J. Med. Chem. 1984,27,1493-1502
1493
Quantitative Structure-Activity Relationship of Insect Juvenile Hormone Mimetic Compounds Akira Nakayama, Hajime Iwamura,* and Toshio Fujita Department of Agricultural Chemistry, Faculty of Agriculture, Kyoto University, Kyoto 606, Japan. Received September 7, 1983 Juvenile hormone mimetic activities on Aedes aegypti (yellow-fevermosquito) and Tenebrio molitor (yellow mealworm) of compounds having (2E,4E)-3,7,11-trimethyl-2,4-dodecadienone structures were comparatively and quantitatively analyzed in terms of their physicochemical structural parameters and by regression analysis. They were structurally composed of three classes, ester and thiol ester derivatives, amides, and ketones, depending on the C1 substituents. The results indicated that the steric dimensions and the hydrophobicity of the whole molecule are important factors in governing the activity through these classes as well as through both insect species. The effects of the structure of the C1 and Cll substituents, the two ends of the chain molecule, are specific to the insect. The length along the bond axis of the C1 substituents is significant and the hydroxy and alkoxy functions attached to the Cll atom favor the activity on A. aegypti, whereas with T. molitor the width of the C1 substituents in the direction perpendicular to the bond axis is significant and the position-specific hydrophobicity of the C1 moiety enhances the activity. The activity is also affected differently by the compound types. The amide and ketone series of compounds are more active than the corresponding ester type of compounds on T. molitor, while the favorable types on A. aegypti are the ester and ketone derivatives. Correlation equations formulated for 85 active compounds on A. aegypti and 84 compounds on T. molitor led us to draw a hypothetical “mode of action” model for each species, which visualizes the overall similarity as well LW the species differences of the interaction site or the receptor and may show the structural conditions necessary for activity.
Since the discovery of the insect juvenile hormone J H I,’ followed by J H 11,2J H 111: and J H :0 many analogous compounds have been prepared and tested for their activity on the metamorphosis of the larvae and pupae of many insect species to explore the structures that confer the activity. They are structurally divided roughly into two classes, terpenoid and nonterpenoid types. Isopropyl (2E,4E)-ll-methoxy-3,7,11-trimethyl-2,4-dodecadienoate ( m e t h ~ p r e n eand ) ~ 2-propynyl (2E,4E)-3,7,11-trimethyl2,4-dodecadienoate (kin~prene)~?’ are compounds of the first type and have been developed to obtain higher potency as well as more field stability than that of the naturally occurring mother compounds. One representative of the nonterpenoid type is ethyl 2- (4-phenoxyphenoxy)ethyl carbamate: which is more active than methoprene on Culex pi pi en^.^ S,S’-Diisobutyl N-ethyl-N,N’ethylenebis(thi0carbamate)has also been shown to possess outstanding activity in the mealworm Tenebrio molitor morphogenetic assay.1° Some chrysanthemic acid esters reportedly show significant morphogenetic activity on the barred stainer bug, Dysdercus fasciatus, when compared with several known terpenoid compounds.ll Other compounds in the nonterpenoid class are not always conspic(1) Riiller, H.; Dahn, K. H.; Sweely, C. C.; Trost, B. M. Angew.
Chem., Znt. Ed. Engl. 1967,6,179. (2) Meyer, A. S.;Schneiderman, H. A.; Hanzman, E.; KO,J. H. Proc. Natl. Acad. Sci. U.S.A. 1968,60, 853. (3) Judy, K. J.; Schooley, D. A.; Dunham, L. I.; Hall, M. S.; Bergot, B. J.; Siddall, J. B. Roc. Natl. Acad. Sci. U.S.A. 1973,70,1509. (4) Bergot, B. J.; Jameison, G. C.; Ratcliff, M. A.; Schooley, D. A. Science 1980. 210. 336. (5) Henrick, C. A:;Stak,G. B.; Siddall, J. B. J.Agric. Food Chem. 1973,21,354. (6) Henrick, C.A.; Willy, W. E.; Staal,G. B. J.Agric. Food Chem. 1976,24,207. (7) Henrick, C. A. W.S. Patent 4021461,May 3, 1977. (8) Fisher, W.; Schneider, F.; Zurfluh, R. Chem. Abstr. 1980,92, 58473~. (9) Manser, P.; Dorn, S.; Vogel, W.; Kalin, M.; Graft, 0.; Gunthart, E. “Regulation of Insect Development and Behavior”; Technical University of Wroclaw: Wroclaw, Poland, 1981;p 809. (10) Pallos, F. M.; Letchworth, P. E.; Menn, J. J. J. Agric. Food Chem. 1976,24,218. (11) Punja, N.;Ruscose, C. N. E.; Treasgol, C. Nature New Biol. 1976,242,94.
uous for activity, but they have novel structures. Active compounds hitherto reported and having a great deviation from the terpenoid skeleton are the peptide derivatives and ethyl ethyl L-isoleucyl-L-alany1-p-aminobenzoatel2 pivaloyl-~-alanyl-p-aminobenzoate,~~ and N-[4-(benzylo~y)benzyl]anilines,’~ compounds of high aromatic content. The number of effective nonterpenoid compounds is relatively small, but they provide possibilities in the development of useful compounds without the deficiencies like poor field stability and costly synthesis of compounds having the integrity of the terpenoid structure. Recent developments in quantitative structure-activity studies have shown that this is a useful tool to investigate the structural correspondence between different types of compounds having the same type of activity, for example, that between NB-substituted adenines and N,N‘-diphenylureas, both agonists of the plant hormones called cytokinins,15and that between the terpenoid sweeteners perillartiies and sweet L-aspartyl dipeptides.l6 The results suggest the possibility that the information on the structure vs. activity relationship of one class of compounds can be transposed to other types of compounds. The necessary condition for this is probably that the analysis is performed on the basis of the whole molecule rather than on the effects of substituents at one particular position or those of the structural variations at only a part of the molecule. Among the compounds hitherto known to have J H mimetic activity, the (2E,4E)-3,7,11-trimethyl-2,4-dodecadienoates and related compounds are a class that has been intensively investigated by Henrick and his coworkerse and have brought to us valuable insight into the structure vs. activity relationship of the J H mimetic compounds. The structure is systematically varied at both ends of the chain molecule and the total number of compounds tested for activity is highest, as far as we know. Although they are all terpenoids, a similar mode of action (12) Zoral, M.; S l h a , K. Science 1970,170,92. (13) Babu, T.H.; S l h a , K.Science 1972,175, 78. (14) DeMilo, A. B.; Redfern, R. E. J. Agric. Food Chem. 1979,27, 760. (15) Iwamura, H.; Fujita, T.; Koyama, S.; Koshimizu, K.; Kumazawa, Z. Phytochemistry 1980,19, 1309. (16) Iwamura, H. J. Med. Chem. 1981,24,572.
0022-2623/84/1827-1493$01.50/00 1984 American Chemical Society
1494 Journal of Medicinal Chemistry, 1984, Vol. 27, No. 11
Nakayama et al.
Table I. Activity and Physicochemical Parameters of 2,4-Dodecadien~nes~
A activity
no.
x
1 2
OMe OEt 0-n-Pr 0-i-Pr 0-i-Bu 0-sec-Bu 0-t-Bu OCH,C=CH OCH2Cz CCH, OCH,CH-CH2 OPh OCHzPh OH OMe OEt 0-n-Pr 0-i-Pr 0-n-Bu 0-sec-Bu 0-t-Bu 0-i-amyl OCH,C=CH O(CH2)2C=CH OCH,CH-CHZ OCH,CH== CHMe OCH(Me)CH= CH, 0-c-Pr 0-C-BU O-C-C~H~ OH OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt 0-i-Pr 0-i-Pr 0-i-Pr 0-i-Pr 0-i-Pr 0-i-Pr 0-i-Pr 0-i-Pr 0-i-Pr 0-i-Pr 0-i-Pr 0-i-Pr
3 4 5 6 7ef 8 9
10 lle
12f 13’
14 15 16 17 18 19 20
21 22
23f 24
25 26 27 28 29e
3d 31 32f 338 34 358 36‘8 378 38 39’ 40e 41fJ 4Zeg 43 44 45 4d 478 48 498 508 51 52
53e9 548 5sB 56 57O9 58e8
T.molitor, ~160,ccmoV Pupa obsd calcdd 2.20 1.43 3.03 2.81 2.71 3.11 4.03 4.11 3.80 3.30 3.87 4.38 (1.01) 4.31 2.33 1.90 2.12 2.55 3.51
Me Me Me Me Me Me Me Me Me
H H H H H H H H H
A. aegypti, PIW,mM B obsd calcdC ApIW H 3.23 3.51 -0.28 H 4.53 4.32 0.21 H 4.24 4.18 0.06 H 5.17 5.04 0.13 H 4.07 4.13 -0.06 H 4.21 4.84 -0.63 H (
