Fig 1.
Chemical structures natural drimane-type compounds.
Cinnamodial (1), warburganal (2), polygodial (3), capsicodendrin (4). Compounds 1, 3, and 4 have been isolated from C. fragrans.
Fig 2.
Derivatization of 1 into structural analogues.
Reagents and conditions: (a) NaClO2, NaH2PO4·H2O, H2O2, MeCN, H2O, r.t., 24 h; (b) TMS-CHN2, MeOH:Et2O, 0 oC, 30 min; (c) H2N-NH2, CH2Cl2:EtOH, 2 h; (d) MeOH, r.t.; (e) HOCH2CH2OH, p-TsOH, benzene, reflux, 24 h.
Fig 3.
Synthesis of lactols 8 and 9, and formation of 10 from lactol 9.
Reagents and conditions: (a) 1 equiv MeMgBr, THF, −78°C, 2 h; (b) CDCl3, 22 d.
Fig 4.
Reagents and conditions: (a) 5 equiv MeMgBr, THF, −78°C, 2 h; (b) 3.3 equiv PCC, DCM, 0 oC → r.t., 2 h.
Fig 5.
Chemical structures of α,ß-unsaturated 1,4-dialdehydes.
Polygodial (3), 1ß-acetoxy-9-deoxy-isomuzigadial (17), miogadial (14), (+)-isovelleral (15).
Fig 6.
Reaction mechanism of the reaction of 1 with L-cysteine methyl ester via a cationic azomethine A to form the thiazolidine 16.
Fig 7.
Toxic efficacy of cinnamodial and derivatives against larval (A) and adult female (B) Ae. aegypti. The efficacy values were calculated using Abbott’s correction to account for control (100% acetone) mortality [26]. In A), compounds were added to the rearing water of 1st instar larvae (100 μM) and efficacy was defined as the percentage of larvae that died within 24 h. In B), compounds were applied to the thoracic cuticle of adult females (1.5 nmol/mosquito) and efficacy was defined as the percentage of adults that were incapacitated (dead or flightless) within 24 h. Values are means ± SEM based on at least 6 replicates of 5 larvae each or 3 replicates of 10 adult females each. The specific numbers of replicates for each are indicated in parentheses below the compound number. Shading indicates statistical categorization of a derivative’s efficacy relative to CDIAL as determined by a one-way ANOVA with a Bonferroni post-test: gray = similar (P > 0.05); filled = superior (P < 0.05); open = inferior (P < 0.05).
Fig 8.
Antifeedant activity of CDIAL and semi-synthetic derivatives as determined via choice CAFE assays in adult female Ae. aegypti (LVP strain).
Mosquitoes were allowed to feed equally on two capillaries of 10% sucrose with 0.01% trypan blue; the control capillary included 1% DMSO, and the treatment capillary included 1% DMSO and 1mM test compound. The difference in volume consumed between the capillaries was used to calculate the antifeedant activity [21]. Values are means ± SEM based on at least 8 replicates of 5 adult females each. The specific numbers of replicates for each are indicated in parentheses below the compound number. Shading indicates statistical categorization of derivative’s efficacy relative to CDIAL as in Fig 7.
Fig 9.
The computationally docked structure of CDIAL (1) in AgTRPA1.
The tetrameric AgTRPA1 structure is shown on the right in a cartoon representation. Two zoomed views of the CDIAL binding site are shown on the left. The ligand is shown in a yellow licorice representation and the protein in a cyan cartoon representation. Nearby Cys and Lys residues are labeled.