Pesticide Synthesis Through Rational Approaches - American

5 Synthesis-Directing Structure-Activity Relationships of Some Fungicides Inhibiting Ergosterol Biosynthesis I. F. BROWN, JR., H. M. TAYLOR, and R. E. HACKLER

Downloaded by CORNELL UNIV on September 24, 2016 | http://pubs.acs.org Publication Date: June 26, 1984 | doi: 10.1021/bk-1984-0255.ch005

Lilly Research Laboratories, Eli Lilly and Company, Greenfield, IN 46140

Substances of considerably diverse chemical structure all i n h i b i t i n g ergosterol biosynthesis i n numerous fungi have achieved considerable success as fungicides i n many important a g r i c u l t u r a l crops. These chemicals can be characterized generally as broad spectrum l o c a l l y systemic fungicides. Information regarding synthesis directing structure a c t i v i t y relationships of 1 , 2 , 4 - t r i a z o l y l - 1 aroyloxbutanes [2-aryl-2-(1,2,4-triazolylmethyl)1,3dioxolane], α,α-diaryl-5-pyrimidinemethanols w i l l be presented. The d i s c o v e r y o f t h e a n t i f u n g a l a c t i v i t y o f ( Y - ( 2 , 4 dichlorophenyl)-a-phenyl-5-pyrimidine methanol (EL-273, t r i a r i m o l ) ( F i g . 1) as r e p o r t e d b y B r o w n , T a y l o r and H a l l (1) and the i n i t i a l d e t e r m i n a t i o n by R a g s d a l e and S i s l e r (2) o f i t s i n h i b i t i o n o f b i o s y n t h e s i s o f t h e f u n g a l s t e r o l e r g o s t e r o l was the forerunner to the i n t r o d u c t i o n of a succession of s e v e r a l s t e r o l i n h i b i t i n g (SI) fungicides of quite diverse chemical structure. S e v e r a l o f these s t e r o l i n h i b i t i n g f u n g i c i d e s have b e e n m a r k e t e d c o m m e r c i a l l y w i t h i n t h e l a s t few y e a r s f o r t h e c o n t r o l o f a wide range o f fungus i n c i t e d p l a n t diseases. A l t h o u g h many o f t h e f u n g i t o x i c a n t s d e s c r i b e d as S I c o m p o u n d s i n h i b i t t h e same m e t a b o l i c r e a c t i o n i n e r g o s t e r o l b i o s y n t h e s i s , t h e b i o l o g i c a l a c t i v i t y o f t h e s e compounds d i f f e r i n many r e s p e c t s . T h i s d i f f e r e n c e suggests t h a t apart from the aspects i n f l u e n c i n g the b a s i c i n h i b i t o r y a c t i o n against the fungus, the molecular s t r u c t u r e i n f l u e n c e s other parameters associated w i t h or responsible f o r the a c t i v i t y spectrum o f the compound. F o r i n s t a n c e , c e r t a i n members o f t h e S I f u n g i c i d e group demonstrate strong a p o p l a s t i c s y s t e m i c i t y w i t h i n p l a n t t i s s u e w h e r e a s o t h e r s do n o t . Some c o m p o u n d s a r e m o r e a c t i v e a g a i n s t c e r t a i n pathogens and l e s s a c t i v e a g a i n s t o t h e r s . The s t r u c t u r e o f t h e m o l e c u l e as i t i n f l u e n c e s t h e numerous

0097-6156/ 84/ 0255-0065S06.00/ 0 © 1984 American Chemical Society

Magee et al.; Pesticide Synthesis Through Rational Approaches ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

66

PESTICIDE SYNTHESIS THROUGH RATIONAL APPROACHES

p a r a m e t e r s a s s o c i a t e d w i t h p e n e t r a t i o n and d i s t r i b u t i o n w i t h i n the h o s t and pathogen i s critical. A l t h o u g h termed " S I " o r " E B I " compounds, the latter r e f e r r i n g t o e r g o s t e r o l b i o s y t h e s i s i n h i b i t o r s , t h e s e compounds do n o t a l l i n h i b i t e r g o s t e r o l b i o s y n t h e s i s a t t h e same m e t a b o l i c site (Fig. 2). F o r i n s t a n c e , the f u n g i c i d e tridemorph, u n l i k e most E B I compounds, does not i n h i b i t d e m e t h y l a t i o n at C-14 but r a t h e r i t apparently prevents the Δ Δ isomerization r e s u l t i n g i n the accumulation of Δ containing sterols i n treated cells (3). I n t h i s r e p o r t we w i l l l i m i t o u r d i s c u s s i o n o f c h e m i c a l s t r u c t u r e and b i o l o g i c a l a c t i v i t y to s u b s t i t u t e d p y r i d i n e and p y r i m i d i n e m e t h a n o l s w h i c h have b e e n shown o r a r e b e l i e v e d t o i n h i b i t d e m e t h y l a t i o n at carbon 14, an a c t i o n which leads to i n h i b i t i o n of demethylation, also at carbon 4. Fungal c e l l s t r e a t e d w i t h an E B I f u n g i c i d e are g e n e r a l l y c h a r a c t e r i z e d b y s h o r t g e r m t u b e s d e m o n s t r a t i n g some a b n o r m a l m o r p h o l o g i c a l f o r m s u c h as b u l b o u s s w e l l i n g s o f t e n r e s u l t i n g i n cytoplasmic leakage (4). I n F i g u r e 3 i s shown a c o n i d i u m o f the f u n g u s H e l m i n t h o s p o r i u m s a t i v u m t r e a t e d w i t h 1 0 ppm o f fenarimol. T y p i c a l o f E B I compounds, the spore g e r m i n a t i o n and i n i t i a l development o f t h e germ t u b e s i s n o t v i s i b l y i n f l u e n c e d . However, g r o w t h and development o f t h e germ t u b e i s u l t i m a t e l y a r r e s t e d by the a p p a r e n t d i s i n t e g r a t i o n and f u n c t i o n a l i t y o f c y t o p l a s m i c membrane. E r g o s t e r o l i s an i n t e g r a l structural component o f t h e membranes o f f u n g a l c e l l s . Diminution of e r g o s t e r o l a v a i l a b i l i t y i s b e l i e v e d t o be t h e p r i m a r y mechanism by w h i c h E B I f u n g i c i d e s i n h i b i t f u n g a l g r o w t h . 8

7


8

The s c h e m a t i c p r e s e n t a t i o n o f e r g o s t e r o l b i o s y n t h e s i s and EBI s i t e s o f i n h i b i t i o n i s a v a i l a b l e i n references (Siegel [5]; K a t o [6]) and o n l y t h a t segment d i r e c t l y r e l a t e d t o the i n t e r e s t s o f t h i s r e p o r t w i l l be p r e s e n t e d h e r e ( F i g u r e 4 ) . An e a r l y p r e c u r s o r i n the s y n t h e s i s o f e r g o s t e r o l is mevalonic a c i d which i s condensed by s e v e r a l steps to squalene. The c y c l i z a t i o n o f s q u a l e n e l e a d s t o the f o r m a t i o n o f l a n o s t e r o l and 2 4 - m e t h y l e n e d i h y d r o l a n o s t e r o l . T h i s l a t t e r compound accumulates i n EBI t r e a t e d c e l l s because of the i n a b i l i t y of t h e s e c e l l s t o remove t h e C-14 m e t h y l g r o u p . Demethylation would y i e l d 4 , 4 - d i m e t h y l f e c o s t e r o l , the next s t e r o l i n the b i o s y n t h e t i c pathway l e a d i n g to e r g o s t e r o l . R a g s d a l e (7) showed t h e e r g o s t e r o l b i o s y n t h e s i s i n U s t i l a g o m a y d i s was g r e a t l y i n h i b i t e d w i t h i n 30 m i n u t e s a f t e r t r e a t m e n t w i t h t r i a r i m o l . The e r g o s t e r o l c o n t e n t o f t o t a l d e c l i n e d from a n o r m a l 70-80% o f t o t a l t o l e s s t h a n 4% w i t h i n 6 - 9 h o u r s f o l l o w i n g t r e a t m e n t . The s p e c i f i c a c t i o n o f t h e E B I f u n g i c i d e s i n p r e v e n t i n g d e m e t h y l a t i o n a t C-14 a p p e a r s t o be d i r e c t e d a t a cytochrome P - 4 5 0 enzyme i n v o l v e d i n t h e d e m e t h y l a t i o n p r o c e s s ( 8 ) . Gadher e t a l . (9) p r o v i d e i n f o r m a t i o n t h a t i n d i c a t e s the i n t e r a c t i o n o f


Fungicides Inhibiting Ergosterol Biosynthesis


BROWN ET AL.


67


68


F i g u r e 3. Conidium of Helminthosporium sativum Treated With 10 ppm of Fenarimol.


5. BROWN ET AL.


69


iH Ο

u ω 4-1 CO

ο

00

u

W Ό

CO

•H CO CU u

C

CO

ο

•Η

PQ

ο υ •Η

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§ Ο

en M-l Q)

•H PQ

ω u W>

•H p4



70


an EBI compound and cytochrome P-450 involves an a s s o c i a t i o n of a h e t e r o c y c l i c n i t r o g e n atom with the protoheme i r o n of cytochrome P-450. The demethylation at C-14 of the s t e r o l nucleus involves three r e a c t i o n steps. These are shown i n F i g u r e 5. The data of Gadher et a l . i n d i c a t e that the C-14 demethylation i n h i b i t i n g compounds attack the f i r s t step of the r e a c t i o n . This r e a c t i o n step u t i l i z e s cytochrome P-450 (10). The i n h i b i t i o n of C-14 demethylation i s thought to be due to the b i n d i n g of a h e t e r o c y c l i c n i t r o g e n atom (probably N-4) i n t r i a z o l e c o n t a i n i n g EBI f u n g i c i d e s to the protoheme i r o n atom which i n t u r n r e s u l t s i n the e x c l u s i o n of oxygen t h a t would normally take p a r t i n the r e a c t i o n . The authors f u r t h e r suggest that the n o n - h e t e r o c y c l i c p o r t i o n of the f u n g i t o x i c a n t binds to the l i p o p h i l i c s i t e s of cytochrome P-450. The s t r u c t u r e of s e v e r a l EBI f u n g i c i d e s are presented i n F i g . 6 . The recent reviews by Jager (11) and Kramer et a l (12) describe the s y n t h e t i c routes and b i o l o g i c a l a c t i v i t y of s e l e c t e d t r i t y l i m i d a z o l e s , t r i t y l t r i a z o l e s and other v a r i o u s l y s u b s t i t u t e d N-azole f u n g i c i d e s . The information that follows w i l l describe c e r t a i n s t r u c t u r a l a c t i v i t y r e l a t i o n s h i p s of s e l e c t e d EBI f u n g i c i d e s c o n t a i n i n g p y r i d i n e and pyrimidine h e t e r o c y c l i c moieties. The greenhouse methods used to evaluate our compounds are s i m i l a r to those used by most companies. Generally candidate f u n g i c i d e s are (1) a p p l i e d to the f o l i a g e of t e s t p l a n t s , and (2) allowed to dry f o r v a r y i n g periods of time. Test p l a n t s are (1) i n o c u l a t e d with the appropriate pathogen, (2) placed i n environmental chambers f o r expression fo disease symptoms or s i g n s ; and (3) evaluated. In the e a r l y I960's we came across the a n t i f u n g a l a c t i v i t y of c e r t a i n α,a-diphenyl-3-pyridine methanols and α,β-diphenyl3-pyridine ethanols. Generic s t r u c t u r e s are shown i n F i g . 7. These p y r i d i n e s are p r i m a r i l y a c t i v e against fungal genera causing powdery mildew diseases. Depending on the a r y l r i n g s u b s t i t u t i o n , some a c t i v i t y i s seen against r i c e b l a s t and cucumber anthracnose. The p y r i d i n e s are not systemic but do demonstrate a measure of translaminar movement as i n d i c a t e d by the c o n t r o l of powdery mildew on the upper l e a f surface when the f u n g i t o x i c a n t i s a p p l i e d to the lower l e a f surface only ( F i g . 8). The s i g n i f i c a n c e of h e t e r o c y c l i c b i n d i n g to cytochrome P-450 as i n d i c a t e d by Gadher et a l . was not recognized i n the e a r l y I960's when the s t r u c t u r e / a c t i v i t y r e l a t i o n s h i p s of the l e a d compounds was being developed. However, numerous Οί,α-diphenylmethane h e t e r o c y c l i c compounds were evaluated. The a c t i v i t y of these compounds against bean powdery mildew i s presented i n Table I . C r i t i c a l f o r a c t i v i t y i s the p o s i t i o n i n g of the methane s u b s t i t u t i o n beta to a n i t r o g e n atom i n the


BROWN ET AL.

Fungicides inhibiting Ergosterol Biosynthesis


5.


71


^

Pyridine

OH un

/

N

S-CH.

4

S-C H

. ,

9

F i g u r e 6.

N=C

Pyrimidine

3

3

buthiobate

Sumitomo

Elanco

Elanco

nuarimol

parinol

Elanco

Elanco

Manufacturer

fenarimol

triarimol

Common Name

Ergosterol Biosynthetic Inhibitors.

CH

C-CH

4-F

2-CI

4-CI

4-CI

2-CI

4-CI

Η

2,4-CI

Ri



Il

Ί

R—C—R I

?'

2

R

2

2

C3H7

2

CH — C —

^ - C - N - C

Triazole

|^

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H

4

/ Cl

~ 0 - - ^ ~ ^ - C l

Cl

2

- ^ ^ - C I

Cl

2

N

vy-CI

3

3

3

Ο CH Il I -C-C-CH3 I CH

CH

Ο ÇH Il I -C-C-CH3 3

A — '/ Ο

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H

/ Ο

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3

3

- ^ ~ " ^ - C I

Ο CH Il I -C-C-CH3 I CH

Continued.

H

n —C4H9

Figure 6.

- C H

—CN

-OCH-CH=CH

Cl


diclobutazol

biloxazol

proplconazol

triadimefon

prochloraz

fenapanil

imazilil

Common Name

ICI

Bayer

Clba-Geigy

Bayer

Fisons-Boots

Rohm & Haas

Janssen

Manufacturer



R,Rl = 4CI Parinol Figure 7.

Figure 8.

R, Ri = halogens 3-Pyridine Methanol/Ethanol.

Systematic

Movement of P a r i n o l .



Rating Scale: 0 = no control; 10 = complete control.

Table I. Control of Bean Powdery Mildew (BPM) by a,ûf-Diphenylmethaneheterocyclic Compounds Applied at 400 ppm



76

PESTICIDE SYNTHESIS T H R O U G H RATIONAL APPROACHES

heterocyclic ring. T h i s r e q u i r e m e n t i s c l e a r l y shown b y t h e i n a c t i v i t y o f t h e - 2 - p y r i d i n e and 4 - p y r i d i n e compounds compared t o the h i g h l e v e l o f a c t i v i t y o f the 3 - p y r i d i n e compound. F u r t h e r support f o r t h i s statement i s seen i n the i n a c t i v i t y o f the 2 - p y r i m i d i n e i n w h i c h b o t h n i t r o g e n atoms a r e a l p h a t o the methane s u b s t i t u t i o n as compared t o the h i g h l y a c t i v e 5 - p y r i m i d i n e i n w h i c h b o t h n i t r o g e n atoms are b e t a . The h e t e r o c y c l e s 1 , 3 - i m i d a z o l - l - y l and 1 , 2 , 4 - t r i a z o l - l - y l b o t h c o n t a i n a n i t r o g e n b e t a t o the methane s u b s t i t u t i o n and demonstrated good a c t i v i t y a g a i n s t the bean powdery mildew fungus. T h e s e h e t e r o c y c l e s a r e u s e d i n many o f t h e E B I fungicides marketed today. Whereas t h e 4 - p y r i d a z i n e compound d e m o n s t r a t e d some a c t i v i t y t h e 3 - p y r i d a z i n e was i n a c t i v e . Both d e r i v a t i v e s have a h e t e r o c y c l i c n i t r o g e n b e t a to the methane substitution. H o w e v e r , i n t h e i n a c t i v e 3 - p y r i d a z i n e compound a n o t h e r n i t r o g e n atom i s p o s i t i o n e d between the b e t a n i t r o g e n and the methane s u b s t i t u t i o n . The p r e s e n c e o f t h i s nitrogen might i n t e r f e r e w i t h the b i n d i n g of the beta n i t r o g e n to cytochrome P-450. The p r e s e n c e o f a n i t r o g e n atom a l p h a t o the methane s u b s t i t u t i o n does n o t d e s t r o y a c t i v i t y as l o n g as i t i s n o t a d j a c e n t t o the meta p o s i t i o n e d n i t r o g e n atom. Examples o f t h i s are 1 , 2 , 4 - t r i a z o l e and 2 - p y r a z i n e . A n o t h e r p a r a m e t e r i n v e s t i g a t e d was t h e u s e f u l n e s s of d i f f e r e n t s u b s t i t u e n t s o t h e r than hydrogen o r h y d r o x y l on the α-carbon. Table I I provides the r e l a t i v e a c t i v i t y o f s e v e r a l diphenylmethyl substituted 5-pyrimidines. C l e a r l y , the h y d r o x y l s u b s t i t u t e d compound i s t h e most a c t i v e a g a i n s t b e a n powdery mildew. The a c t i v i t y o f α - c a r b o n a l k y l and c y c l o a l k y l substitutions i s p r e s e n t e d i n Table I I I . These data i n d i c a t e t h a t the α , α - d i c y c l o h e x y l moiety i s v e r y a c t i v e a g a i n s t bean powdery mildew. F u r t h e r , the data i n d i c a t e t h a t the Of-cycloalkyl-aphenyl moieties are not o n l y superior to a - a l k y l - a - p h e n y l s u b s t i t u t i o n s f o r powdery mildew c o n t r o l , but t h a t they a l s o c o n f e r some a c t i v i t y a g a i n s t c u c u m b e r a n t h r a c n o s e . Based on t h e s e a n d o t h e r d a t a , t h e α , a - d i p h e n y l s u b s t i t u t i o n was c o n s i d e r e d t o be the b e s t c h o i c e . The n e x t l o g i c a l s t e p was t o d e t e r m i n e t h e i n f l u e n c e o f p h e n y l r i n g s u b s t i t u t i o n on the scope and degree o f a n t i f u n g a l activity. T h e a c t i v i t y o f some o f t h e s e c o m p o u n d s i s p r e s e n t e d i n T a b l e I V . When one p h e n y l r i n g i s s u b s t i t u t e d a n d t h e other ring unsubstituted, foliar protectant a c t i v i t y is optimized with halogens at the 2 or 4 p o s i t i o n . Specifically, the 4 - f l u o r o - s u b s t i t u t i o n (cmpd. 6) a p p e a r s more a c t i v e t h a n other mono s u b s t i t u t i o n s o f t h e p h e n y l r i n g a n d e q u a l t o the 2 , 4 - d i c h l o r o p h e n y l moiety which i s the o r i g i n a l p y r i m i d i n e fungicide, triarimol. Ortho-chloro or ortho-fluoro-substitution imparts e x c e l l e n t systemic a c t i v i t y against the bean r u s t



-OH

4

5

9

Disease Rating: 0 = no control;

10

2

-OC H

-H

9

4

10

-CN

5

10 = complete control.

6

-NHC H

5

6

10

2

-NH

-NHCOCH3

X=

5

16

10

80

10

400

-CL

X=

Parts Per Million

DISEASE CONTROL

2

4 10

10

10

4 6

10

2

6 10 10

16 80 400

Parts Per Million

Table I I . A c t i v i t y of Diphenylmethyl-Substituted 5-Pyrimidines Against Bean Powdery Mildew



.

OH

t

v

10 5 0

400 80 16

6 2 0

5 2 0

0

4

Disease Rating:

10 9 5

400 80 16

PM = Powdery Mildew A = Anthracnose

10 10 5

4

400 80 16

400 80 16

Disease Control Bean Cuke PM A PPm

Ç)H

3

0 = no control;

OH

1 3

.

400 80 16

400 80 16

400 80 16

10 = complete control.

.

-C—CgH

Ο ο

Ο -Ç—CH

OH

10 10 9

6 0 0

4 0 0

Disease Control Bean PM ppm

A c t i v i t y of CY-Phenyl-a-alkyl or C y c l o a l k y l - 5 - p y r i m i d i n e Methane or Methanols

0&S>

.

Table I I I .


0

0

0

Cuke A

Table

IV.

Comparative A c t i v i t y pyrimidine


79


BROWN ET AL.

5.

of

Substituted

Diphenyl-5-

Methanols

DISEASE CONTROL

Beam

Cuke

Rice

Apple

Bean Rust

PM

A

Blast

Scab

(Systemic) 10

3.2

400

400

100

25

20

~2

0

"Ô"

0

1

0

10

9

8

5

4

0

0

-

10

10

2-F

6

4

6

2

0

9

0

10

10

3-CI

1

0

0

0

0

1

0

0

0

#5

4-CI

10

5

9

3

0

9

2

10

6

#6

4-F

10

5

10

3

7

10

10

10

10

#7

3-CF3

7

0

3

0

6

-

2

0 0

Cmpd.

R

ppm: 16

"ΊΓ

#1

H

#2

2-CI

#3 #4

80

#8

4-CF3

5

0

4

0

0

-

5

#9

4-0CH-3

5

0

7

2

0

-

10

7

#10

4-N02

9

4

0

0

0

-

0

0

#11

2,4-DiCI

10

9

9

5

5

10

10

10

8

#12

2,5-DiCI

7

7

8

5

0

10

10

0

0

#13

3,4-DiCI

10

7

9

2

0

-

0

0

PM = Powdery Mildew A = Anthracnose

Disease Rating: = no control; 10 = complete control



80


fungus. I n t h i s t e s t , compound i s added as a o n e - t i m e soil drench to pots c o n t a i n i n g rust i n o c u l a t e d bean p l a n t s . The m e t a - c h l o r o p h e n y l compound ( c m p d . 4 ) was n o t as f u n g i t o x i c as the o r t h o - o r p a r a - c h l o r o p h e n y l d e r i v a t i v e s and p r o b a b l y not systemic although i n the absence of s u f f i c i e n t a n t i f u n g a l a c t i v i t y , s y s t e m i c movement i s d i f f i c u l t , i f n o t i m p o s s i b l e , t o assay. However, the 2,5 and 3,4 d i c h l o r o p h e n y l compounds, w h i c h c o n t a i n a h a l o g e n meta to the Of-carbon s u b s t i t u t i o n , d e m o n s t r a t e d n o s y s t e m i c i t y a l t h o u g h some a n t i f u n g a l a c t i v i t y i s indicated. The scope and degree o f a n t i f u n g a l a c t i v i t y i s i n c r e a s e d w h e n s u b s t i t u t i o n s a r e made o n e a c h p h e n y l r i n g . Results of our greenhouse evaluations are presented i n Table V . The i m p o r t a n c e o f an o r t h o - h a l o s u b s t i t u t i o n f o r degree o f a n t i f u n g a l a c t i v i t y is r e a d i l y observed. F o r i n s t a n c e , c o m p o u n d 15 ( 2 - c h l o r o p h e n y l α - 3 - c h l o r o p h e n y l ) shows c o n s i d e r a b l y more a c t i v i t y t h a n c o m p o u n d 17 w h i c h i s b i s ( 3 - c h l o r o p h e n y l ) . A similar observation i s m a d e b e t w e e n c o m p o u n d s 19 a n d 2 0 . Of i n t e r e s t i s the lower l e v e l o f a c t i v i t y i n the b i s (4-chlorophenyl) d e r i v a t i v e (18). The p o o r a c t i v i t y o f α - b i s - ( 4 - c h l o r o p h e n y l ) - 5 - p y r i m i d i n e methane (cmpd. 18) i s somewhat s u r p r i s i n g s i n c e t h e similarly s u b s t i t u t e d 3 - p y r i d i n e m e t h a n o l ( p a r i n o l , P a r n o n ) was t h e compound s e l e c t e d and p o s i t i o n e d i n t h e U . S . o r n a m e n t a l c r o p market. G e n e r a l l y , f l u o r o s u b s t i t u t i o n s on the p h e n y l r i n g s provide s l i g h t l y b e t t e r a c t i v i t y than the corresponding chloro substitutions. From o u r r e s e a r c h two compounds were s e l e c t e d f r o m t h i s group f o r m a r k e t i n g . They are the a-(2-chlorophenyl)-a-(4c h l o r o p h e n y l ) (cmpd. 16) and a - ( 2 - c h l o r o p h e n y l ) - a - ( 4 f l u o r o p h e n y l ) (cmpd. 25) s u b s t i t u t e d 5 - p y r i m i d i n e m e t h a n o l s , known as f e n a r i m o l and n u a r i m o l , r e s p e c t i v e l y . D I S C U S S I O N AND C O N C L U S I O N S The work o f Gadher e t a l and t h e awareness o f t h e d i v e r s i t y o f the b i o l o g i c a l a c t i v i t y o f EBI fungicides suggests that the s t r u c t u r e o f t h e f u n g i t o x i c a n t must s a t i s f y more t h a n one requirement. The a b i l i t y t o b i n d t o t h e protoheme i r o n o f cytochrome P-450 appears t o be a r e q u i r e d f u n c t i o n f o r a c t i v i t y . The f i t n e s s t o b i n d c o u l d be dependent upon s e v e r a l f a c e t s such as: 1.

The h e t e r o c y c l e i t s e l f and the p o s i t i o n o f t h e n i t r o g e n atoms w i t h i n the r i n g . F o r e x a m p l e , i n T a b l e 1 we s h o w e d that a,a-diphenylmethyl-3-pyridazine was i n a c t i v e d e s p i t e the presence o f a beta p o s i t i o n e d n i t r o g e n . We s u p p o s e d t h a t the p r e s e n c e o f the a l p h a n i t r o g e n atom a d j a c e n t to t h e b e t a n i t r o g e n was r e s p o n s i b l e f o r t h e l a c k o f a c t i v i t y .


5. BROWN ET AL.

Table V.

Fungicides inhibiting Ergosterol Biosynthesis

Comparative A c t i v i t y of D i s u b s t i t u t e d

81

Diphenyl-5-


pyrimidine Methanols

DISEASE CONTROL

Bean PM R1

Cmpd. R

Cuke A

ppm: 16

3.2

400

Rice Blast

Bean Rust (Systemic)

Apple Scab

80

400

50

10

20

10

#14

2-CI

2-CI

9

4

4

0

0

10

10

10

7

#15

2-CI

3-CI

10

9

10

10

5

10

10

9

10

#16

2-CI

4-CI

9

8

10

5

6

10

10

10

8

#17

3-CI

3-CI

6

7

8

0

4

4

2

0

0

#18

4-CI

4-CI

1

0

0

0

0

0

-

-

#19

2-CI

4-0CH3

10

9

8

0

10

2

10

10

0

-

0

-

#20 4-CI

4-0CH3

4

0

0

4

5

#21

4-CH3

4-CH3

-

-

0

#22

2-F

3-F

9

5

10

0

-

-

0

6

5

10

10

#23

3-F

0

3-F

3

1

#24

4-F

4-F

9

6

8

2

4

-

3

7

0

-

-

6

10

10

10

#25

2-CI

4-F

10

10

10

#26

3,4-DiCI 3,4-DiCI

9

5

10

10

10

10

4

0

0

0

-

-

0

-

PM = Powdery Mildew A = Anthracnose Disease Rating: 0 = no control; 10 = complete control.


82


2.


This s u p p o s i t i o n may be v a l i d f o r p y r i d a z i n e but i n the Bayer U.S. Patent 4,098,894, they show good a n t i f u n g a l a c t i v i t y f o r 1-(3-trifluoromethyltriphenyl) 1,2,3-triazole, a compound which a l s o contains a n i t r o g e n atom alpha to the s u b s t i t u t i o n and adjacent to the beta n i t r o g e n . The " s p a g h e t t i " attached to the h e t e r o c y c l i c r i n g could g r e a t l y i n f l u e n c e the degree of a s s o c i a t i o n with cytochrome P-450 as w e l l as many o f the other f a c e t s of EBI f u n g i c i d e activity.

The a b i l i t y of these chemicals to penetrate the c u t i c l e , the c e l l membrane, move i n t o the p r o t o p l a s t and d i s t r i b u t e i n the p l a n t i s t o a l a r g e measure dependent upon the h y d r o p h i l i c / l i p o p h i l i c balance, the s t e r i c c o n f i g u r a t i o n and i t s s t a b i l i t y i n or on the p l a n t . S i m i l a r l y , these same chemical and p h y s i c a l f a c t o r s are c r i t i c a l f o r t o x i c i t y of the chemical t o the fungus.

LITERATURE CITED 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Brown, I. F . ; Hall, H. R.; Miller, J . R. Phytopathology 1970, 60, 1013-1014. Ragsdale, N. N.; Sisler, H. D. Biochem. Biophys. Res. Comm. 1972, 46, 2048-2053. Kato, T.; Shoami, M.; Kawase, Y. J . Pestic. Sci. 1980, 5, 69-79. Sherald, J . L . ; Ragsdale, Ν. N.; Sisler, H. D. J . Pestic. Sci. 1973, 4, 719-727. Siegel, M. R. Plant Disease 1981, 65, 986-989. Kato, T. J . Pestic. Sci. 1982, 7, 427-437. Ragsdale, Ν. N. Biochem. Biophys. Acta. 1975, 380, 81-96. Mitropoulos, Κ. Α.; Gibbons, G. F . ; Connel, C. M.; Woods, R. A. Biochem. Biophys. Res. Comm. 1976, 71, 892-900. Gadher, P.; Mercer, Ε. I.; Baldwin, B. C.; Wiggins, T. E. 1983, Pest. Biochem and Phys. 19, 1-10. Gibbons, G. F . ; Pulliger, C. R.; Mitropoulos, K. A. Biochem. J . 1979, 183, 309. Jager, G. in "Pesticide Chemistry", Miyamato, J.; Kearney, P.C., eds., Pergamon, New York, 1982, Vol. 1, pp. 55-65. Kramer in "Pesticide Chemistry", Miyamato, J.; Kearney, P.C., eds., Pergamon, New York, 1982, Vol. 1, pp. 223-232.

RECEIVED January 13, 1984


Pesticide Synthesis Through Rational Approaches - American

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