Semi-synthetic Cinnamodial Analogues: Structural Insights into the Insecticidal and Antifeedant Activities of Drimane Sesquiterpenes Against the Mosquito Aedes aegypti

Abstract

The Aedes aegypti mosquito serves as a major vector for viral diseases, such as dengue, chikungunya, and Zika, which are spreading across the globe and threatening public health. In addition to increased vector transmission, the prevalence of insecticideresistant mosquitoes is also on the rise, thus solidifying the need for new, safe and effective insecticides to control mosquito populations. We recently discovered that cinnamodial, a unique drimane sesquiterpene dialdehyde of the Malagasy medicinal plant Cinnamosma fragrans, exhibited significant larval and adult toxicity to Ae. aegypti and was more efficacious than DEET -the gold standard for insect repellents -at repelling adult female Ae. aegypti from blood feeding. In this study several semisynthetic analogues of cinnamodial were prepared to probe the structure-activity relationship (SAR) for larvicidal, adulticidal and antifeedant activity against Ae. aegypti. Initial efforts were focused on modification of the dialdehyde functionality to produce more stable active analogues and to understand the importance of the 1,4-dialdehyde and the α,ßunsaturated carbonyl in the observed bioactivity of cinnamodial against mosquitoes. This study represents the first investigation into the SAR of cinnamodial as an insecticide and repellent against the medically important Ae. aegypti mosquito. Scheme 1. Derivatization of 1 into structural analogues. Reagents and conditions: (a) NaClO 2 , NaH 2 PO 4 •H 2 O, H 2 O 2 , MeCN, H 2 O, r.t., 24 h; (b) TMS-CHN 2 , MeOH:Et 2 O, 0 o C, 30 min;( c) H 2 N-NH 2 , CH 2 Cl 2 :EtOH, 2 h; (d) MeOH, r.t.; (e) HOCH 2 CH 2 OH, p-TsOH, benzene, reflux, 24 h. Scheme 2. Synthesis of lactols 8 and 9, and formation of 10 from lactol 9. Reagents and conditions: (a) 1 eq. MeMgBr, THF, 78 o C, 2 h; (b) CDCl 3 , 22 d. Scheme 3. Synthesis of 1,4-dione 13. Reagents and conditions: (a) 5 eq. MeMgBr, THF, 78 o C, 2 h; (b) 3.3 eq. PCC, DCM, 0 o C → r.t., 2h. Scheme 4. Reaction mechanism of the reaction of 1 with L-cysteine methyl ester via a cationic azomethine (A) to form the pyrrolidine (16).

Stop the crop: insights into the insecticidal mode of action of cinnamodial against mosquitoes

“…All natural drimane sesquiterpenes were isolated from medicinal plants and their structures were determined as previously described (He et al, 2017;Inocente et al, 2019;Inocente et al, 2018;Manwill et al, 2020).…”

“…1. Semi-synthetic derivatives of CDIAL were produced as described previously (Manwill et al, 2020). Herein, the derivatives are referred to as CD02, CD03, CD04, CD05, CD06, CD08, CD09, CD10, CD11, CD12.…”

“…We also tested CDIAL on the adult female hindgut to determine if it inhibited spontaneous contractions of another visceral muscle. As shown in Supplemental We next investigated whether several natural or semi-synthetic derivatives of CDIAL, which we have previously assessed for insecticidal and antifeedant activities against mosquitoes (Inocente et al, 2019;Inocente et al, 2018;Manwill et al, 2020), affected the frequency of crop contractions. First, we confirmed that 10 µM CDIAL completely inhibited the spontaneous contractions (Supplemental Fig.…”

“…3) against adult female and/or larval Ae. aegypti (Inocente et al, 2019;Inocente et al, 2018;Manwill et al, 2020). Ae.…”

“…Although agonism of TRPA1 channels by CDIAL was responsible for its antifeedant activity, and likely contributed to the repellent effects against mosquitoes, TRPA1 modulation was not required for the insecticidal activity of CDIAL (Inocente et al, 2018). Consistent with this notion, the insecticidal and antifeedant activities of various natural and semi-synthetic derivates of CDIAL often do not correlate (Inocente et al, 2019;Manwill et al, 2020). Thus, the mode of insecticidal activity for CDIAL is currently unknown and appears to be independent from its mode of antifeedant activity, which is by TRPA1 activation.…”