemonchus contortus</em> In Vitro |
| title_fullStr | Synthetic Kavalactone Analogues with Increased Potency and Selective Anthelmintic Activity against Larvae of <em>Haemonchus contortus</em> In Vitro |
| title_full_unstemmed | Synthetic Kavalactone Analogues with Increased Potency and Selective Anthelmintic Activity against Larvae of <em>Haemonchus contortus</em> In Vitro |
| title_short | Synthetic Kavalactone Analogues with Increased Potency and Selective Anthelmintic Activity against Larvae of <em>Haemonchus contortus</em> In Vitro |
| title_sort | synthetic kavalactone analogues with increased potency and selective anthelmintic activity against larvae of em haemonchus contortus em in vitro |
| topic | kavalactone synthetic analogues anthelmintic in vitro-activity <i>Haemonchus contortus</i> |
| url | https://www.mdpi.com/1420-3049/25/8/2004 |
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