Natural Compounds from the Marine Brown Alga Caulocystis cephalornithos with Potent In Vitro-Activity against the Parasitic Nematode Haemonchus contortus

Abstract

<jats:p>Eight secondary metabolites (1 to 8) were isolated from a marine sponge, a marine alga and three terrestrial plants collected in Australia and subsequently chemically characterised. Here, these natural product-derived compounds were screened for in vitro-anthelmintic activity against the larvae and adult stages of Haemonchus contortus (barber’s pole worm)—a highly pathogenic parasitic nematode of ruminants. Using an optimised, whole-organism screening system, compounds were tested on exsheathed third-stage larvae (xL3s) and fourth-stage larvae (L4s). Anthelmintic activity was initially evaluated on these stages based on the inhibition of motility, development and/or changes in morphology (phenotype). We identified two compounds, 6-undecylsalicylic acid (3) and 6-tridecylsalicylic acid (4) isolated from the marine brown alga, Caulocystis cephalornithos, with inhibitory effects on xL3 and L4 motility and larval development, and the induction of a “skinny-straight” phenotype. Subsequent testing showed that these two compounds had an acute nematocidal effect (within 1–12 h) on adult males and females of H. contortus. Ultrastructural analysis of adult worms treated with compound 4 revealed significant damage to subcuticular musculature and associated tissues and cellular organelles including mitochondria. In conclusion, the present study has discovered two algal compounds possessing acute anthelmintic effects and with potential for hit-to-lead progression. Future work should focus on undertaking a structure-activity relationship study and on elucidating the mode(s) of action of optimised compounds.</jats:p>

Dysidenin from the Marine Sponge Citronia sp. Affects the Motility and Morphology of Haemonchus contortus Larvae In Vitro

“…Both compounds 1 and 2 induced a Ski phenotype in 50% and 28% of in vitro-raised L4s (Table 1), with IC 50 values of 31 and 62 µM, respectively. This phenotype has previously been associated with damage of subcuticular musculature and mitochondria [15]. In addition, all L4s exposed to 100 µM of 1 exhibited marked destruction of somatic (gut and muscle) cells and tissue disintegration (Figure 3).…”

Identification of Anthelmintic Bishomoscalarane Sesterterpenes from the Australian Marine Sponge Phyllospongia bergquistae and Structure Revision of Phyllolactones A–D

“…While none of the fractions were active against H. contortus xL3 motility and development, fractions F52 and F53 induced an abnormal skinny ( Ski ) phenotype in 45.4% and 66.6% of developing larvae, respectively, on day 7 (Figure ). Larvae with the Ski phenotype have a reduced width and a shrivelled, dehydrated appearance, as previously described, , with reference to the untreated control. Additionally, a newly identified vacuolar ( Vac ) phenotype was displayed in L4s treated with F52 (2.5%) at day 7; this phenotype exhibited major damage to various tissues in the L4 stage (Figure ).…”

Natural products as anthelmintics: safeguarding animal health

“…445 In 1980 researchers from the Roche Research Institute for Marine Pharmacology reported 6-tridecylsalicylic acid (7.93) as the anti-inammatory principle from a southern Australian (Victorian) collection of the brown alga Caulocystis cephalornithos, 446 while a subsequent 2006 analysis of Tasmanian samples of C. cephalornithos reported the major metabolites as 7.93 and 6-undecylsalicylic acid (7.94), with trace amounts of the 6-dodecyl, 6-tetradecyl and 6-pentadecyl homologues. 447 In 2020, 448 7.93 and 7.94 were re-isolated from southern Australian (Victorian) collections of C. cephalornithos, as inhibitors of H. contortus L4 larvae motility, 7.93 (EC 65 29 mg mL −1 aer 72 h) and 7.94 (EC 46 29 mg mL −1 aer 72 h), with both inducing a distinctive skinny-straight (Sks) phenotype with substantial subcuticular tissue destruction (>90% aer 72 h). Interestingly, two reports in 2017 revealed 7.93 and 7.94 as rst-in-class small molecule inhibitors of the transcription factor SOX18, leading to the development of a new small molecule treatment for breast cancer and for the suppression of cancer metastatic spread.…”