TY - JOUR
T1 - Synthetic kavalactone analogues with increased potency and selective anthelmintic activity against larvae of haemonchus contortus in vitro
AU - Dilrukshi Herath, H. M.P.
AU - Taki, Aya C.
AU - Nguyen, Nghi
AU - Garcia-Bustos, José
AU - Hofmann, Andreas
AU - Wang, Tao
AU - Ma, Guangxu
AU - Chang, Bill C.H.
AU - Jabbar, Abdul
AU - Sleebs, Brad E.
AU - Gasser, Robin B.
PY - 2020/4/24
Y1 - 2020/4/24
N2 - 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.
AB - 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.
KW - Anthelmintic
KW - Haemonchus contortus
KW - In vitro-activity
KW - Kavalactone
KW - Synthetic analogues
UR - http://www.scopus.com/inward/record.url?scp=85083860118&partnerID=8YFLogxK
U2 - 10.3390/molecules25082004
DO - 10.3390/molecules25082004
M3 - Article
C2 - 32344703
AN - SCOPUS:85083860118
SN - 1420-3049
VL - 25
JO - Molecules
JF - Molecules
IS - 8
M1 - 2004
ER -