The Design of Triazole Fungicides - ACS Symposium Series (ACS

11 The Design of Triazole Fungicides

Pesticide Synthesis Through Rational Approaches Downloaded from pubs.acs.org by UNIV OF QUEENSLAND on 04/28/16. For personal use only.

A. F. MARCHINGTON ICI Plant Protection PLC, Jealotts Hill Research Station, Bracknell, Berkshire RG12 6EY, England The use of high performance computer graphics with theoretical calculations is demonstrated to be an imaginative approach in the study of triazole fungicides. As an example, theoretical work is presented which when taken with the results from x-ray, infra-red, and n.m.r. experiments can, with the help of computer graphics, be used to construct a model of the cytochrome P-450 active site. In this way the triazole fungicides can be compared directly with the natural substrate, 24methylene-24,25 dihydrolanosterol, to provide insight into the design of novel inhibitors. L e t us begin with a fundamental q u e s t i o n . What are the research departments o f the major drug and crop p r o t e c t i o n companies t r y i n g bo do? They are t r y i n g to invent s m a l l , b i o l o g i c a l l y a c t i v e molecules whose e f f e c t s have commercial worth o r advantage. In t h a t case, what makes a molecule b i o l o g i c a l l y a c t i v e ? U s u a l l y a molecule possesses a c t i v i t y p r i m a r i l y because i t binds to an a c t i v e s i t e on a b i o l o g i c a l macromolecule, most commonly a three-dimensional p r o t e i n s t r u c t u r e . In the p a s t , the d i s c o v e r y and subsequent development o f b i o l o g i c a l a c t i v i t y has been done i n three conceptual ways: (a) l a r g e s c a l e e m p i r i c a l screening; (b) c l o s e analogue chemistry; (c) the more r a t i o n a l design o f b i o l o g i c a l l y a c t i v e molecules a t the molecular l e v e l . Although o f g r e a t e r f i n a n c i a l p o t e n t i a l , the great d i f f i c u l t y with the l a t t e r approach has always been our s t a r k i n a b i l i t y to answer s e v e r a l c r u c i a l questions concerning the b i n d i n g o f a small molecule t o i t s p r o t e i n r e c e p t o r . For i n s t a n c e , what do (a) the s u b s t r a t e and (b) the a c t i v e - s i t e o f the r e c e p t o r a c t u a l l y look l i k e as the one approaches the o t h e r . The f r e e energy changes a s s o c i a t e d with the removal o f a molecule from i t s s o l v e n t sheath are to some extent amenable t o experimental e v a l u a t i o n , but the exact nature and geometry o f the r e c o g n i t i o n process, c o l l i s i o n and chemical b i n d i n g o f a small s u b s t r a t e to a p r o t e i n i s s t i l l l a r g e l y a mystery.

0097-6156/84/0255-0173S06.00/0 © 1984 American Chemical Society

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In molecular terms, how one molecule appears to another, whether i t be the s u b s t r a t e or the b i n d i n g s i t e , i s r e a l l y two questions. Where are the n u c l e i ? . T h i s i s not j u s t a question of e q u i l i b r i u m shape as measured by n.m.r., x-ray or neutron spectroscopy, but a l s o concerns what p o s s i b l e shapes the molecule can assume as i t i n t e r a c t s with i t s p a r t n e r ; i n general, what f l e x i b i l i t y i t possesses. Flexibility is clearly a property of both small molecules and the p r o t e i n b i n d i n g sites. Where are the e l e c t r o n s ? . T h i s question too can only be s t u d i e d experimentally f o r molecules i n e q u i l i b r i u m and i n a roughly homogeneous environment such as a c r y s t a l or i n s o l u t i o n . What we r e a l l y want to know i s how the d i s t r i b u t i o n o f these e l e c t r o n s around the n u c l e i determine the l i k e l i h o o d of e f f e c t i v e c o l l i s i o n and how they then behave d u r i n g the interaction. Since molecules i n t e r a c t most s t r o n g l y a t t h e i r a c c e s s i b l e s u r f a c e s , i t i s important to know what these s u r f a c e s look l i k e . Advances i n t h e o r e t i c a l methods and computer technology mean t h a t both these questions can now be answered u s i n g a computer and any number of e a s i l y obtained programs. Having obtained the answer to our problem t h e o r e t i c a l l y however, there i s a further d i f f i c u l t y . How can these o f t e n complex molecular p r o p e r t i e s be d i s p l a y e d . T h i s i s r e a l l y the crux of the matter f o r the world's drug and crop p r o t e c t i o n companies. I t i s a f a c t o f l i f e t h a t the s c i e n t i s t s t r a i n e d to make molecules w i l l not be i n f l u e n c e d by those t r a i n e d to design them unless the proposed r a t i o n a l e can be seen to be obvious. Computer Molecular Graphics provides t h i s l i n k between a chemist's i n t u i t i o n and the v a s t a r r a y o f chemical, p h y s i c a l and b i o l o g i c a l i n f o r m a t i o n . As an example of the use of computer graphics and t h e o r e t i c a l methods t h i s paper d e s c r i b e s a study i n the design of the t r i a z o l e f u n g i c i d e s , f o r instance the ICI compounds d i c l o b u t r a z o l ( ' V i g i l ' ) and the new PP450 ('Impact'), and the Bayer compound t r i a d i m e f o n ('Bayleton'). The E l i L i l l y m a t e r i a l t r i a r i m o l ('Elancocide') though not a t r i a z o l e f u n g i c i d e i s e q u i v a l e n t i n i t s mode of a c t i o n . T h i s general c l a s s of f u n g i c i d e i s now a t t r a c t i n g wide commercial i n t e r e s t i n both the crop p r o t e c t i o n and pharmaceutical i n d u s t r i e s as i n h i b i t o r s o f f u n g a l e r g o s t e r o l b i o s y n t h e s i s ( F i g 1). T h i s design work can be d i v i d e d i n t o three stages 1.

:-

Assembly o f b i o c h e m i c a l , p h y s i c a l and b i o l o g i c a l information mostly from the l i t e r a t u r e , but a l s o experiment, to c o n s t r u c t a crude two dimensional p i c t u r e o f the s i t e of a c t i o n of these compounds.


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2.

A computer graphics f a c i l i t y , was then used with a v a i l a b l e c r y s t a l data, molecular o r b i t a l and molecular mechanics c a l c u l a t i o n s , i n f r a - r e d and n.m.r. s t u d i e s to c o n s t r u c t a three dimensional model o f the t a r g e t enzyme a c t i v e s i t e (a cytochrome P-450) designed s p e c i f i c a l l y to accommodate both the n a t u r a l substrate (24 methylene 24,25 d i h y d r o l a n o s t e r o l ) and these known antagonists i n t h e i r minimum or low energy forms·

3.

T h i s model was then used to suggest new 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 and c o n t r i b u t e towards novel f u n g i c i d e design.

The Q u a l i t a t i v e Enzyme Model I t has been shown (1) that the t r i a z o l e f u n g i c i d e s i n h i b i t the 14o(-demethylation o f 24-methylene 24,25-dihydrolanosterol, the e r g o s t e r o l p r e c u r s o r . This i s a c r u c i a l step i n e r g o s t e r o l b i o s y n t h e s i s which has to be completed before a number o f other steps can begin more or l e s s i n p a r a l l e l . This i n h i b i t i o n i s brought about by the compounds b i n d i n g to the heme p r o s t h e t i c group o f the cytochrome P-450 oxidase enzyme system which c a t a l y s e s t h i s transformation. When added to a r a t l i v e r cytochrome P-450 p r e p a r a t i o n , f o r instance, an unmistakable Type II Soret d i f f e r e n c e spectrum i s produced i n d i c a t i n g t h a t the t r i a z o l e 4-nitrogen coordinates to the heme f e r r i c i o n which maintains i t s f e r r i c (Fe^*) low spin r e s t i n g s t a t e . In so doing the antagonist has to d i s p l a c e the n a t u r a l s i x t h l i g a n d of the heme which i s probably a water molecular (2) o r p o s s i b l y an imidazole group derived from a p r o t e i n h i s t i d i n e . The other a x i a l l i g a n d , below the heme plane i s b e l i e v e d t o be a c y s t e i n e sulphur as f i r s t suggested by Murakami and Mason ( 3 ) . The 14o(-demethylation o f d i h y d r o l a n o s t e r o l proceeds i n three main stages with the two intermediates - the a l c o h o l , 5 o < lanost-8-ene-3p,32-diol, and the aldehyde, 3p-hydroxy-5D(lanost-8-en-32-al, being t i g h t l y p r o t e i n bound. The cytochrome P-450 i s the component o f the enzyme system r e q u i r e d t o i n i t i a t e o x i d a t i o n of the 14c< -methyl group, but not of t h a t r e s p o n s i b l e f o r the subsequent o x i d a t i o n steps r e q u i r e d f o r i t s e l i m i n a t i o n as formic a c i d ( 4 ) . This i n i t i a l o x i d a t i o n a l s o seems to be d i r e c t l y i n h i b i t e d by the a l c o h o l and aldehyde metabolities·

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Consequently i n computer modelling the antagonism of these heme b i n d i n g f u n g i c i d e s i t seemed necessary to consider only the f i r s t o x i d a t i o n of the parent l a n o s t e r o l to the 14-methyl alcohol. I t i s only i n the l a s t few years t h a t a p l a u s i b l e mechanism f o r t h i s o x i d a t i o n has been suggested ( 5 ) . On b i n d i n g the substrate the f e r r i c porphyrin i s converted from low to high s p i n due to the displacement of the high f i e l d s i x t h l i g a n d . Studies with s p i n l a b e l l e d substrates have shown t h a t t h i s substrate b i n d i n g s i t e p l a c e s the bound molecule very c l o s e to the i r o n ( 6 ) . T h i s complex i s then reduced and as F e can then bind molecular oxygen. Further one e l e c t r o n reduction y i e l d s a species which i s l e s s w e l l d e f i n e d but corresponds to the h y p o t h e t i c a l s t a t e [ F e 0 ~ ] which has a l l the e l e c t r o n e q u i v a l e n t s r e q u i r e d f o r methyl h y d r o x y l a t i o n , water p r o d u c t i o n and regeneration of the f e r r i c r e s t i n g s t a t e . T h i s f i n a l step, however, r e q u i r e s an e f f e c t o r molecule - a f r e e a c y l a t i n g group, provided i n b a c t e r i a l hydroxylase by the carboxy t e r m i n a l tryptophan, or the penultimate glutamine o f putidaredoxin. This a c y l group i s r e s p o n s i b l e through a p e r a c y l group of generating the f i n a l iron-oxene intermediate.


2

3 +

2

2

F i g u r e 2 shows the crude two dimensional model of the P-450 active s i t e . In d e s i g n i n g an i n h i b i t o r f o r t h i s process there are three c e n t r a l features to consider :1.

The heme p r o s t h e t i c group a v a i l a b l e f o r complexation.

2.

The hydrophobic substrate b i n d i n g s i t e s p e c i f i c f o r lanosterol. Indeed a r e c e n t paper by Dus (7) i m p l i c a t e s two b i n d i n g s i t e s f o r v a r i o u s cytochrome P-450 s - one f o r s u b s t r a t e and the other f o r nascent product, and both with a c t i v a t e d t h i o l groups. 1

3.

The occurence of h y d r o p h i l i c groups i n an otherwise g r o s s l y hydrophobic environment. The porphyrin propionate s i d e chains as suggested by Peterson e t a l . (8) and the a c y l e f f e c t o r group could both intervene between the bound s u b s t r a t e and the plane of the heme. There i s a l s o the p o s s i b i l i t y o f hydrogen bonding with the d i s p l a c e d h i s t i d i n e ( i f present) and a l s o a general p o l a r i n t e r a c t i o n with the p o l a r i n t e r f a c e which e x i s t s by v i r t u e of the enzyme s i t t i n g i n a membrane.

The task now was to l o c a t e the n a t u r a l s u b s t r a t e and the f l e x i b l e i n h i b i t o r s i n a three dimensional computer model of the enzyme s i t e to examine i f i n t e r a c t i o n s with these f e a t u r e s c o u l d go some way to p r o v i d i n g p l a u s i b l e s t r u c t u r e / a c t i v i t y relationships·


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Computer M o d e l l i n g Of Enzyme S i t e The c r y s t a l s t r u c t u r e s of the protoporphyrin IX and the l a n o s t e r o l nucleus were obtained d i r e c t l y by computer l i n k t o the C r y s t a l S t r u c t u r e Search and R e t r i e v a l (CSSR) l i b r a r y p r o v i d e d by the SERC on the Edinburgh Dec 10 Computer. The approach and i n t e r a c t i o n of the l a n o s t e r o l with the iron-oxene system was then modelled on the graphics screen. I d e a l l y , one might p r e f e r t o model some t r a n s i t i o n s t a t e f o r the r e a c t i o n of the oxene with the 14-methyl group. However, s i n c e the intermediary a l c o h o l could w e l l be an i n h i b i t o r f o r t h i s enzyme, the a l c o h o l ground s t a t e geometry was chosen with an iron-oxygen distance of 1.9A° and a carbon-oxygen-iron angle of 130°. These values are those obtained t h e o r e t i c a l l y by Loew f o r an i r o n car bene system ( 9 ) . There are now three s i n g l e bonds :- i r o n oxygen, oxygen-carbon and carbon-carbon about which the bound l a n o s t e r o l can e x e r c i s e i n t e r n a l r o t a t i o n s . The computer graphics f a c i l i t y c o u l d now be used to i n v e s t i g a t e the p o s s i b l e o r i e n t a t i o n s of the l a n o s t e r o l r e l a t i v e t o the porphyrin r i n g and c a l c u l a t e sumultaneously, by molecular mechanics, the t o t a l i n t e r n a l energy of i n t e r a c t i o n . F i g u r e 3, f o r example, places the l a n o s t e r o l so as the 3p hydroxyl p o l a r group l i e s over the propionate s i d e chains. To reduce the complexity of t h i s p i c t u r e one can now r e p l a c e the l a n o s t e r o l s t r u c t u r e by a surface canopy t o represent the extent of the hydrophobic s u b s t r a t e b i n d i n g s i t e . There i s a l s o the f a c i l i t y t o code t h i s surface t o s i g n i f y the e l e c t r o n i c p r o p e r t i e s of the substrates such as t h e i r e l e c t r o n d e n s i t y , e l e c t r o s t a t i c p o t e n t i a l , or HOMO/LUMO values. T h e o r e t i c a l work of t h i s type i s c u r r e n t l y suggesting q u i t e remarkable complementarity of e l e c t r o n p r o p e r t i e s between bound substrates and p r o t e i n b i n d i n g s i t e s . (10).

The Shapes of Bound

Antagonists

At the beginning of t h i s study the c r y s t a l s t r u c t u r e s of specimen antagonists were unknown. T h e o r e t i c a l l y the task of c a l c u l a t i n g a l l the low energy shapes f o r j u s t one molecule of i n t e r e s t i s c o n s i d e r a b l e . A complete g l o b a l minimisation f o r a t y p i c a l t r i a z o l e f u n g i c i d e eg. d i c l o b u t r a z o l with f i v e axes of r o t a t i o n , sampled at 30° i n t e r v a l s , i n v o l v e s a quarter of a m i l l i o n i n d i v i d u a l c a l c u l a t i o n s . Even with a l a r g e computer t h i s s e v e r e l y degades the q u a l i t y of c a l c u l a t i o n which can be done a t each p o i n t . A s t r a t e g y was used, t h e r e f o r e , which attempted t o reduce t h i s number t o a manageable l e v e l . Firstly,


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a crude molecular mechanics method based on Van der Waals contacts was used t o e l i m i n a t e from a f u l l conformational search a l l those shapes which are s t e r i c a l l y too high i n energy t o be considered f o r f u r t h e r a n a l y s i s . A l l the remaining s t e r i c minima were then analysed u s i n g semi-empirical molecular o r b i t a l methods and subject t o a s i n g l e f u l l a b - i n i t i o c a l c u l a t i o n t o o b t a i n the absolute minimum energy conformation. The c a l c u l a t e d s t r u c t u r e f o r R R - d i c l o b u t r a z o l , f o r example, agrees very w e l l with the c r y s t a l s t r u c t u r e as determined by Branch and Nowell (11). Good agreement between c a l c u l a t e d and x-ray was a l s o observed f o r the l e s s f u n g i c i d a l l y a c t i v e isomer (RR-) of t r i a d i m e n o l (12). The c a l c u l a t e d s t r u c t u r e f o r both d i c l o b u t r a z o l and t r i a d i m e n o l (Bayer) a l s o seemed c o n s i s t e n t with measured n.m.r. c o u p l i n g constants.

Hydrogen bonding. In s e t t i n g up these c a l c u l a t i o n s the hydroxyl proton was p l a c e d so as to be u n a v a i l a b l e f o r p o s s i b l e hydrogen bonding with the 2-N of the t r i a z o l e . T h e o r e t i c a l l y i t i s w e l l known t h a t e x t r a o r d i n a r y lengths have to be undertaken t o account f o r t h i s phenomenon p r o p e r l y , even f o r simple molecules. I t seemed more s e n s i b l e t o c a l c u l a t e the other energy c o n t r i b u t i o n t h e o r e t i c a l l y but to look f o r the formation of i n t e r n a l hydrogen bonding i n a d i l u t i o n experiment i n the i n f r a red. Intra-molecular hydrogen bonds are not observed i n the a v a i l a b l e c r y s t a l s t r u c t u r e s . I n f r a - r e d d i l u t i o n s t u d i e s show i n t e r n a l hydrogen bonds i n both d i c l o b u t r a z o l diastereoisomers but i n n e i t h e r the a c t i v e RS-, SR- or the l e s s a c t i v e RR-, SSt r i a d i m e n o l . In s h o r t , the presence of an i n t r a - m o l e c u l a r hydrogen bond between the hydroxyl group and the t r i a z o l e 2n i t r o g e n does not i n i t s e l f r e l a t e d i r e c t l y t o a c t i v i t y .

A Comparison of the Antagonists with the N a t u r a l Substrate As an example of the techniques, Figure 4 shows a comparison of the f u n g i c i d a l l y a c t i v e RR- d i c l o b u t r a z o l with the n a t u r a l s u b s t r a t e l a n o s t e r o l . The s t e r o l C-32 a l c o h o l i s c h e l a t e d t o the i r o n p o r p h y r i n . The three c e n t r a l f e a t u r e s of the model cytochrome P-450 can be e l u c i d a t e d . The hydrophobic b i n d i n g s i t e , the p o l a r r e g i o n between t h i s hydrophobic r e g i o n and the heme plane, and a common complexation t o the p o r p h y r i n i r o n .



F i g u r e 4. Comparison of d i c l o b u t r a z o l and l a n o s t e r o l i n P-450 a c t i v e s i t e .

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Three f e a t u r e s might be noted :


1·

The hydrophobic volumes :-

substrate b i n d i n g s i t e c o n s i s t s of three

a)

a r e g i o n corresponding to the l a n o s t e r o l A r i n g which terminates i n a p o l a r group, the 3p-hydroxyl. The i n h i b i t o r makes no use of t h i s space i n the enzyme cleft.

b)

a bulky volume occupied by the i n h i b i t o r t e r t i a r y b u t y l group and i n p a r t by the s t e r o l 6 c* -methyl· I t might be expected t h e r e f o r e that extension of the t - b u t y l group other than onto the A r i n g would reduce activity. In f a c t , in v i t r o a c t i v i t y has been shown t o be h i g h l y s e n s i t i v e t o the s i z e of the t h i s l i p o p h i l i c moiety·

c)

a deep c a v i t y i n t o which the l a n o s t e r o l molecule protudes i t s s i d e chain and the t r i a z o l e f u n g i c i d e p r o j e c t s the benzyl group. T h i s suggests t h a t the benzyl group c o u l d be g r e a t l y extended, which again agrees with in v i t r o data. The paraphenyl benzyl compound f o r example, shows good a c t i v i t y .

2.

The antagonist hydroxyl f u n c t i o n l i e s at a d i s t a n c e r e l a t i v e t o the heme group which would make i t a candidate f o r hydrogen bonding to e i t h e r a heme propionate s i d e chain or an e f f e c t o r a c y l group. More g e n e r a l l y the p o l a r hydroxyl and the t r i a z o l e 2-N c o u l d mark the i n t e r f a c e with p o l a r p r o t e i n , membrane p h o s p h o l i p i d head groups or s o l u t i o n . T h i s agrees very much with the model proposed by Peterson e t al. (8) f o r the 5-exo h y d r o x y l a t i o n of d and 1 camphor i n mammalian cytochrome P-450, and i s a l s o c o n s i s t e n t with the r e l a t i o n s h i p they noted from s t e r o i d metabolism by cytochrome P-450, between the p o s i t i o n hydroxylated and i t s r e l a t i o n t o a p o l a r f u n t i o n a l group.

3.

The t r i a z o l e group binds p e r p e n d i c u l a r l y to the heme group and gauche t o the i r o n - n i t r o g e n bonds i n the p o r p h y r i n plane.

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Structure

and A c t i v i t y

F i g u r e 5 now summarises what the model r e q u i r e s f o r J^i v i t r o a n t i 14-demethylase a c t i v i t y . A gauche conformation i s r e q u i r e d between the p o l a r function and the i r o n c h e l a t i n g group l e a d i n g to r e s t r i c t i o n s on the s u b s t i t u t i o n p a t t e r n at A, B, C and D. L o g i c a l l y t h i s leads t o the p o s s i b i l i t y of other s u b s t i t u t i o n p a t t e r n s which w i l l achieve t h i s gauche conformational requirement with groups of the r i g h t k i n d . Substitution at A and B, f o r example, l e a v i n g C and D as hydrogen y i e l d s a s e r i e s of compounds which have a l l the c o r r e c t requirements f o r a c t i v i t y and y e t are d i f f e r e n t i n o v e r a l l appearance. The new ICI f u n g i c i d e PP450 has orthofluorophenyl and parafluorophenyl i n these two p o s i t i o n s . Theoretical c a l c u l a t i o n s on PP450 give e x c e l l e n t agreement with a recent c r y s t a l s t r u c t u r e determination by Kendrick.and Owsten a t the P o l y t e c h n i c of North London, which again shows no i n t r a molecular hydrogen bonding but a gauche r e l a t i o n s h i p between the hydroxyl f u n c t i o n and t r i a z o l e .

lipophilic

A

Β

backbone

C

D

>

Fe A ,B :- rigid , limited

length

C ,D : - articulated , extended

Figure

5.

length

Model P-450 14-demethylase i n h i b i t o r .

11. M A RC HINGTON ET AL.


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