Synthetic Kavalactone Analogues with Increased Potency and Selective Anthelmintic Activity against Larvae of Haemonchus contortus In Vitro

Abstract

Kava extract, an aqueous rhizome emulsion of the plant Piper methysticum, 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 Haemonchus contortus 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-N-morpholine substitutions had anthelmintic activities (IC50 values in the range of 1.9 to 8.9 µM) that were greater than either of the parent natural products—desmethoxyyangonin (IC50 of 37.1 µM) and yangonin (IC50 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.

Natural products as anthelmintics: safeguarding animal health

“…108 An SAR investigation identified a superior synthetic analogue WEHI-408 ( 3.93 ) (IC 50 0.59 μg mL −1 ) with no cytotoxicity against HepG2 cells (IC 50 > 40 μg mL −1 ). 109 The previous study also reported goniothalamin ( 3.94 ) from the commercial hardwood tree Cryptocarya novoguineensis (Lauraceae) as active (arguably inactive!) against H. contortus L4 larval development (IC 50 1000 μg mL −1 ), but with more promising activity against H. contortus L4 motility (IC 50 40–60 μg mL −1 ).…”

“…108 Notwithstanding these observations, it should be noted that 3.94 is known to be cytotoxic. 109,110 The Bhutanese medicinal plant Pleurospermum amabile (Apiaceae) which is traditionally used as a cleansing and detoxication agent produces bergapten (3.95) and isomyristicin (3.96). 111 Application of the xWORM 112 technique and SEM-based imaging on T. muris established activity for 3.95 (IC 50 11 mg mL −1 ) and 3.96 (IC 50 21 mg mL −1 ), 113 with 3.95 (IC 50 100 mg mL −1 ) and 3.96 (IC 50 150 mg mL −1 ) also showing activity against the human water-borne parasite Schistosoma mansoni.…”

Drug Discovery and Development for Soil-Transmitted Helminthiasis: Current Anthelmentics and Compounds in the Pipeline

“…Four of synthesized analogs showed activities far greater than either of the parent compounds. All the synthesized compounds including the original kavalactones did not show toxicity against human HepG2 hepatoma cells in vitro with the most potent derivative showing the most selectivity [59]. A diverse set of natural compounds with prodigious potential to drug discovery is marine compounds.…”

Biological Activity, Hepatotoxicity, and Structure-Activity Relationship of Kavalactones and Flavokavins, the Two Main Bioactive Components in Kava (Piper methysticum)

“…Kavalactone Analogues. Lately, it was explored that kavalactone analogues exhibited in vitro anthelmintic activities against Haemonchus contortus larvae [75]. rough the chemical modifications of 2-,3-, and 4-substituent on the pendant aryl ring (Figure 7), two kavalactones (yangonin and desmethoxyyangonin) and 17 analogues were synthesized.…”

“…Through the chemical modifications of 2- ,3-, and 4-substituent on the pendant aryl ring ( Figure 7 ), two kavalactones (yangonin and desmethoxyyangonin) and 17 analogues were synthesized. Among these analogues, compounds with 4-trifluoromethoxy, 4-phenoxy, 4-difluoromethoxy, and 4-N-morpholine substitutions showed convinced anthelmintic activities (1.9 μ M < IC 50 < 8.9 μ M) which were superior to desmethoxyyangonin (IC 50 = 37.1 μ M) and yangonin (IC 50 = 15.0 μ M) and, thus, provided an opportunity for developing novel anthelmintic agents [ 75 ].…”