Fungicide Chemistry - American Chemical Society

5 Progress in the Chemical Control of Diseases Caused by Oomycetes F. J. Schwinn and P. A. Urech

Downloaded by UNIV OF ARIZONA on January 7, 2013 | http://pubs.acs.org Publication Date: April 22, 1986 | doi: 10.1021/bk-1986-0304.ch005

Research and Development Department, Agricultural Division, Ciba-Geigy Limited, CH-4002 Basel, Switzerland

Among the fungi, the class Oomycetes is by number the smallest of the five classes, comprising some 70 genera with 500 species. However, in many respects, they are a unique and important class: 1) their c e l l walls differ from those of all other fungi, inasmuch as they contain cellulose instead of chitin; 2) they do not synthesize sterols; 3) their l i f e cycle is diploid (in contrast to all other fungi); and 4) they form motile spores (zoospores). Their classification is shown in Figure 1. From the phytopathologist's point of view, the Peronosporales are the most impor tant order with the Peronosporaceae as the major family. Plant diseases caused by Peronosporales can be put into the three following groups: 1) foliar diseases, mainly downy mildews and late blight; 2) root and crown diseases, such as damping-off, seedling blights, root, collar and stem rot on annual and perennial crops; and 3) systemic diseases, that is diseases caused by infection of the roots from the s o i l or seed, distribution of the pathogen by the vascular system of the plant and manifestation of symptoms at the vegetation point or on the foliage. Most annual or perennial agronomical, horticultural and ornamental crops (such as grapes, potatoes, tobacco, tomato, hops, citrus, sunflowers, vegetables and soybeans), both in temperate and tropical climates, can be attacked by Peronosporales (Table I)(29, revised). The potential of the Peronosporales to result in epidemics within very short periods of favorable climatic conditions makes them an extremely devastating group of plant pathogens, the control of which has been a high priority for a long time and at present, amounts to about 25% of the total world fungicide market (Figure 2). Until about ten years ago, protectant foliar fungicides (such as ethylene bis-dithiocarbamates and phthalimides) and s o i l sterilants (such as vapam or methylbromide) were the only chemical means of controlling diseases caused by Oomycetes. These compounds are nonspecific biocides affecting many vital c e l l processes of both the pathogen and the host plant. This means that they are non-selective, 0097-6156/86/0304-0089$06.00/ 0 © 1986 American Chemical Society

In Fungicide Chemistry; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.

90

FUNGICIDE CHEMISTRY

class

Ascomycetes

Oomycetes

Deuteromycetes

Peronosporales

order


Basidiomycetes

family

1 Pythiaceae (non-obligate)

genus

Pythium Phytophthora

Figure

1.

Peronosporaceae (obligate) Downy Mildews Peronospora Plasmopara Pseudoperonospora Bremia Peronosclerospora Sclerospora Sclerophthora

1 Albuginaceae (obligate) Albugo

P l a n t pathogenic f u n g i .

Grower level 1982 2,1 Billion US $

Downy Mildews 500 Mio US $

F i g u r e 2.

World f u n g i c i d e market.


5.

SCH WINN AND U RECH


Table I . :

Control of Diseases Caused by Oomycetes

Major P l a n t Pathogens

i n t h e C l a s s Oomycetes

91

(29)

F o l i a r Pathogens Plasmopara v i t i c o l a P h y t o p h t h o r a spp. Peronospora t a b a c i n a

Crop grape v i n e s p o t a t o e s , tomatoes, tobacco

Root and Crown Pathogens Pythium spp. P h y t o p h t h o r a spp.

Crop sugar b e e t s , v e g e t a b l e s , ornamentals

cocoa

avocado, soybean, c i t r u s , a p p l e s , ornamentals Systemic Pathogens Peronosclerospora/ Sclerospora/Sclerophthora Plasmopara h a l s t e d i i Pseudoperonospora h u m u l i

Crop m a i z e , sorghum, m i l l e t sunflower hops

and y e t , can be used f o r the s e l e c t i v e c o n t r o l o f t h e pathogens. I n the case o f t h e s o i l s t e r i l a n t s , s e l e c t i v i t y i s a c h i e v e d by t h e absence o f t h e h o s t p l a n t a t t h e time o f a p p l i c a t i o n , t h a t i s , treatment b e f o r e p l a n t i n g . The s e l e c t i v i t y o f t h e f o l i a r p r o t e c t a n t s i s based on t h e i r n o n - p e n e t r a t i o n i n t o p l a n t t i s s u e . To be e f f e c t i v e , they must be a p p l i e d b e f o r e i n f e c t i o n o c c u r s and must be p r e s e n t on t h e p l a n t s u r f a c e as l o n g as i t i s s u s c e p t i b l e . I n view of t h e i r exposure t o r a i n f a l l and w e a t h e r i n g , t h i s r e q u i r e s r e p e a t e d a p p l i c a t i o n s a t f a i r l y h i g h dosage r a t e s . The l i m i t a t i o n s o f t h e s e p r o t e c t i v e fungicides are obvious: they do n o t a f f e c t e s t a b l i s h e d l o c a l i n f e c t i o n s and cannot c o n t r o l s y s t e m i c d i s e a s e s . On t h e o t h e r hand, when used p r o p e r l y w i t h narrow s p r a y i n t e r v a l s and over t h e whole season, they have p r o v i d e d good p r o t e c t i o n from d i s e a s e s over many decades and s t i l l c o n t i n u e t o do s o , as l o n g as no s e r i o u s epidemics develop. W i t h i n t h e p a s t t e n y e a r s , the market i n t r o d u c t i o n o f s e v e r a l new t y p e s o f f u n g i c i d e s h a s s i g n i f i c a n t l y improved t h e p r o s p e c t s o f c o n t r o l l i n g t h e Oomycetes. They b e l o n g t o f i v e d i f f e r e n t c h e m i c a l classes: t h e carbamates, t h e i s o x a z o l e s , t h e cyanoacetamide oximes, the e t h e y l phosphonates, and the a c y l a l a n i n e s and r e l a t e d compounds. The c h e m i c a l s t r u c t u r e s o f those c h e m i c a l s t h a t have reached t h e commercial l e v e l a r e shown i n F i g u r e s 3-5 ( 2 9 , r e v i s e d ) . Trade names, f o r m u l a t i o n s and f i r s t r e p o r t s a r e summarized i n Table I I ( 2 9 , r e v i s e d ) . The b i o l o g i c a l c h a r a c t e r i s t i c s o f these new f u n g i c i d e s and t h e i r impact on d i s e a s e c o n t r o l have been r e v i e w e d by s e v e r a l a u t h o r s (10, 16, 27, 28, 29, 3 3 ) .


FUNGICIDE CHEMISTRY

92

Isoxazoles

Carbamates prothiocarb (Schering, SN 41703)

hymexazol (Sankyo, F-319, SF-6505)

r-T

C H ^N-(CH )3-NH-C-S-C H5 · HCI CH 3 s

2

2

3

CrOc/ propamocarb (Schering, SN 66752) ^N-(CH h-NH-C-0-C H 2


CH

3

/

7

· HCI

g

3

Ethyl phosphonates fosetyl (Rhône-Poulenc, LS 74-783)

Cyanoacetamide-oximes cymoxanil (Du Pont, DPX 3217) ^N-0-CH C H -NH-CO-NH-CO-C: 2

3

C2H5O,

5

->3

Figure

3.

Chemistry

o f new

f u n g i c i d e s a g a i n s t Oomycetes

(I).

Phenylamides Acylalanines metalaxyl (Ciba-Geigy, CGA 48988) ,CH C H 3

CH jf\

^CH-COOCH,

f-\ \ = \

^CO-CH -OCH 2

CH

furalaxyl (Ciba-Geigy, CGA 38140)

3

3

CH CH-C00CH 3

3

3

0 3

benalaxyl (Montedison, M 9834) y

CH

ÇH £H-C00CH

3

3

3

-Ν

\=/

^C0-CH CH

Figure

4.

Chemistry

2

3

o f new

f u n g i c i d e s a g a i n s t Oomycetes ( I I ) .


(S2.)



SCHWINN AND URECH

Acylamino-Butyrolactones ofurace (Chevron, RE 20615)

cyprofuram (Schering SN 78314)

Acylamino-Oxazolidinones oxadixyl (Sandoz, SAN 371 F)

CH .

3

/

I Ν

\ Ο

f > < Y \ = /

CO-CH-OCH, CH

3

F i g u r e 5. C h e m i s t r y o f new f u n g i c i d e s a g a i n s t Oomycetes ( I I I ) .


94

FUNGICIDE CHEMISTRY


( i n o r d e r οf t h e i r

introduction)

Common Name

Trade Name(s) Formulation(s)

Chemical Group

First Report

prothiocarb

PREVICUR S 70 ; SCW

carbamates

1

hymexazol

TACHIGAREN

isoxazoles

42, 43

cymoxanil

CURZATE ; WP

cyanoacetamideoximes

34

furalaxyl

FONGARID ; WP, G

acylalanines

30, 31

fosetyl A l

ALIETTE ; WP

e t h y l phosphonates

4 46

metalaxyl

RIDOMIL ; WP, G ACYLON ; WP APRON ; SD

acylalanines

44

propamocarb

PREVICUR Ν ; SCW

carbamates

25

milfuram

PATAFOL ; WP

butyrolactones

23

benalaxyl

GALBEN ; WP, G

acylalanines

3

cyprofuram

VINICUR ; WP

butyrolactones

2

oxadixyl

SANDOFAN

oxazolidinones

19

The spectrum o f a c t i v i t y o f these compounds i s shown i n T a b l e III. I t v a r i e s from hymexazol, w i t h an e x t r e m e l y narrow spectrum c o v e r i n g o n l y t h e genus P y t h i u m , t o t h e phenylamides and r e l a t e d compounds c o v e r i n g a l l P e r o n o s p o r a l e s . The spectrum o f f o s e t y l comprises even pathogens o u t s i d e t h i s o r d e r , such as G u i g n a r d i a b i d w e l l i i ( b l a c k r o t o f g r a p e s ) , Phomopsis v i t i c o l a (dead-arm o f grapes) and P s e u d o p e z i z a t r a c h e i p h i l a ( r e d f i r e o f g r a p e s ) . The r e a s o n s f o r these s u r p r i s i n g d i f f e r e n c e s a r e unknown.


5.

Table I I I :

Pathogens (Genera) Downloaded by UNIV OF ARIZONA on January 7, 2013 | http://pubs.acs.org Publication Date: April 22, 1986 | doi: 10.1021/bk-1986-0304.ch005


SCHWINN AND URECH

95

Spectrum o f A c t i v i t y A g a i n s t P e r o n o s p o r a l e s

prothiocarb/ propamocarb

F u n g i c i d e and A c t i v i t y * hymex- cymox- f o s e t y l azol anil

metalaxyl and r e l a t e d compounds

Pythium

+

+

+

+

Phytophthora on r o o t s / s t e m s on f o l i a g e

+

-

-

+

+

-

+

Peronospora on r o o t s / s t e m s on f o l i a g e

+

-

-

+ +

Pseudoperonospora

+

+

+

+

Plasmopara

-

+

+

+

Bremia

+

+

+

+

-

Peronosclerospora/ Sclerospora/ Sclerophthora Albugo *

-

_

_

-

-

+

+

-

+

+ * highly active - * no u s e f u l a c t i v i t y

S i m i l i a r l y v a r i a b l e i s the s y s t e m i c a c t i v i t y o f t h e s e compounds, t h a t i s the t r a n s l o c a t i o n i n the v a s c u l a r system o f t h e p l a n t . I n t h i s r e s p e c t , c y m o x a n i l w i t h i t s v e r y l o c a l i z e d d i s t r i b u t i o n , and f o s e t y l w i t h i t s f a s t and s t r o n g t r a n s l o c a t i o n b o t h a c r o p e t a l l y and b a s i p e t a l l y , a r e the extremes (Table I V ) . From t h i s p o i n t o f v i e w , f o s e t y l i s the most remarkable s t r u c t u r e ; i t i s the o n l y commercial p e s t i c i d e showing e f f e c t i v e a c r o p e t a l and b a s i p e t a l t r a n s l o c a t i o n a t normal use r a t e s .


FUNGICIDE CHEMISTRY

96

Table IV:

S y s t e m i c i t y o f the New

Oomycetes

Fungicides

C h a r a c t e r i s t i c s of T r a n s l o c a t i o n local basipetal acropetal (penetration)

Chemical prothiocarb/ propamocarb hymexazol


cymoxanil fosetyl metalaxyl (and r e l a t e d compounds)

(+)

++ = strong, fast transport + - weak, s l o w t r a n s p o r t (+) = depending on crop s p e c i e s - no t r a n s p o r t i n e f f e c t i v e q u a n t i t i e s

The new compounds are used a t s u b s t a n t i a l l y lower r a t e s than the c o n v e n t i o n a l p r o t e c t a n t f u n g i c i d e s (Table V ) , thus r e d u c i n g the amount o f c h e m i c a l s brought i n t o the environment. I n a d d i t i o n , the a c y l a l a n i n e s can be used as seed d r e s s i n g s a t e x t r e m e l y low r a t e s .

T a b l e V:

Comparison

o f Rates

Type o f Disease

Rates of Standards

Rates of Systemics

Foliar

1.5 - 2.4 kg/ha (Dithiocarbamates)

a c : 0.25 cy: 0.1 f o : 1.5

Root and Crown

2 2 - 4«g/m (Terrazole) 5 g/m (Captafol)

2 s o i l fo: 4-8 g/ms o i l ac: 0.2-2 g/m f o l i a g e f o : 300 g / h l seed ac: 17 - 35 g/100

kg

Systemic

-

seed a c :

kg

kg/ha o r kg/ha o r kg/ha o r

25 g / h l 12 g / h l 150 g / h l

70 - 210 g/100

ac = a c y l a l a n i n e s cy = c y m o x a n i l fo = f o s e t y l


5.

SCHWINN AND URECH

97


D e s p i t e t h e f a c t t h a t t h e new compounds have been known and a v a i l a b l e f o r y e a r s , r e l a t i v e l y l i t t l e i s known about t h e i r mode o f action. T a b l e V I r e f l e c t s t h e s t a t e o f t h e a r t . The l a c k o f i n f o r m a t i o n i s p a r t i c u l a r l y s u r p r i s i n g i n t h e case o f f o s e t y l and m e t a l a x y l as f a r as t h e i r i n d i r e c t e f f e c t i s concerned, t h a t i s , t h e s t i m u l a t i o n o f t h e h o s t p l a n t ' s defense r e a c t i o n s ( e . g . f o r m a t i o n o f phytoalexins). I t i s f o r the f i r s t time i n t h e h i s t o r y o f f u n g i c i d e s t h a t such e f f e c t s have been r e p o r t e d .

Table V I : Mode o f A c t i o n o f Oomycetes

Fungicides


Mode o f A c t i o n Compound

Physiological

Biochemical

Level

prothiocarb/ propamocarb

I n t e r f e r e n c e w i t h membrane structure or function

Unknown

hymexazol

D e l a y e d growth i n h i b i t i o n

Metabolite i n h i b i t i n g RNA s y n t h e s i s ?

cymoxamil

Unknown

I n h i b i t i o n o f RNA s y n thesis

fosetyl

D i r e c t f u n g i t o x i c i t y ; sec ondary e f f e c t s v i a p l a n t defense

Unknown

metalaxyl

D i r e c t f u n g i t o x i c i t y on mycelium; secondary e f f e c t s v i a p l a n t defense

Single s i t e i n h i b i t i o n of RNA s y n t h e s i s

The i n d i r e c t mode o f a c t i o n has been p o s t u l a t e d as t h e p r i m a r y event i n t h e case o f f o s e t y l ( 5 , (3, j ^ , 20, 2 6 ) . However, r e c e n t l y Fenn and C o f f e y (17) showed t h a t f o s e t y l and p h o s p h o r i c a c i d (H^PO^), the d e g r a d a t i o n p r o d u c t o f f o s e t y l i n t h e p l a n t , e x h i b i t a s t r o n g f u n g i t o x i c e f f e c t i n v i t r o i f t e s t e d i n a medium w i t h low phosphate content. I n a d d i t i o n , H^PO^ S f u n g i c i d a l e f f e c t i n the p l a n t . A c c o r d i n g t o M. D. C o f f e y (1984, p e r s . comm.), f o s e t y l - r e s i s t a n t s t r a i n s s e l e c t e d under l a b o r a t o r y c o n d i t i o n s d i d n o t t r i g g e r the secondary e f f e c t s d e s c r i b e d above. T h i s would suggest t h a t , i n c o n t r a s t t o p r e v i o u s c l a i m s , the sequence o f events i n the h o s t p l a n t i s t h e f o l l o w i n g : 1) a p r i m a r y d i r e c t t o x i c e f f e c t on t h e pathogen, l e a d i n g t o a r e t a r d a t i o n o r even c e s s a t i o n o f f u n g a l growth ( f u n g i s t a s i s ) ; 2) under such c o n d i t i o n s , n a t u r a l defense r e a c t i o n s o f t h e host p l a n t , normally t o o weak i n s u s c e p t i b l e c u l t i v a r s , become e f f e c t i v e and k i l l the pathogen; 3) t h u s , the death o f the pathogen i s due t o combined a c t i o n o f t h e f u n g i c i d e and t h e h o s t p l a n t . When m e t a l a x y l was u s e d , n e c r o t i c r e a c t i o n s i n s u s c e p t i b l e crop c u l t i v a r s s i m i l a r t o those o f r e s i s t a n t ones, as w e l l as p h y t o a l e x i n a c c u m u l a t i o n , have been r e p o r t e d (12, 1^» 2Λ, 37, 41, 4 5 ) . Here t h e use o f m e t a l a x y l - r e s i s t a n t s t r a i n s c o u l d a l s o c l a r i f y t h e s i g n i f i h

a

s

a

s t r o n


FUNGICIDE CHEMISTRY

98

cance o f these f i n d i n g s , i n p a r t i c u l a r c o n c e r n i n g the a c c u m u l a t i o n of phytoalexins. Spectrum of a c t i v i t y , c r o p t o l e r a n c e and s y s t e m i c i t y a r e the parameters d e f i n i n g the c r o p spectrum, the a p p l i c a t i o n method and the d i s e a s e s c o n t r o l l e d by the d i f f e r e n t t y p e s o f compounds, as shown i n Table V I I .


Table V I I :

Compound prothiocarb propamocarb

Main Uses o f the New

Main Usage Against

Main T a r g e t Crops "1 o r n a m e n t a l s , J vegetables ornamentals

hymexazol

r i c e , sugar beets-

m e t a l a x y l and related compounds

dust

f o l i a r diseases

cymoxamil viticulture, agricultural - crops, vegetables, (ornamentals)

Application Methods

d i s e a s e s on ~Vdrench, dip " r o o t s and stems J

furalaxyl

fosetyl

Oomycetes F u n g i c i d e s

f o l i a r , r o o t and ~stem diseases -

spray spray, drench, dip, injection spray, drench, dip, granule, seed d r e s s i n g

From a p r a c t i c a l and commercial p o i n t of v i e w , the compounds shown i n the lower p a r t o f T a b l e V I I a r e o f much g r e a t e r importance than t h o s e i n the upper p a r t . Whereas, p r o t h i o c a r b , propamocarb, hymexazol, f u r a l a x y l have t o be r e g a r d e d as s p e c i a l t y p r o d u c t s f o r s p e c i a l t y c r o p s , those l i s t e d i n the lower p a r t o f the t a b l e have made broad a p p l i c a t i o n s i n a g r i c u l t u r e : c y m o x a n i l due t o i t s c u r a t i v e a c t i o n w h i c h makes i t a v a l u a b l e m i x i n g p a r t n e r f o r p r o t e c t a n t s , f o s e t y l due t o i t s upward and downward s y s t e m i c i t y , and m e t a l a x y l and the o t h e r phenylamides due t o t h e i r h i g h l e v e l o f p r o t e c t i v e and c u r a t i v e a c t i v i t y , combined w i t h a f a s t upward t r a n s l o c a t i o n i n the plant. The o v e r a l l p r o g r e s s i n d i s e a s e c o n t r o l a c h i e v e d by them i s shown on Table V I I I ,


5.

Table V I I I :



SCHWINN AND URECH

P r o g r e s s A c h i e v e d by the New Oomycetes

99

Fungicides

Type o f Disease

Comparative Performance Standards Systemics

Foliar

Good, i f used p r o t e c t i v e l y and i n t e n s i v e l y

o u t s t a n d i n g (ac) t o good ( c y , f o ) : f a s t u p t a k e / distribution, curative action

Root and Crown

Unsatisfactory

Excellent after s o i l a p p l i c a t i o n (ac, fo) o r f o l i a r use ( f o )

Systemic

Ineffective

Breakthrough ( a c ) ; high inherent a c t i v i t y , f a s t uptake by s e e d l i n g s

ac = a c y l a l a n i n e s cy = c y m o x a n i l fo = f o s e t y l

C o n c e r n i n g t h e h i s t o r y and b i o l o g i c a l c h a r a c t e r i s t i c s o f t h e t h r e e p r o d u c t groups, my l e v e l o f i n f o r m a t i o n i s not u n i f o r m . This, and the f a c t t h a t the a c y l a l a n i n e s are t h e l a r g e s t group, e x p l a i n s why more emphasis w i l l be put on them i n the r e m a i n i n g p a r t o f t h i s paper. W h i l e t h e r e i s l i t t l e i n f o r m a t i o n about the h i s t o r y o f t h e d i s c o v e r y o f c y m o x a n i l , t h e r e i s e v i d e n c e (4) t h a t t h e f u n g i c i d a l v a l u e o f the e t h y l phosphonates was d i s c o v e r e d by i n c i d e n t a l o b s e r v a tion i n a field t r i a l . Thus, t h e i n i t i a l s t e p was a b i o l o g i c a l observation. The h i s t o r y o f the a c y l a l a n i n e s began i n h e r b i c i d e r e s e a r c h o f Ciba-Geigy, L t d . , B a s e l , Switzerland. I n the e a r l y seventies, a s y n t h e s i s program was e s t a b l i s h e d a i m i n g a t new h e r b i c i d e s w i t h a b r o a d e r spectrum o f b i o l o g i c a l a c t i v i t y i n t h e c l a s s o f a n i l i d e s . The replacement o f the a l k o x y a l k y l m o i e t y o f the rape seed h e r b i c i d e d i m e t h a c h l o r ( T e r i d o x ) by the e t h y l p r o p i o n a t e s u b s t i t u e n t , as found i n the w i l d oats h e r b i c i d e benzoylprop-ethyl (Suffix), l e dto a compound (CGA 22*574). T h i s compound showed good h e r b i c i d a l a c t i v i t y and, s u r p r i s i n g l y , some s y s t e m i c and c u r a t i v e f u n g i c i d a l e f f e c t against l a t e b l i g h t (Figure 6). T h i s n o v e l , y e t weak, f u n g i c i d a l performance o f CGA 22 574 c o u l d have been e a s i l y o v e r l o o k e d i f t h e c o r r e s p o n d i n g m e t h y l e s t e r (CGA 29 212) had not been p r e p a r e d i n the c o u r s e o f the h e r b i c i d e s y n t h e s i s program. T h i s m o l e c u l e e x h i b i t e d much s t r o n g e r f u n g i c i d a l a c t i o n . I t outperformed a l l s t a n d a r d s i n our f u n g i c i d e s c r e e n i n g a g a i n s t the P e r o n o s p o r a l e s , b o t h i n r e s p e c t to r e s i d u a l and s y s t e m i c b e h a v i o r , as w e l l as t o p r o t e c t i v e and curative a c t i v i t y . However, i t s p h y t o t o x i c i t y was t h e l i m i t i n g factor. I n f u r t h e r s y n t h e s i s programs, the h e r b i c i d a l e f f e c t c o u l d be e l i m i n a t e d by r e p l a c i n g the c h l o r o a c e t y l group by two o t h e r a c y l f r a g m e n t s , namely the 2 - f u r o y l group, thus l e a d i n g t o f u r a l a x y l i n 1973, and the m e t h o x y a c e t y l group, l e a d i n g to m e t a l a x y l i n 1974. 1

1


FUNGICIDE CHEMISTRY

100

a

,CH

H

= \

/

CH -CH -OCH 2

2

\

^H-COOCjHs

° V // ^Γ.Π- ^ ^

CO-CH -CI 2

CH

=

/

3

^ // Vn.ru _r>, X

Biol, activity herb. fung.

Ç3

3

+++

3

CGA17020 (benzoylprop-ethyl)


(dimethachlor) CH

CH

3

3

CH-COOC H, 2

+ + N

(+)

CO-CH -CI 2

CH

3

574 CGA 22574 CH / V

=

\ γ

/

X

~ CH

I

CH

3

3

CH-COOCH

3

+

CO-CH -CI 2

3

CGA 29212 (lead structure, 1972) ,CH

3

CH

CH

3

CH-COOCH

3

/ y

CH

=

CH

X

y

CO-CH -OCH 2

+++

3

3

CGA 38140

CGA 48988

(furalaxyl, 1973)

(metalaxyl, 1974)

F i g u r e 6.

-

3

CH-COOCH3

CH

3

3

(

History of acylalanines.



5.

SCHWINN AND URECH


101

None o f t h e many hundred analogues s y n t h e s i z e d s i n c e then by C i b a - G e i g y has l e d t o a more p o w e r f u l f u n g i c i d e w i t h as good a c r o p t o l e r a n c e as m e t a l a x y l (22). S i n c e i t s i n t r o d u c t i o n i n t o the market i n 1979, f o u r c h e m i c a l l y r e l a t e d compounds have been l a u n c h e d by o t h e r companies, as shown i n F i g u r e s 4 and 5. Regarding t h e i r i n h e r e n t f u n g i c i d a l p o t e n c y , i t can be s t a t e d t h a t none o f them i s more a c t i v e than m e t a l a x y l . Therefore i n the f o l l o w i n g d i s c u s s i o n , m e t a l a x y l w i l l be used as t h e b e s t r e p r e s e n t a t i v e o f t h e a c y l a l a nines. M e t a l a x y l and most o f i t s a c t i v e analogues are c h i r a l m o l e c u l e s . C h i r a l i t y i s caused by t h e asymmetric c a r b o n atom i n t h e a l k y l s i d e chain of the alanine moiety. The two o p t i c a l l y pure enantiomers S (+) and R (-) d i f f e r w i d e l y i n t h e i r b i o l o g i c a l a c t i v i t y b o t h i n v i t r o and i n v i v o . I n a l l e x p e r i m e n t s , the R (-) enantiomer was more a c t i v e than i t s a n t i p o d e S (+) (22, 24, 30). The main c h a r a c t e r i s t i c s o f m e t a l a x y l have been d i s c u s s e d i n d e t a i l by s e v e r a l a u t h o r s (Z» !Z» !§> 12» 11» 1*9· p a r t i c u l a r v a l u e i s the r a p i d uptake o f m e t a l a x y l by t h e p l a n t t i s s u e , e s p e c i a l l y under t h e wet c o n d i t i o n s t h a t f a v o r f o l i a r Oomycete d i s e a s e s . Acylalanines areeasily trans l o c a t e d i n t h e v a s c u l a r system o f t h e p l a n t a f t e r f o l i a r , stem o r r o o t t r e a t m e n t (35, 47). The predominant r o u t e o f t r a n s p o r t i s t h e t r a n s p i r a t i o n s t r e a m , thus a p o p l a s t i c Q 2 , 35). S y m p l a s t i c t r a n s p o r t o c c u r s b u t i s much l e s s e v i d e n t (35, 47). I n p o t a t o e s t r e a t e d by f o l i a r s p r a y s o f m e t a l a x y l c o n c e n t r a t i o n s ( 0 . 0 2 - 0 . 0 4 ppm), B r u i n e t a l . (9) were a b l e t o demonstrate p r o t e c t i o n o f h a r v e s t e d t u b e r s from late blight. M e t a l a x y l and r e l a t e d m o l e c u l e s are the o n l y f u n g i c i d e s w h i c h so f a r c o n t r o l s y s t e m i c d i s e a s e s , such as downy mildew o f hops (Pseudop e r o n o s p o r a h u m u l i ) , b l a c k shank o f tobacco ( P h y t o p h t h o r a n i c o t i a n a e v a r . n i c o t i a n a e ) , downy mildew o f s u n f l o w e r (Plasmopara h a l s t e d i i ) , and downy mildew o f t r o p i c a l m a i z e , sorghum and m i l l e t ( P e r o n o s c l e r o spora s o r g h i , Sclerospora g r a m i n i c o l a ) . The a c y l a l a n i n e s have a h i g h inherent fungitoxicity. I n v i t r o ^^Q values f o r metalaxyl of t y p i c a l t a r g e t f u n g i a r e i n t h e o r d e r o f 0.01 t o 1 ppm (7^, 32). Based on c i r c u m s t a n t i a l e v i d e n c e , i t c a n be assumed t h a t t h e dose r a t e s a c t i v e on the c e l l u l a r l e v e l i n v i v o are i n a s i m i l a r range. The b i o l o g i c a l s i t e o f a c t i o n o f t h e a c y l a l a n i n e s has been d e s c r i b e d by Staub e t a l . (37). I n c o n t r a s t t o the c l a s s i c a l p r o t e c t i v e f u n g i c i d e s w h i c h k i l l t h e g e r m i n a t i n g s p o r e s on t h e h o s t s u r face, metalaxyl e x h i b i t s i t s f u n g i t o x i c e f f e c t only i n s i d e the host tissue. N e i t h e r zoospore o r c o n i d i a l g e r m i n a t i o n , n o r t h e p e n e t r a t i o n hypha o r the f o r m a t i o n o f the i n i t i a l h a u s t o r i a i s a f f e c t e d . I n c o n t r a s t , t h e f u r t h e r development o f t h e pathogen i s s t r o n g l y and quickly inhibited. R e g a r d i n g t h e development c y c l e o f t h e pathogen, m e t a l a x y l i n t e r f e r e s w i t h i t over a much l o n g e r p e r i o d o f time than protective fungicides. The b i o c h e m i c a l mode o f a c t i o n has been s t u d i e d by s e v e r a l a u t h o r s ( L 6 , 18). I t appears t h a t m e t a l a x y l i n h i b i t s RNA s y n t h e s i s by i n t e r f e r e n c e w i t h template-bound and α - a m a n i t i n - i n s e n s i t i v e RNA polymerase a c t i o n (15). From t h e b e g i n n i n g o f market i n t r o d u c t i o n , t h e e x c e l l e n t p e r formance o f m e t a l a x y l under v a r i a b l e c l i m a t i c c o n d i t i o n s and on a b r o a d spectrum o f c r o p s made i t v e r y a t t r a c t i v e t o t h e f a r m e r . I t o

f

e



102

FUNGICIDE CHEMISTRY

looked l i k e a p e r f e c t s o l u t i o n f o r c e n t u r y - o l d problems had been found. However, s i n c e we l i v e i n an i m p e r f e c t w o r l d , t h e r e i s no such t h i n g as a p e r f e c t s o l u t i o n . I n t h e case o f t h e a c y l a l a n i n e s , r e s i s t a n c e t u r n e d out t o be t h e element o f i m p e r f e c t i o n . I t has developed i n some a r e a s , a l l o u t s i d e t h e USA, i n t h e f o l l o w i n g pathogens: Pseudoperonospora cubensis, Phytophthora infestans, Plasmopara v i t i c o l a and Peronospora t a b a c i n a . I n v i e w o f t h e s p e c i f i c i t y and h i g h e f f e c t i v e n e s s o f t h e a c y l a l a n i n e s , i n v e s t i g a t i o n s t o check t h e r i s k o f r e s i s t a n c e were i n i t i a t e d a t e a r l y s t a g e s o f i t s development. I n model s t u d i e s w i t h Plasmopara v i t i c o l a and m i l f u r a m , Lukens e t a l . (23) observed no change i n s e n s i t i v i t y o v e r n i n e s u c c e s s i v e g e n e r a t i o n s . In training and spore mass s e l e c t i o n experiments u s i n g P h y t o p h t h o r a i n f e s t a n s and metalaxyl, spontaneous mutants showing i n v i t r o r e s i s t a n c e were found. However, they had l o s t t h e i r p a t h o g e n i c i t y . A large selec t i o n t r i a l t h r o u g h 14 d i s e a s e c y c l e s on p o t a t o p l a n t s i n a greenhouse y i e l d e d no changes i n s e n s i t i v i t y o f t h e i n i t i a l p o p u l a t i o n ( 3 6 ) . T h e r e f o r e , i t was concluded t h a t t h e r e was no i n d i c a t i o n o f a major r i s k o f r e s i s t a n c e . A d d i t i o n a l s t u d i e s on tobacco b l u e mold and on downy mildew o f l e t t u c e (Bremia l a c t u c a e ) c o n f i r m e d t h i s c o n c l u s i o n . I n s t u d i e s by B r u i n (7) » B r u i n and E d g i n g t o n (8) and Davidse (14) u s i n g c h e m i c a l mutagens, s t r a i n s o f P h y t o p h t h o r a c a p s i c i and P. megasperma f . s p . m e d i c a g i n i s were found w i t h b o t h i n v i t r o and i n v i v o a c t i v i t y and unchanged p a t h o g e n i c i t y . Also, cross resistance to o t h e r a c y l a l a n i n e s and r e l a t e d m o l e c u l e s , such as m i l f u r a m , was demonstrated ( 8 ) . At about t h e same t i m e , t h e f i r s t i n f o r m a t i o n was r e c e i v e d about p r o d u c t f a i l u r e a f t e r c o n t i n u o u s and e x c l u s i v e u s e . The i n v e s t i g a t i o n o f t h e pathogen p o p u l a t i o n s o f such f i e l d s y i e l d e d h i g h l y r e s i s t a n t s t r a i n s (28, 29, 4 0 ) , whereas so f a r no f i e l d r e s i s t a n c e has been r e p o r t e d f o r c y m o x a n i l o r f o s e t y l . Thus, i n c o n t r a s t t o t h e f a v o r a b l e r e s u l t s o f a broad range o f model s t u d i e s , r e s i s t a n c e had appeared v e r y f a s t under f i e l d c o n d i t i o n s . The l e s s o n t o be l e a r n e d from t h i s e x p e r i e n c e i s t h a t r e s u l t s o f model s t u d i e s have t o be used with caution. Model s t u d i e s must i n c l u d e the use o f c h e m i c a l muta gens and h i g h l y a c t i v e , s y s t e m i c f u n g i c i d e s s h o u l d be used as i f a r i s k o f r e s i s t a n c e e x i s t s u n t i l t h e i r mode o f a c t i o n i s known. A f t e r appearance o f r e s i s t a n c e i n p r a c t i c e , m e t a l a x y l as a s i n g l e p r o d u c t f o r use a g a i n s t f o l i a r d i s e a s e s was withdrawn from t h e market. S t r a t e g i e s t o reduce t h e r i s k o f r e s i s t a n c e were developed and i n t r o d u c e d , based on prepack m i x t u r e s w i t h f u n g i c i d e p a r t n e r s w i t h a d i f f e r e n t mode o f a c t i o n . I n d u s t r y , under t h e a u s p i c e s o f GIFAP, formed a F u n g i c i d e R e s i s t a n c e A c t i o n Committee (FRAC), i n order t o coordinate t h e i m p l e m e n t a t i o n o f use s t r a t e g i e s . This committee c o n s i s t s o f w o r k i n g teams comprised o f those companies h a v i n g p r o d u c t s o f a p a r t i c u l a r c h e m i c a l c l a s s , such as a c y l a l a n i n e s , benzimidazoles, dicarboximides or e r g o s t e r o l biosynthesis i n h i b i t o r s . With reference t o t h e a c y l a l a n i n e s , i t can be s t a t e d t h a t whenever they were i n t r o d u c e d i n m i x t u r e s , a c c o r d i n g t o t h e recom mended use c o n c e p t , no cases o f r e s i s t a n c e l e a d i n g t o economic l o s s e s occurred. T h i s use concept recommends a l i m i t e d number o f a p p l i c a t i o n s a t t h e time o f s e r i o u s damage p o t e n t i a l combined w i t h f i e l d m o n i t o r i n g programs ( 3 9 ) . I n t h e i n t e r e s t o f t h e u s e r , the manufac-



5. SCHWINN AND URECH

103 Control of Diseases Caused by Oomycetes

turer and the adviser, it is to be hoped that in the future all fungicides of this class will be used strictly on the basis of recommendations, which should help safeguard their availability. Concerning the other major new Oomycetes fungicides, cymoxanil and fosetyl, it can be stated that no resistance has yet been reported to date. The practical uses of the new Oomycetes fungicides and the progress achieved by these products have been discussed previously (Table VII). It is worth mentioning that apart from propamocarb and prothiocarb, all compounds are used in combination with another fungicide: hymexazol in combination with metalaxyl, cymoxanil, or fosetyl, and the acylalanines in combination with protectants. In analyzing the reasons for these use concepts, the following can be said: 1) hymexazol with its extremely narrow spectrum needs a mixing partner to make it a useful broad spectrum rice fungicide; 2) cymox anil with its purely curative action and its short persistence in the plant requires a protectant partner to make it a useful protectant product against the target pathogens; 3) fosetyl with its variability in performance against foliar diseases requires a partner to stabi lize its effectiveness on a high level; 4) acylalanines need a partner to reduce the risk of resistance and to broaden the spectrum on crops like potatoes and grapes. In conclusion, all the new systemic fungicides against Oomycetes had an immediate need for mixing partners. It can be assumed that this will also hold true for future systemic fungicides. This use concept calls for flexibility both on the part of industry, national registration authorities, and the extension services to make safe and powerful products available for plant protection. Literature Cited 1.

Bastiaansen, M.G., Pieroh, E.A., and Aelbers, E. 1974. Prothio carb, a new fungicide to control Phytophthora fragariae in strawberries and Pythium ultimum in flower bulbs. Meded. Fac. Landbouwwet. Rijksuniv. Gent 39, 1019-1025. 2. Baumert, D. and Buschhaus, H. 1982. Cyprofuram, a new fungicide for the control of Phycomycetes. Meded. Fac. Landbouwwet. Rijksuniv. Gent 47, 979-83. 3. Bergamaschi, P., Borsari, T., Garavaglia, C. and Mirenna, L. 1981. Methyl N-phenyl-acetyl-N-2,6-xylyldl-alaúnate (M9834), a new systemic fungicide controlling downy mildew and other diseases caused by Peronosporales. Br. Crop Prot. Conf. 11th. 1, 11-18. 4. Bertrand, Α., Ducret, J., Debourge, J.-C., and Horriere, D. 1977. Etude des proprietes d'une nouvelle famille de fongicides. Les monoethylphosphites metalliques. Characteristiques physico chimiques et proprietes biologiques. Phytiatr. Phytopharm. 26, 3-18. 5. Bompeix, G., Ravise, Α., Raynal, G., Fettouche, F., and Durand, M. 1980. Modalites de l'obtention de necroses bloquantes sur feuilles detachees de tomate par l'action du tris-O-ethylphosphonate d'aluminium (phoseethyl d'aluminium), hypothese sur son mode d'action in vivo. Ann. Phytopathol. 12, 337-351.


104 6. 7. 8. 9.


10.

11.

12. 13. 14. 15.

16. 17. 18. 19.

20.

21. 22.

FUNGICIDE CHEMISTRY Bompeix, G., Fettouche, F., and Saurdressan, P. 1981. Mode d'action du phosethyl Al. Phytiatr. Phytopharm. 30, 257-272. Bruin, G.C.A. 1980. Resistance in Peronosporales to acylalaninetype fungicides. Ph.D. thesis Univ. Guelph, Ontario, Canada, 110 pp. Bruin, G.C.A., and Edgington, L.V. 1980. Induced resistance to Ridomil of some oomycetes. (Abstr.) Phytopathology 70, 459-460. Bruin, G.C.A., Edgington, L.V., and Ripley, B.D. 1982. Bioactivity of the fungicide metalaxyl in potato tubers after foliar sprays. Canad. J . Pl. Path. 4. 353-356. Bruin, G.C.A., and Edgington, L.V. 1983. The chemical control of diseases caused by zoosporic fungi. In: Zoosporic plant pathogens. A modern perspective, (ed. S.T. Buczacki). Academic Press, London, 193-233. Clairjeau, M., and Beyries, A. 1977. Etude comparee de l'action preventive et du pouvoir systemique de quelques fongicides nouveaux (phosphites-prothiocarb-pyroxychlore) sur poivron vis-a-vis de Phytophthora capsici (Leon). Phytiatr. Phytopharm. 26, 73-83. Cohen, Y., Reuven, M., and Eyal, H. 1979. The systemic anti fungal activity of Ridomil against Phytophthora infestans on tomato plants. Phytopathology 69, 645-649. Crute, I.R. 1979. Lettuce mildew - Destroyer of quality. Agric. Res. Counc. (U.K.) Res. Rev. 5, 9-12. Davidse, L. C. 1981. Resistance to acylalanine fungicides in Phytophthora megasperma f. sp. medicaginis. Neth. J. Pl. Path. 87, 11-24. Davidse, L . C . , Hofman, A.E., Velthuis, G.C.M. 1983. Specific interference of metalaxyl with endogenous RNA polymerase activ ity in isolated nuclei of Phytophthora megasperma f.sp.medica ginis. Exp. Mycol. 7, 344-361. Davidse, L.C., and de Waard, M.A. 1984. Systemic fungicides. In: Advances in Plant Pathology (ed: D.S. Ingram and P.H. Williams), 2, 191-257. Fenn, M.E., and Coffey, M.D. 1984. Studies on the in vitro and in vivo antifungal activity of fosetyl-Al and phosphorous acid. Phytopathology 74, 606-611. Fisher, D.J., and Hayes, A.L. 1984. Studies of mechanism of metalaxyl fungitoxicity and resistance to metalaxyl. Crop. Prot. 3, 177-185. Gisi, U., Harr, J., Sandmeier, R., Wiedmer, H. 1983. A new systemic oxazolidinone fungicide (SAN 371) against diseases caused by Peronosporales. Meded. Fac. Landbouwwet. Rijksuniv. Gent 48, 541-549. Hai, V.T., Bompeix, G., and Ravise, A. 1979. Role due tris-Oethyl-phosphonate d'aluminium dans la stimulation des reactions de defense des tissus de tomate contre la Phytophthora capsici. C.R. Hebd. Seances Acd. Sci., Ser. D. 228, 1171-1174. Hickey, E.L., and Coffey, M.D. 1980. The effects of Ridomil on Peronospora pisi parasitizing Pisum sativum: An ultrastructural investigation. Physiol. Plant Pathol. 17, 199-204. Hubele, Α., Kunz, W., Eckhardt, W., and Sturm, H. 1983. The fungicidal activity of acylanilines. In: IUPAC pesticide


5. SCHWINN AND URECH

23. 24. 25.


26.

27. 28. 29.

30. 31.

32.

33. 34.

35.

36. 37.


105

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