Screening and Structure-Activity Relationships of Synthetic Juvenile Hormone Analogues for Panstrongylus megistus,l a Primary Vector of Chagas' Disease in Brazil2 R. PINCHIN,
A. M. DE OLIVEIRA FILHO, M. J. FIGUEIREDO, C. A. MULLER, A. P. SZUMLEWICZ,4 AND W. W. BENSON5
B. GILBER'f3,
Nucleo de Pesquisas de Produlos Nalurais, Centro de Ciencias da Saude, Universidade Federal do Rio de Janeiro, Brazil ABSTRACT J. Econ. Enlomol.
71: 950--955 (1978)
As part of the search for new agents and methods for the control of triatomine bugs: 40 compounds were bioassayed for juvenile hormone activity on Panstrongylus megistus (Burmels(~r), one of the most important transmitters of Chagas' dis~a~e..jn Brazil. Compounds of seve~al d1ffere~t structural classes were tested, and high levels of actiVity were observed for some aroma~lc terpenOid ethers and amines. The most active compound wasN-(5-chloro-2-methylphe~yl)-3,7-d1met.hyl-2:~octadienylamine; a single topical application of 0.1 p.glinsect resulted m a high degree of Juvemhzation. From a comparison of the structures of the active comp?un~s, the pre~ence of an .el.eclronegative group, such as alkoxy or chlorine, meta to the terpenOid Side cham, IS a prerequISIte for high juvenile hormone activity on this insect.
~ptera: Reduviidae. • Received for publication May 31, 1978. .. 3 (nstituto de Pesquisas da Marinha, Rua Ipirn, IIha do Govemador. RIO de JaneIro, Brazil. • Laborat6rio de Biologia e Controle de Vetores da Doen~a de Chagas. Funda~.o Oswaldo Cruz, Estrada da Covanca 56, Jacarepagua, Rio de Janeiro. Brazil. . Ii Departamento de Zoologia. Universidade Estadual de Campmas. Campmas. Brazil.
Materials and Methods The specimens of P. megisfus used in these experiments were from a laboratory culture derived from insects collected in the state of Ceara, Brazil, in 1969. The bugs were bred in mass cultures in wide-mouthed battery jars (5.3 liters) held at 24°±3°C and 75± 15 % RH and fed weekly on chickens (Szumlewicz 1973). Under these conditions, P. megistus completed its life cycle in ca. 6 mo with ca. 5 wk spent as 5th instars (Szumlewicz 1975). Specimens, weighing 107 ±4 mg and within 5 days after transition from the 4th instar, were used throughout the experiments. The compounds were tested by topically administering I p.l of a solution of JHA, diluted in an appropriate solvent (acetone or n-hexane), to experimental insects, whereas each insect of the control groups received 1 ILl of pure solvent. Depending on the experimental group, from 0.01-10 p.g of JHA were applied to the dorsal abdomen of each insect. Ten insects were used in each group. After treatment, the insects were put into 400-ml cylindrical glass jars fitted with pleated filter paper roosts. The top of each jar was covered with nylon netting held in place with elastic bands. An opportunity to feed on chickens was provided during I h each week. As the nymphs moulted, data were taken on the degree of juvenilization exhibited based on both the external characteristics observed and whether or not the insects were sterile, as judged by oviposition and egg hatchability upon pairing with normal adults. The insects were then scored using the following 5-point system: O--full adult characteristics; I-meta-, and mesothoracic wings extending beyond 4/5 of the length of the abdomen, wings deformed; 2-meta-, and mesothoracic wings highly crumpled and extending between 1/2 and 4/5 of the length of the abdomen, body morphologically adultlike; 3-metathoracic wings at least partially exposed from under the wing pads (greatly reduced mesothoracic wings), wings not extending more than half way along the abdomen; and 4-extranumerary nymph, body size abnormally large, body form and wing pads as in the 5th instar. JHA No. 10 (or 25) was used as a positive control throughout the screening experiments and invariably gave 100% score 4 at I p.g/insect.
950
© 1978
Entomological Society of America
0022-0493/78/0609-5006$00.75/0
Downloaded from http://jee.oxfordjournals.org/ by guest on June 7, 2016
Chagas' disease remains one of the most serious public health problems in Brazil. Unfortunately, there is no widely accepted prophylaxis or cure for the disease itself, thus containment and control of infection depends almost entirely on freeing houses of triatomine bugs, the vectors of the disease. Although it must be conceded that much could be achieved through an improvement in the standard of housing conditions allied with an educational program, the use of chemical control agents will continue to be necessary. Insecticides currently in use, notably BHC (30% lindane), can only give effective control when frequently reapplied. Recently much attention has been given worldwide to the possibility of using insect juvenile hormone analogues (JHAs) as alternative control agents (Williams 1967, Bowers 1971, Slama 1971, Slama et al. 1974). These hormone mimics often show optimal biological activity at extremely low dose levels; hence, the risk that environmental pollution may result from their use is minimal. Also, since the principle of activity does not involve toxicity, sensu stricto, vertebrate health problems should not be a by-product (Staal 1975). However, only a fraction of the research in this field so far has been concentrated on the particular case of Chagas' disease vectors (Wigglesworth 1969, 1973, Patterson 1973, Gilbert 1975, Patterson and Schwarz 1977). As part of our research program directed towards the search for improved methods for the control of tropical, endemic diseases, a number of JHAs was bioassayed for juvenilizing activity on Panstrongylus megistus (Burmeister), one of the most important Chagas' disease transmitters in Brazil (Pessoa and Martins 1977). The JHAs initially chosen were representative of several different structural classes. Subsequently, many derivatives of geranylamine were synthesized and screened in the search for highly active compounds.
December
1978
After classifying the insects, the avg juvenilization was calculated from the formula:
-
J=
I (No.
951
PINCHIN ET AL.: JH ANALOGUES FOR CHAGAS DISEASE VECTORS
insects scored x juvenilization
score
score)
Total no. of insects scored
The compounds donated by other research institutions were used without further purification. The compounds prepared in these laboratories were synthesized by standard methods and purified by chromatography on silica gel or by high-vacuum distillation. Table I.-Degree
Results and Discussion Table 1 presents the results of the biological screening expressed as the avg juvenilization score obtained for the dosages tested. The JHAs are listed with consideration for chemical structure. Initially, compounds were tested at 2 dosages, I and 10 J.l.g/insect, but later the I-J.l.g dose was adopted as standard. Active compounds were retested at this and other dose levels. Compounds representing several different basic structural classes were tested, i.e., aliphatic branched chain compounds _(1-7), aromatic terpenoid ethers (8-11), and de-
of juvenillzation produced by topical appUcation of JHAs to 5th instars of Panstrongylus megistus. Avg score (/Lglinsect)
No.
Structure
10.0
1.0
0.1
2
o
3
o
4
2.1
5
\.8
6
o
7
o
8
0.88
9
4.0
1.1
10
4.0
1.4
II
o
12
3.38
3.1
13
o
14
o
15
o
16
0.71
0.45
17
2.63
0.13
18
3.6
0.9
Downloaded from http://jee.oxfordjournals.org/ by guest on June 7, 2016
o
952
JOURNAL
OF ECONOMIC
Vol. 71, no. 6
ENTOMOLOGY
Table 1.-Continued. Avg score (/Jog/insect) No.
10.0
Structure
j)CI
19
1.0
0.1
0
~NHI~ CI
20
~NHI~
4.0
CIx)
2.67
0.5
CI 21
0.5
CIx) ~NHI~
22
J():CI
~NHI~Cl ~NHI~
Cl:Q
3.0
0.1
Cl
~.JiCl
24
0.2
CIn
25
~NHI~
26
~NHI~CI
CI C~)[)
4.0
4.0
1.38
4.0
3.13
0.63
CI~
27
0
~NI~CI I
Ac CIn 28
0
~NI~CI I
COPh CI~
29
0.25
~NI~CI I
30
31
32
Me~NH Et
~NH
36
2.75
~CI 0.73
~CI
CI:OCI
~NH
35
CI~ I
I~
~NH
33
34
Ts CI~ I
~NH ~NHI~CI ~I~
j()Me I~ CI Me~ I~ Cl Me»
EtOC NIl
3.67
CI 3.7
0.4
3.9
0
0
CI
0
3.33
Downloaded from http://jee.oxfordjournals.org/ by guest on June 7, 2016
23
3.6
December 1978
PINCHIN
ET AL.:
JH
ANALOGUES
FOR CHAGAS
DISEASE
953
VECTORS
Table l.-Continued.
Avg score No.
Structure
10.0
(/L
1.0
insect) 0.1
~OMe
37
3.0
~~Cl ~OEt
38
1.75
~NHMCl M~ 3.88
39
~NHMN02 40
Il
In ~OMe
I
0
0.25
4.0
1.25
Compound 7 was found to be toxic to the:insects; al 10 J.Lg/nympha)1the insects died within 48 h of application. At I J.Lg/nymph,30% mortality was recorded; the other nymphs
moulted to give normal adults (score 0).
the ethers 9 and 10. These anilines have a chlorine atom at C-5 of the aromatic ring and a chlorine and a methyl group, respectively, at C-2. Of the 3 monochloro-derivatives 17, ] 8, and 19, the meta-isomer was the most active and the para-, the least. The 7 dichloroanilines tested, 2026, with either geranyl or citronellyl side chains, were on the whole active compounds, though again one chlorine atom has to be mela to the side chain for pronounced activity. Incongruously, the analogue 24, with both chlorine atoms meta to the nitrogen, gave a very low activity rating. Patterson and Schwarz (1977) reported similar findings for the JH activity of several of these chloroanilines on R. pro/ixus. Modifications to the aliphatic side chain of the chloroaniline JHAs previously discussed invariably caused a reduction or loss of activity. Thus, the citronellyl derivatives 21 and 26 of 20 and 25, respectively, were less efficient JHAs. Reductive alkoxylation of the 6',7' -double bond of 25 (30, 31) as well as the introduction of an amide linkage at the nitrogen atom (27-29), resulted in a loss of activity. The effects of groups other than chlorine on the JH activity were investigated using m-chlorogeranylaniline (18) as the basic skeleton. 2-Methyl-5-chlorogeranylaniline (34) has been mentioned for its potency and, at 0.1 J,tg/insect, it was clearly the most active compound tested. Substituting methoxy or ethoxy groups for the methyl of 34, as in compounds 35 and 36, caused loss of biological activity, whereas these 2 radicals when introduced para to the nitrogen gave rise to compounds 37 and 38 with the same order of activity as the corresponding 3,4-dichloro- compound 22. Even lower activity was noted for 3-chloro-4-methylgeranylaniline (33), whereas the 2,4,5-trichloro analogue 32 was highly active. Other substituents on the aromatic nucleus which confer JH-like properties on these geranylanilines include 2-methyl5-nitro (39) and the 3,4-methylenedioxy ring (12). Separation of the nitrogen atom in the latter compound from the aromatic nucleus by one or 2 methylene units (13, 14) caused complete loss of activity, as did the introduction of a propyl group ortho to the side chain (]5). Comparison of 12 with the structurally similar ethers 9 and 10 served to highlight the importance of the methylenedioxy function, which was presumably related to its multifunction oxidase
Downloaded from http://jee.oxfordjournals.org/ by guest on June 7, 2016
rivatives of N-geranylaniline (12-39). Patterson (1973) and Wigglesworth (1969) reported that methyl farnesyl ether (I), ethyl 10, II-epoxy-3,7, II-trimethyl-2-dodecenoate (2), and the Cecropia JH I were effective against the related insect Rhodnius prolixus (Stal) at doses of the order of I J,tg/insect. However, no such effect was noted for compounds 1 and 2 on P. megislus at the dosages applied (I J,tg) nor for JH I even when 8 weekly doses of I J,tg were used (Benson, unpublished data). The derivatives of 2,4-dodecadienoic acid (3-6) were either inactive or showed weak JH activity at the elevated dose of 10 /-Lg/insect though some of these compounds are well known to be potent JHAs for many other insects (Henrick et al. 1973). For example, compounds 3 and 6, hydroprene and methoprene, which between them possess a broad spectrum of activity (Henrick et al. 1975) did not cause any observable morphogenic effect when applied at I J,tglinsect. Analogue 7. in which an ethyl ketone group replaced the more usual carboxylic acid derivative, had a pronounced toxic effect at a dosage level of 10 /-Lg on the insects with death occurring within 48 h of application. This JHA has been reported by Henrick et al. (1976) to have considerable JH activity, especially on Lepidoptera. Some aromatic terpenoid compounds, as exemplified by the geranyl phenyl ethers and aniline derivatives, showed pronounced JH activity. The presence of the methylenedioxy, 6' ,T-epoxy, and T-ethyl groups in compounds 9 and 10 apparently was necessary for high activity in aromatic ethers of this type, an observation reported by Bowers (1969), Pallos et al. (1971), Walker and Bowers (1973), Hammock et al. (1974), and Hangartner et al. (1976). The epoxygeranyl ether 8, lacking the T -ethyl group, was surprisingly less active. The effect of varying the length of the carbon atom chain in this manner has been discussed by Bull et al. (1973), who found for 2 hemipteran species, Gl!ocoris pUl/clipes (Say) and Lygus lineolaris (Palisot de Beauvois), that the presence of a T -ethyl group increased the activity rating against G. pUl/ctipes but not for L. lineo/aris. The other ary I terpenoid ether tested (II), known as JH 25 (Sarmiento et al. 1975), was devoid of JH activity, even at 10 /-Lg/insect. Of the geranylaniline derivatives screened, 25 and 34 had JH activity at dosage levels comparable with those of
954
JOURNAL
OF ECONOMIC
Acknowledgment We are indebted to the Ministry of Planning (FINEP), the National Research Council (CNPq), and the Research Council of this University (CEPG/UFRJ) for financial assistance. Thanks are due to the following for donations of some of the JHAs used: Dr. J. B. Siddall, Zoecon Corp., Palo Alto, Calif., (Cmpds. 2-8, II); Dr. W. S. Bowers, Cornell University, Geneva, N.Y. (9,10); Dr. M. Schwarz, USDA, Beltsville, Md., (20, 21, 23-26); and Prof. A. W. Johnson, University of Sussex, Great Britain, (Cmpd. 40).
REFERENCES
CITED
Bowers, W. S. 1969. Juvenile honnone: activity of aromatic terpenoid ethers. Science 164: 323-5. 1971. Insect hormones and their derivatives as insecticides. Bull. WHO 44: 381-9.
Vol. 71, no. 6
Bull, D. L., R. L. Ridgway, W. E. Buxkemper, M. Schwarz, T. P. McGovern, and R. Sarmiento. 1973. Effects of synthetic juvenile honnone analogues on certain injurious and beneficial arthropods associated with cotton. J. Econ. Entomol. 66: 623-6. Gilbert, B. 1975. Possible use of juvenile honnone mimics in vector control. P. 282-8. In New Approaches in American Trypanosomiasis Research, Pan Am. Health Organ., Washington, D.C., 410 pp. Grove, J. F., R. C. Jennings, A. W. Johnson, and A. F. White. 1974. Synthesis of some juvenile honnone mimics and biological activity on Rhodnius prolixus. Chern. Ind. (London), 346-7. Hammock, B. D., S. S. Gill, and J. E. Casida. 1974. Synthesis and morphogenetic activity of derivatives and analogues of aryl geranyl ether juvenoids. J. Agric. Food Chern. 22: 37885. Hangartner, W. W., M. Suchy, H. K. Wipf, and R. C. Zurflueh. 1976. Synthesis and laboratory and field evaluation of a new, highly active and stable insect growth regulator. Ibid. 24: 169-75. Henrick, C. A., G. B. Staal, and J. B. Siddall. 1973. Alkyl 3.7,1 ]-trimethyl-2,4-dodecadienoates, a new class of potent insect growth regulators with juvenile honnone activity. Ibid. 21: 35ceptibilily of the insecls to gut infection with Trypano· somll end. Rev. Ins!. Med. Trop. Sao Paulo. 17: 97-102. Walker, W. F., and W. S. Bowers. 1973. Comparative juvenile hormone activity of some terpenoid ethers and esters on se·
FOR CHAGAS
DISEASE
VECTORS
955
lected Coleoptera. J. Agric. Food Chem. 21: 145-8. Wigglesworth, V. B. 1969. Chemical structure and juvenile hor· mone activily: comparative tests on Rhodnius prolixus. J. In· seCl Physiol. 15: 73-94. 1973. Assays on Rhodnius for juvenile hormone activity. Ibid. 19: 205-11. Williams, C. M. 1967. Third-generalion pesticides. Sci. Am. 217:
13-7.
Downloaded from http://jee.oxfordjournals.org/ by guest on June 7, 2016
A. M. DE OLIVEIRA FILHO, M. J. FIGUEIREDO, C. A. MULLER, A. P. SZUMLEWICZ,4 AND W. W. BENSON5
B. GILBER'f3,
Nucleo de Pesquisas de Produlos Nalurais, Centro de Ciencias da Saude, Universidade Federal do Rio de Janeiro, Brazil ABSTRACT J. Econ. Enlomol.
71: 950--955 (1978)
As part of the search for new agents and methods for the control of triatomine bugs: 40 compounds were bioassayed for juvenile hormone activity on Panstrongylus megistus (Burmels(~r), one of the most important transmitters of Chagas' dis~a~e..jn Brazil. Compounds of seve~al d1ffere~t structural classes were tested, and high levels of actiVity were observed for some aroma~lc terpenOid ethers and amines. The most active compound wasN-(5-chloro-2-methylphe~yl)-3,7-d1met.hyl-2:~octadienylamine; a single topical application of 0.1 p.glinsect resulted m a high degree of Juvemhzation. From a comparison of the structures of the active comp?un~s, the pre~ence of an .el.eclronegative group, such as alkoxy or chlorine, meta to the terpenOid Side cham, IS a prerequISIte for high juvenile hormone activity on this insect.
~ptera: Reduviidae. • Received for publication May 31, 1978. .. 3 (nstituto de Pesquisas da Marinha, Rua Ipirn, IIha do Govemador. RIO de JaneIro, Brazil. • Laborat6rio de Biologia e Controle de Vetores da Doen~a de Chagas. Funda~.o Oswaldo Cruz, Estrada da Covanca 56, Jacarepagua, Rio de Janeiro. Brazil. . Ii Departamento de Zoologia. Universidade Estadual de Campmas. Campmas. Brazil.
Materials and Methods The specimens of P. megisfus used in these experiments were from a laboratory culture derived from insects collected in the state of Ceara, Brazil, in 1969. The bugs were bred in mass cultures in wide-mouthed battery jars (5.3 liters) held at 24°±3°C and 75± 15 % RH and fed weekly on chickens (Szumlewicz 1973). Under these conditions, P. megistus completed its life cycle in ca. 6 mo with ca. 5 wk spent as 5th instars (Szumlewicz 1975). Specimens, weighing 107 ±4 mg and within 5 days after transition from the 4th instar, were used throughout the experiments. The compounds were tested by topically administering I p.l of a solution of JHA, diluted in an appropriate solvent (acetone or n-hexane), to experimental insects, whereas each insect of the control groups received 1 ILl of pure solvent. Depending on the experimental group, from 0.01-10 p.g of JHA were applied to the dorsal abdomen of each insect. Ten insects were used in each group. After treatment, the insects were put into 400-ml cylindrical glass jars fitted with pleated filter paper roosts. The top of each jar was covered with nylon netting held in place with elastic bands. An opportunity to feed on chickens was provided during I h each week. As the nymphs moulted, data were taken on the degree of juvenilization exhibited based on both the external characteristics observed and whether or not the insects were sterile, as judged by oviposition and egg hatchability upon pairing with normal adults. The insects were then scored using the following 5-point system: O--full adult characteristics; I-meta-, and mesothoracic wings extending beyond 4/5 of the length of the abdomen, wings deformed; 2-meta-, and mesothoracic wings highly crumpled and extending between 1/2 and 4/5 of the length of the abdomen, body morphologically adultlike; 3-metathoracic wings at least partially exposed from under the wing pads (greatly reduced mesothoracic wings), wings not extending more than half way along the abdomen; and 4-extranumerary nymph, body size abnormally large, body form and wing pads as in the 5th instar. JHA No. 10 (or 25) was used as a positive control throughout the screening experiments and invariably gave 100% score 4 at I p.g/insect.
950
© 1978
Entomological Society of America
0022-0493/78/0609-5006$00.75/0
Downloaded from http://jee.oxfordjournals.org/ by guest on June 7, 2016
Chagas' disease remains one of the most serious public health problems in Brazil. Unfortunately, there is no widely accepted prophylaxis or cure for the disease itself, thus containment and control of infection depends almost entirely on freeing houses of triatomine bugs, the vectors of the disease. Although it must be conceded that much could be achieved through an improvement in the standard of housing conditions allied with an educational program, the use of chemical control agents will continue to be necessary. Insecticides currently in use, notably BHC (30% lindane), can only give effective control when frequently reapplied. Recently much attention has been given worldwide to the possibility of using insect juvenile hormone analogues (JHAs) as alternative control agents (Williams 1967, Bowers 1971, Slama 1971, Slama et al. 1974). These hormone mimics often show optimal biological activity at extremely low dose levels; hence, the risk that environmental pollution may result from their use is minimal. Also, since the principle of activity does not involve toxicity, sensu stricto, vertebrate health problems should not be a by-product (Staal 1975). However, only a fraction of the research in this field so far has been concentrated on the particular case of Chagas' disease vectors (Wigglesworth 1969, 1973, Patterson 1973, Gilbert 1975, Patterson and Schwarz 1977). As part of our research program directed towards the search for improved methods for the control of tropical, endemic diseases, a number of JHAs was bioassayed for juvenilizing activity on Panstrongylus megistus (Burmeister), one of the most important Chagas' disease transmitters in Brazil (Pessoa and Martins 1977). The JHAs initially chosen were representative of several different structural classes. Subsequently, many derivatives of geranylamine were synthesized and screened in the search for highly active compounds.
December
1978
After classifying the insects, the avg juvenilization was calculated from the formula:
-
J=
I (No.
951
PINCHIN ET AL.: JH ANALOGUES FOR CHAGAS DISEASE VECTORS
insects scored x juvenilization
score
score)
Total no. of insects scored
The compounds donated by other research institutions were used without further purification. The compounds prepared in these laboratories were synthesized by standard methods and purified by chromatography on silica gel or by high-vacuum distillation. Table I.-Degree
Results and Discussion Table 1 presents the results of the biological screening expressed as the avg juvenilization score obtained for the dosages tested. The JHAs are listed with consideration for chemical structure. Initially, compounds were tested at 2 dosages, I and 10 J.l.g/insect, but later the I-J.l.g dose was adopted as standard. Active compounds were retested at this and other dose levels. Compounds representing several different basic structural classes were tested, i.e., aliphatic branched chain compounds _(1-7), aromatic terpenoid ethers (8-11), and de-
of juvenillzation produced by topical appUcation of JHAs to 5th instars of Panstrongylus megistus. Avg score (/Lglinsect)
No.
Structure
10.0
1.0
0.1
2
o
3
o
4
2.1
5
\.8
6
o
7
o
8
0.88
9
4.0
1.1
10
4.0
1.4
II
o
12
3.38
3.1
13
o
14
o
15
o
16
0.71
0.45
17
2.63
0.13
18
3.6
0.9
Downloaded from http://jee.oxfordjournals.org/ by guest on June 7, 2016
o
952
JOURNAL
OF ECONOMIC
Vol. 71, no. 6
ENTOMOLOGY
Table 1.-Continued. Avg score (/Jog/insect) No.
10.0
Structure
j)CI
19
1.0
0.1
0
~NHI~ CI
20
~NHI~
4.0
CIx)
2.67
0.5
CI 21
0.5
CIx) ~NHI~
22
J():CI
~NHI~Cl ~NHI~
Cl:Q
3.0
0.1
Cl
~.JiCl
24
0.2
CIn
25
~NHI~
26
~NHI~CI
CI C~)[)
4.0
4.0
1.38
4.0
3.13
0.63
CI~
27
0
~NI~CI I
Ac CIn 28
0
~NI~CI I
COPh CI~
29
0.25
~NI~CI I
30
31
32
Me~NH Et
~NH
36
2.75
~CI 0.73
~CI
CI:OCI
~NH
35
CI~ I
I~
~NH
33
34
Ts CI~ I
~NH ~NHI~CI ~I~
j()Me I~ CI Me~ I~ Cl Me»
EtOC NIl
3.67
CI 3.7
0.4
3.9
0
0
CI
0
3.33
Downloaded from http://jee.oxfordjournals.org/ by guest on June 7, 2016
23
3.6
December 1978
PINCHIN
ET AL.:
JH
ANALOGUES
FOR CHAGAS
DISEASE
953
VECTORS
Table l.-Continued.
Avg score No.
Structure
10.0
(/L
1.0
insect) 0.1
~OMe
37
3.0
~~Cl ~OEt
38
1.75
~NHMCl M~ 3.88
39
~NHMN02 40
Il
In ~OMe
I
0
0.25
4.0
1.25
Compound 7 was found to be toxic to the:insects; al 10 J.Lg/nympha)1the insects died within 48 h of application. At I J.Lg/nymph,30% mortality was recorded; the other nymphs
moulted to give normal adults (score 0).
the ethers 9 and 10. These anilines have a chlorine atom at C-5 of the aromatic ring and a chlorine and a methyl group, respectively, at C-2. Of the 3 monochloro-derivatives 17, ] 8, and 19, the meta-isomer was the most active and the para-, the least. The 7 dichloroanilines tested, 2026, with either geranyl or citronellyl side chains, were on the whole active compounds, though again one chlorine atom has to be mela to the side chain for pronounced activity. Incongruously, the analogue 24, with both chlorine atoms meta to the nitrogen, gave a very low activity rating. Patterson and Schwarz (1977) reported similar findings for the JH activity of several of these chloroanilines on R. pro/ixus. Modifications to the aliphatic side chain of the chloroaniline JHAs previously discussed invariably caused a reduction or loss of activity. Thus, the citronellyl derivatives 21 and 26 of 20 and 25, respectively, were less efficient JHAs. Reductive alkoxylation of the 6',7' -double bond of 25 (30, 31) as well as the introduction of an amide linkage at the nitrogen atom (27-29), resulted in a loss of activity. The effects of groups other than chlorine on the JH activity were investigated using m-chlorogeranylaniline (18) as the basic skeleton. 2-Methyl-5-chlorogeranylaniline (34) has been mentioned for its potency and, at 0.1 J,tg/insect, it was clearly the most active compound tested. Substituting methoxy or ethoxy groups for the methyl of 34, as in compounds 35 and 36, caused loss of biological activity, whereas these 2 radicals when introduced para to the nitrogen gave rise to compounds 37 and 38 with the same order of activity as the corresponding 3,4-dichloro- compound 22. Even lower activity was noted for 3-chloro-4-methylgeranylaniline (33), whereas the 2,4,5-trichloro analogue 32 was highly active. Other substituents on the aromatic nucleus which confer JH-like properties on these geranylanilines include 2-methyl5-nitro (39) and the 3,4-methylenedioxy ring (12). Separation of the nitrogen atom in the latter compound from the aromatic nucleus by one or 2 methylene units (13, 14) caused complete loss of activity, as did the introduction of a propyl group ortho to the side chain (]5). Comparison of 12 with the structurally similar ethers 9 and 10 served to highlight the importance of the methylenedioxy function, which was presumably related to its multifunction oxidase
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rivatives of N-geranylaniline (12-39). Patterson (1973) and Wigglesworth (1969) reported that methyl farnesyl ether (I), ethyl 10, II-epoxy-3,7, II-trimethyl-2-dodecenoate (2), and the Cecropia JH I were effective against the related insect Rhodnius prolixus (Stal) at doses of the order of I J,tg/insect. However, no such effect was noted for compounds 1 and 2 on P. megislus at the dosages applied (I J,tg) nor for JH I even when 8 weekly doses of I J,tg were used (Benson, unpublished data). The derivatives of 2,4-dodecadienoic acid (3-6) were either inactive or showed weak JH activity at the elevated dose of 10 /-Lg/insect though some of these compounds are well known to be potent JHAs for many other insects (Henrick et al. 1973). For example, compounds 3 and 6, hydroprene and methoprene, which between them possess a broad spectrum of activity (Henrick et al. 1975) did not cause any observable morphogenic effect when applied at I J,tglinsect. Analogue 7. in which an ethyl ketone group replaced the more usual carboxylic acid derivative, had a pronounced toxic effect at a dosage level of 10 /-Lg on the insects with death occurring within 48 h of application. This JHA has been reported by Henrick et al. (1976) to have considerable JH activity, especially on Lepidoptera. Some aromatic terpenoid compounds, as exemplified by the geranyl phenyl ethers and aniline derivatives, showed pronounced JH activity. The presence of the methylenedioxy, 6' ,T-epoxy, and T-ethyl groups in compounds 9 and 10 apparently was necessary for high activity in aromatic ethers of this type, an observation reported by Bowers (1969), Pallos et al. (1971), Walker and Bowers (1973), Hammock et al. (1974), and Hangartner et al. (1976). The epoxygeranyl ether 8, lacking the T -ethyl group, was surprisingly less active. The effect of varying the length of the carbon atom chain in this manner has been discussed by Bull et al. (1973), who found for 2 hemipteran species, Gl!ocoris pUl/clipes (Say) and Lygus lineolaris (Palisot de Beauvois), that the presence of a T -ethyl group increased the activity rating against G. pUl/ctipes but not for L. lineo/aris. The other ary I terpenoid ether tested (II), known as JH 25 (Sarmiento et al. 1975), was devoid of JH activity, even at 10 /-Lg/insect. Of the geranylaniline derivatives screened, 25 and 34 had JH activity at dosage levels comparable with those of
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Acknowledgment We are indebted to the Ministry of Planning (FINEP), the National Research Council (CNPq), and the Research Council of this University (CEPG/UFRJ) for financial assistance. Thanks are due to the following for donations of some of the JHAs used: Dr. J. B. Siddall, Zoecon Corp., Palo Alto, Calif., (Cmpds. 2-8, II); Dr. W. S. Bowers, Cornell University, Geneva, N.Y. (9,10); Dr. M. Schwarz, USDA, Beltsville, Md., (20, 21, 23-26); and Prof. A. W. Johnson, University of Sussex, Great Britain, (Cmpd. 40).
REFERENCES
CITED
Bowers, W. S. 1969. Juvenile honnone: activity of aromatic terpenoid ethers. Science 164: 323-5. 1971. Insect hormones and their derivatives as insecticides. Bull. WHO 44: 381-9.
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Bull, D. L., R. L. Ridgway, W. E. Buxkemper, M. Schwarz, T. P. McGovern, and R. Sarmiento. 1973. Effects of synthetic juvenile honnone analogues on certain injurious and beneficial arthropods associated with cotton. J. Econ. Entomol. 66: 623-6. Gilbert, B. 1975. Possible use of juvenile honnone mimics in vector control. P. 282-8. In New Approaches in American Trypanosomiasis Research, Pan Am. Health Organ., Washington, D.C., 410 pp. Grove, J. F., R. C. Jennings, A. W. Johnson, and A. F. White. 1974. Synthesis of some juvenile honnone mimics and biological activity on Rhodnius prolixus. Chern. Ind. (London), 346-7. Hammock, B. D., S. S. Gill, and J. E. Casida. 1974. Synthesis and morphogenetic activity of derivatives and analogues of aryl geranyl ether juvenoids. J. Agric. Food Chern. 22: 37885. Hangartner, W. W., M. Suchy, H. K. Wipf, and R. C. Zurflueh. 1976. Synthesis and laboratory and field evaluation of a new, highly active and stable insect growth regulator. Ibid. 24: 169-75. Henrick, C. A., G. B. Staal, and J. B. Siddall. 1973. Alkyl 3.7,1 ]-trimethyl-2,4-dodecadienoates, a new class of potent insect growth regulators with juvenile honnone activity. Ibid. 21: 35ceptibilily of the insecls to gut infection with Trypano· somll end. Rev. Ins!. Med. Trop. Sao Paulo. 17: 97-102. Walker, W. F., and W. S. Bowers. 1973. Comparative juvenile hormone activity of some terpenoid ethers and esters on se·
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lected Coleoptera. J. Agric. Food Chem. 21: 145-8. Wigglesworth, V. B. 1969. Chemical structure and juvenile hor· mone activily: comparative tests on Rhodnius prolixus. J. In· seCl Physiol. 15: 73-94. 1973. Assays on Rhodnius for juvenile hormone activity. Ibid. 19: 205-11. Williams, C. M. 1967. Third-generalion pesticides. Sci. Am. 217:
13-7.
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