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11 Advances in Fungicide Chemistry and Fungal Control Summary and Comments Hugh D. Sisler
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on November 5, 2015 | http://pubs.acs.org Publication Date: April 22, 1986 | doi: 10.1021/bk-1986-0304.ch011
Department of Botany, University of Maryland, College Park, M D 20742
This publication comprises papers dealing with factors which consti tute the basis for the advancement of chemical control of fungal diseases. This summary provides comment on some of the points made in these papers and also presents additional information from other sources as well as some personal opinions and ideas. Professor Bűchel dealt with the history of azole chemistry and the impact of azole fungicides on the control of fungal pathogens of plants and humans. This presentation made a number of valuable points of interest to organic chemists and biologists. One s i g n i f i cant point made by Professor Bűchel concerns the wide structural variations permissible in the l i p o h i l i c substituent at position 1 of azole fungicides without loss of the basic antifungal activity. This substituent, nevertheless, dictates biochemical and biological specificity as well as properties which determine practical success of these fungicides. In a potent fungicide, this substituent appar ently must have a configuration which permits the interaction of an Ν atom of the azole group with a haem iron atom (or with some other group) of an enzyme while binding tightly to the enzyme to reinforce the linkage of the Ν atom to the iron. As pointed out by Professor Bűchel, the possibilities for designing azole compounds of differing biological activity are almost limitless. One serious challenge which may be encountered in fungicide synthesis is that of designing structures which do not seriously interfere with any of the various mammalian cytochrome P-450 enzymes. Dr. Berg focused attention on the biochemical specificity of fungicides acting in the ergosterol biosynthetic pathway. He pointed out that, while many ergosterol biosynthesis inhibiting (EBI) fungi cides, including the azoles, primarily black sterol C-14 demethylation, the fungicide tridemorph blocks Δ --> Δ isomerization or reduction of the sterol C-14, 15 double bond. Another fungicide, a 15-azasterol antibiotic, is a potent inhibitor of Δ sterol reduc tase with a K i of 2nM (1). New fungicides acting in the sterol biosynthetic pathway at yet another site have been reported recently. Allylamine derivatives of the naftifine group are fungicides which block squalene expoxidation. The derivative SF 86-327, for example, 8
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0097-6156/86/0304-0157$06.00/0 © 1986 American Chemical Society
In Fungicide Chemistry; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on November 5, 2015 | http://pubs.acs.org Publication Date: April 22, 1986 | doi: 10.1021/bk-1986-0304.ch011
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i s a p o t e n t i n h i b i t o r o f squalene e p o x i d a s e w i t h an inhibition c o n s t a n t of 3X10 M ( 2 ) . The l a r g e number of f u n g i c i d e s a c t i n g on e r g o s t e r o l b i o s y n t h e s i s i n d i c a t e t h a t t h i s pathway i s a d e s i r a b l e one to t a r g e t f o r f u n g i t o x i c a c t i o n . However, the q u e s t i o n might be r a i s e d as t o whether i n h i b i t i o n of e r g o s t e r o l b i o s y n t h e s i s a l o n e i s p r i m a r i l y r e s p o n s i b l e f o r a n t i f u n g a l a c t i o n of a l l of the compounds r e p o r t e d to a c t i n the pathway. A good argument might be made t h a t t h i s i s the case f o r the 1 5 - a z a s t e r o l a n t i b i o t i c s i n c e i t s t o x i c i t y can be r e v e r s e d w i t h exogenous e r g o s t e r o l ( 3 ) . However, t o x i c i t y of s t e r o l C-14 demethylation i n h i b i t o r s i s not r e v e r s e d by a d d i n g exogenous e r g o s t e r o l , l e a v i n g some doubt t h a t i n h i b i t i o n of e r g o s t e r o l b i o s y n t h e s i s alone i s r e s p o n s i b l e f o r t o x i c i t y . Perhaps we s h o u l d l o o k beyond the s t e r o l s and i n t o s t e r i o d hormone b i o s y n t h e s i s and f u n c t i o n f o r a b e t t e r u n d e r s t a n d i n g o f the f u n g i t o x i c a c t i o n of EBI compounds. The pathway from l a n o s t e r o l t o e r g o s t e r o l may be o f l e s s s p e c i f i c importance f o r p r o v i d i n g a p p r o p r i a t e s t e r o l s t u c t u r e s f o r membranes than i t i s as a segment o f a pathway f o r s t e r o i d hormone b i o s y n t h e s i s . The recent discovery that Saccharomyces c e r e v i s i a e produces an e s t r o g e n b i n d i n g p r o t e i n (4) and produces an e s t r o g e n i c substance (5) s h o u l d i n t e n s i f y i n t e r e s t i n the p o s s i b i l i t y t h a t f u n g i produce s t e r o i d hormones and t h a t EBI f u n g i c i d e s might block t h e i r s y n t h e s i s or a c t i o n . I t has, f o r example, been shown t h a t t e s t o s t e r o n e and p r o g e s t e r o n e p a r t i a l l y r e v e r s e t o x i c i t y of EBI i n h i b i t o r s i n some f u n g i ( 6 ) . Of i n t e r e s t i s the d e m o n s t r a t i o n t h a t k e t o c o n a z o l e , a s t e r o l C-14 d e m e t h y l a t i o n i n h i b i t o r , not o n l y b l o c k s testosterone production i n mammalian systems but a l s o d i s p l a c e s s t e r o i d hormones from serum t r a n s p o r t p r o t e i n s (7). Cytochrome P-450 enzymes are v e r y prominent i n the b i o s y n t h e s i s o f s t e r o i d hormones from desmethyl s t e r o l s and a c t i o n o f an EBI on t h e s e enzymes c o u l d e x p l a i n why f u n g i t o x i c i t y i n some cases i s not r e v e r s e d by the a d d i t i o n of e r g o s t e r o l . P r o f e s s o r FUhr d i s c u s s e d p e n e t r a t i o n , t r a n s l o c a t i o n and d i s t r i b u t i o n of f u n g i c i d e s i n p l a n t s . These a s p e c t s of f u n g i c i d e p e r formance are o f t e n c r i t i c a l i n d e t e r m i n i n g the s u c c e s s of a s y s t e m i c f u n g i c i d e i n a p a r t i c u l a r type o f a p p l i c a t i o n . The a b i l i t y t o p e n e t r a t e i n t o p l a n t t i s s u e and move w h i l e r e t a i n i n g a c t i v i t y t h e r e i n i s the p r i m a r y b a s i s f o r the s u p e r i o r i t y o f the newer systemic f u n g i c i d e s over the o l d e r s u r f a c e p r o t e c t a n t s . I n t e r n a l therapeut a n t s may a l s o i n f l u e n c e the h o s t p h y s i o l o g y and as a consequence, be a s s i s t e d by the n a t u r a l defense system o f the h o s t . Dr. S c h e i n p f l u g addressed t h i s p o i n t i n h i s p r e s e n t a t i o n . He p r e s e n t e d l i g h t and e l e c t r o n m i c r o s c o p i c e v i d e n c e w h i c h s u g g e s t s t h a t some s y s t e m i c f u n g i c i d e s may induce h o s t r e s i s t a n c e t o an i n v a d i n g f u n g a l pathogen. The r o l e s of d i r e c t f u n g i t o x i c i t y and a c t i v a t e d h o s t r e s i s t a n c e systems i n such cases i s d i f f i c u l t t o r e s o l v e . By s i m p l y s l o w i n g down the r a t e of growth of a pathogen, a compound might p r o v i d e the h o s t p l a n t the time n e c e s s a r y t o m o b i l i z e defense systems and thus g r e a t l y enhance the apparent e f f e c t i v e n e s s o f the compound as a f u n g i c i d e . P r o f e s s o r Schwinn d i s c u s s e d new advances i n the c h e m i c a l c o n t r o l of p l a n t p a r a s i t i c Oomycetes and P e r o n o s p o r a l e s . Some o f the most d e v a s t a t i n g f o l i a r and r o o t d i s e a s e s are caused by these f u n g i , but they are o f t e n not c o n t r o l l e d by s y s t e m i c f u n g i c i d e s w h i c h c o n t r o l
In Fungicide Chemistry; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.
Downloaded by UNIV OF CALIFORNIA SAN DIEGO on November 5, 2015 | http://pubs.acs.org Publication Date: April 22, 1986 | doi: 10.1021/bk-1986-0304.ch011
11.
SISLER
Chemical Control of Fungal Diseases
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pathogens o f o t h e r m y c o l o g i c a l groups. C y m o x n i l , a c y l a l a n i n e s and p h o s e t h y l - A l are some o f the newer f u n g i c i d e s s p e c i f i c a l l y e f f e c t i v e f o r c o n t r o l o f Oomycetes and P e r o n o s p o r a l e s . The a c y l a l a n i n e s have proven t o be h i g h l y a c t i v e f u n g i c i d e s b u t have e x p e r i e n c e d some r e s i s t a n c e problems w h i c h h o p e f u l l y c a n be managed by p r o p e r a n t i resistant strategies. Professor Dekker discussed non-fungicidal compounds which c o n t r o l d i s e a s e by i n c r e a s i n g h o s t r e s i s t a n c e o r by d e c r e a s i n g t h e a b i l i t y o f the pathogen t o a t t a c k the h o s t . The d i c h l o r o c y c l o p r o p a n e c a r b o x y l i c a c i d s and p r o b e n a z o l e (a s a c c h a r i n e r e l a t i v e ) are examples of compounds w h i c h s e n s i t i z e the h o s t p l a n t t o respond i n a r e s i s t a n t manner. Melanin biosynthesis inhibitors such as t r i c y c l a z o l e , pyroquilon and f t h a l i d e a r e r e p r e s e n t a t i v e s o f compounds w h i c h d e c r e a s e p a t h o g e n i c c a p a b i l i t i e s o f the fungus. A l t h o u g h some o f the a f o r e m e n t i o n e d compounds such a p r o b e n a z o l e and t r i c y c l a z o l e have been adopted f o r p r a c t i c a l c o n t r o l o f p l a n t d i s e a s e s , r e p r e s e n t a t i v e s i n t h i s c a t e g o r y are few i n number and o f r e l a t i v e l y minor impor tance. The i d e a o f c o n t r o l l i n g p l a n t d i s e a s e s by m a n i p u l a t i o n o f h o s t - r e s i s t a n c e systems o r p a t h o g e n i c mechanisms i n t h e fungus i s a t t r a c t i v e . The h i g h s p e c i f i c i t y of many h o s t / p a r a s i t e r e l a t i o n s h i p s suggest t h a t r e c o g n i t i o n may o f t e n be the most c r i t i c a l f a c t o r i n the i n i t i a t i o n o f a r a p i d r e s i s t a n t response i n the h o s t . These i n t e r a c t i o n s may be d i f f i c u l t t o r e g u l a t e c h e m i c a l l y w i t h o u t i n j u r y t o the h o s t p l a n t . A much b e t t e r u n d e r s t a n d i n g o f the f a c t o r s i n v o l v e d i s n e c e s s a r y b e f o r e a r a t i o n a l c h e m i c a l m a n i p u l a t i o n o f these i n t e r a c t i o n s can be u t i l i z e d a s a means o f d i s e a s e c o n t r o l . Conventional s c r e e n i n g h o l d s o n l y v e r y l i m i t e d promise f o r d i s c o v e r i n g e f f e c t i v e c h e m i c a l s o f t h i s c a t e g o r y ; however, any compounds d i s c o v e r e d may be v a l u a b l e i n h e l p i n g t o e l u c i d a t e h o s t / p a r a s i t e r e l a t i o n s h i p s and thus promote f u r t h e r advances. P r o f e s s o r s Hoffman, C o l e , Jones and P e a r s o n d i s c u s s e d the use o f new fungicides i n various crops w i t h respect t o increased crop y i e l d s , economics, i n t e g r a t e d p e s t management (IPM) systems, epidemo l o g y and f u n g a l r e s i s t a n c e t o f u n g i c i d e s . The e r a d i c a t i v e a c t i o n o f some o f the newer f u n g i c i d e s p e r m i t s p o s t - i n f e c t i o n a p p l i c a t i o n and t h i s f e a t u r e makes t h e compounds p a r t i c u l a r l y d e s i r a b l e f o r IPM systems. I n some c a s e s , t h e f u n g i c i d e s are l e s s e f f e c t i v e i n p r e i n f e c t i o n a p p l i c a t i o n s than i n p o s t - i n f e c t i o n a p p l i c a t i o n s . T h i s i s a p p a r e n t l y due t o the l o s s o f f u n g i c i d e t o w e a t h e r i n g and u l t r a v i o l e t d e g r a d a t i o n w h i c h o c c u r s when the f u n g i c i d e i s p r e s e n t p r i o r t o t h e infection period. F u n g a l r e s i s t a n c e t o d e s i r a b l e new t y p e s o f f u n g i c i d e s c o n t i n u e s t o be a s e r i o u s c o n c e r n . The b e s t apparent way t o combat t h i s problem i s t o d e v e l o p u s e s t r a t e g i e s w h i c h w i l l decrease the p o s s i b i l i t y f o r s e l e c t i o n o f r e s i s t a n t s t r a i n s . This w i l l r e q u i r e c l o s e c o o p e r a t i o n between i n d u s t r y , s t a t e o r government i n s t i t u t i o n s , and the growers. There i s need f o r new f u n g i c i d e s w i t h modes o f a c t i o n d i f f e r i n g from those o f compounds now i n use i n o r d e r t o d e s i g n a p p l i c a t i o n sequences t h a t m i n i m i z e overuse o f c h e m i c a l s i n one mode o f a c t i o n c a t e g o r y . The f u t u r e h o l d s c o n s i d e r a b l e promise f o r the development o f new s y s t e m i c f u n g i c i d e s and compounds w h i c h m o d i f y h o s t - r e s i s t a n c e o r fungal pathogenicity. Among t h e major o b s t a c l e s w h i c h w i l l be
In Fungicide Chemistry; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.
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encountered are the problems of fungal resistance and increasingly rigid toxicological standards. Literature Cited 1. 2. Downloaded by UNIV OF CALIFORNIA SAN DIEGO on November 5, 2015 | http://pubs.acs.org Publication Date: April 22, 1986 | doi: 10.1021/bk-1986-0304.ch011
3. 4. 5. 6. 7.
Bottema, C.K.; Parks, L.W. Biochim. Biophys. Acta 1978, 531, 301-7. Petranyi, G.; Ryder, N.S.; Stűtz, A. Science 1984, 224, 123941. Taylor, F.R.; Rodriguez, R.J.; Parks, L.W. Antimicrob. Agents Chemother. 1983, 23, 515-21. Feldman, D.; Do, Y.; Burshell, Α.; Stathis, P.; Loose, D.S. Science 1982, 218, 297-8. Feldman, D.; Stathis, P.Α.; Hirst, M.A.; Stover, E.P.; Do, Y.S. Science 1984, 224, 1109-11. Sherald, J.L.; Ragsdale, N.N.; Sisler, H.D. Pesti. Sci. 1973, 4, 719-27. Grosso, D.S.; Boyden, T.W.; Pamenter, R.W.; Johnson, D.G.; Stevens, D.A.; Galgiani, J.N. Antimicrob. Agents Chemother. 1983, 23, 207-12.
RECEIVED January 8, 1986
In Fungicide Chemistry; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.
