(2'-Nitrophenyl)-1,3,4-oxadiazoles - American Chemical Society

Chapter 19

2-(2'-Nitrophenyl)-1,3,4-oxadiazoles Synthesis and Biological Activity

Downloaded by STANFORD UNIV GREEN LIBR on June 23, 2012 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch019

Kirk A. Simmons, Blaik P. Halling, Robert J. Schmidt, and Debra A. Witkowski Agricultural Chemical Group, FMC Corporation, P.O. Box 8, Princeton, NJ 08543 2-(2'-Nitrophenyl)-1,3,4-oxadiazoles i d e n t i f i e d as herbicides through random screening, are described. Based upon whole plant symptoms, these compounds are thought to be i n h i b i t i n g plant growth i n a fashion analogous to paraquat. The development of both the in vitro and in vivo assays which have been used to drive the optimization of t h i s class of chemistry are described. The a c t i v i t y of t h i s chemical class i n these assays i s contrasted with appropriate herbicide standards. F i n a l l y , a QSAR model i s developed and presented. Many a g r i c u l t u r a l chemical companies supplement in-house discovery programs with compounds acquired from outside sources such as u n i v e r s i t i e s and cooperators. When leads arise from these sources the chemist i s confronted with optimization of an area with l i t t l e , i f any, knowledge of the mode of action or toxophore. We were recently confronted with such a compound i d e n t i f i e d through random screening, and would l i k e to present one of our approaches to optimization of a randomly derived lead. During the course of synthesis on an in-house discovery program, 2-(2'-nitrophenyl)-1,3,4-oxadiazole, 1, a synthetic intermediate, was found to be h e r b i c i d a l l y active i n our greenhouse screen. Because t h i s compound afforded control of a l l of the weeds i n our i n i t i a l screen and exhibited s e l e c t i v i t y towards corn and wheat i t was selected f o r optimization (Table I ) . Table I.

Greenhouse response of lead nitrophenyloxadiazole 1.

Grasses Pre Post

73 87

Grasses : Broadleaves:

% Control at 8 kq/ha Broadleaves Soybean Cotton

63 83

60 50

60 80

Corn Wheat

40 30

30 30

Johnsongrass, green f o x t a i l , barnyardgrass Velvetleaf, morningglory, bindweed

0097-6156/91/0443-0236$06.00/0 © 1991 American Chemical Society

In Synthesis and Chemistry of Agrochemicals II; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

19.

SIMMONS ET AL.

2-(2'-Niirophenyl)-l,3,4-oxadiazoles

237


Assay Development The f i r s t step of our optimization process was to i d e n t i f y laboratory assays, both invitro and in vivo, that were responsive to ^. The s e l e c t i o n of the assays was assisted by v i s u a l recognition of the symptoms induced by the herbicide candidate i n a whole plant system. Greenhouse grown plants treated with 2-(2' -nitrophenyl)1,3,4-oxadiazole showed a rapid onset of contact i n j u r y symptoms that included bleaching and desiccation of the f o l i a g e . The syndrome was s i m i l a r to e f f e c t s t y p i c a l l y seen with photosynthetic i n h i b i t o r s such as the t r i a z i n e s and substituted ureas and with electron acceptors such as the b i p y r i d i l i u m herbicides diquat and paraquat. 2-(2'-Nitrophenyl)-1,3,4-oxadiazole had l i t t l e e f f e c t on the l i g h t dependent reduction of 2 6-dichlorophenolindophenol (DCPIP) by i s o l a t e d pea thylakoids i n d i c a t i n g that i t s h e r b i c i d a l a c t i v i t y was not due to i n h i b i t i o n of photosynthetic electron transport. However, 1^ d i d have a s i g n i f i c a n t e f f e c t on variable photosystem II chlorophyll fluorescence both i n i s o l a t e d pea chloroplasts and intact cucumber cotyledons. 2-(2'-Nitrophenyl)1,3,4-oxadiazole at micromolar concentrations dramatically reduced the magnitude of the d i f f e r e n t i a l between the point of i n f l e c t i o n (I) and peak maximum (P) on the fluorescence transients r e l a t i v e to the controls. This e f f e c t i s s i m i l a r to that observed for treatments with paraquat and i s a t t r i b u t e d to i t s a b i l i t y to function as an autooxidizing acceptor of PSI reduction p o t e n t i a l . By serving as an electron shunt, the paraquat treatments prevent the endogenous electron c a r r i e r s from ever becoming f u l l y reduced, thus lowering the fluorescence y i e l d . In contrast, electron transport i n h i b i t o r s such as atrazine block access of PS II to the endogenous redox c a r r i e r s and so greatly stimulates the l e v e l of variable fluorescence. (1) This general behavior i s exemplified i n Figure 1. f

The a b i l i t y of 2-(2'-nitrophenyl)-1,3,4-oxadiazole to serve as a photosynthetic electron acceptor was confirmed by i t s s i g n i f i c a n t stimulation of the rate of oxygen consumption (the Mehler reaction) i n i s o l a t e d chloroplasts s i m i l a r to paraquat. Therefore, the results of the fluorescence and electron transport assays suggest that the h e r b i c i d a l injury induced i n whole plants by 1. i s probably due to a mechanism of phytotoxicity s i m i l a r to bipyridylium herbicides; that i s , l i p i d peroxidation of c e l l membranes i n i t i a t e d through excited oxygen species generated by diversion of electrons from the endogenous electron transport chains. (2) The dose dependent reduction of the fluorescence l e v e l of chlorophyll i n i s o l a t e d pea chloroplast suspensions forms the basis of an invitro assay which was used to optimize the b i o l o g i c a l potency of these compounds. The e f f e c t i n excised cucumber cotyledons forms the basis of an invivo assay. B i o l o g i c a l Testing Plant Material. Cucumber (Cucumis sativus L. c u l t i v a r 'Wisconsin SMR 18') and pea seed (Pisum sativum L. c u l t i v a r " L i t t l e Marvel') were germinated and grown i n vermiculite i r r i g a t e d with a commercial (9-45-15) f e r t i l i z e r . Cucumber seedlings were grown at



238

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

Oxadiazole \ΟμΜ

5000 Time Time Figure 1. Effects of Various I n h i b i t o r s on Chlorophyll Fluorescence


19. SIMMONS ET AL

239

2'(2'-Nitwphenyl)-l,3,4-oxaaVazote

25°C and 80-90% r e l a t i v e h u m i d i t y i n a d a r k i n c u b a t i o n chamber, f i v e days a f t e r p l a n t i n g t h e s e e d l i n g s were g r e e n e d under 15 h o u r s o f c o n t i n u o u s i l l u m i n a t i o n a t a measured i n t e n s i t y o f 150 uE m~^ s" (PAR) p r o v i d e d b y f o u r GE F20T12-CW f l u o r e s c e n t lamps. Pea s e e d l i n g s were grown a t 20°C and 80-90% r e l a t i v e h u m i d i t y i n a growth chamber under a 14/10 hour ( d a y / n i g h t ) l i g h t regime. Light was s u p p l i e d b y two 400 W sodium h a l i d e lamps (Westinghouse LU400) i n c o m b i n a t i o n w i t h two 400 W mercury v a p o r lamps (Westinghouse MVR 400/U) which d e l i v e r e d a measured i n t e n s i t y o f 300-350 uE m~ s (PAR). One day p r i o r t o i s o l a t i o n o f c h l o r o p l a s t s , t h e pea s e e d l i n g s were c o v e r e d w i t h a d a r k c l o t h t o reduce s t a r c h l e v e l s . 1


2

_

1

Chloroplast Isolation. I n t a c t c h l o r o p l a s t s were i s o l a t e d f r o m pea l e a v e s d i s r u p t e d i n a P o l y t r o n homogenizer as d e s c r i b e d by Leegood and Walker. (3) The c h l o r o p l a s t s were r e s u s p e n d e d and h e l d on i c e i n a b u f f e r c o n s i s t i n g o f 0.2 M m a n n i t o l , 450 mM T r i c i n e - N a O H (pH 8.0), 2 mM M g C l f and 10 mM K P i . 2

Electron Transport. The e f f e c t o f t e s t compounds on e l e c t r o n t r a n s p o r t i n i s o l a t e d c h l o r o p l a s t s was measured b y oxygen u t i l i z a t i o n on a C l a r k - t y p e oxygen e l e c t r o d e and by s p e c t r o p h o t o m e t r i c d e t e r m i n a t i o n s o f DCPIP r e d u c t i o n as d e s c r i b e d by Brewer e t a l . (£) Chlorophyll Fluorescence. The v a r i a b l e f l u o r e s c e n c e o f p h o t o s y s t e m I I c h l o r o p h y l l was m o n i t o r e d w i t h an SF-20 P l a n t P r o d u c t i v i t y F l u o r o m e t e r ( R i c h a r d B r a n c k e r R e s e a r c h L t d . , Canada). The e f f e c t o f h e r b i c i d e t r e a t m e n t s on t h e i n c r e a s e i n f l u o r e s c e n c e between t h e i n f l e c t i o n (I) and peak (P) [as d e f i n e d b y t h e c o n v e n t i o n s o f Mohanty and G o v i n d j e e (_1) ] was d e t e r m i n e d from t h e t r a c i n g s made on a s t r i p c h a r t r e c o r d e r and e x p r e s s e d as a p e r c e n t o f t h e s i g n a l from u n t r e a t e d c o n t r o l s . I s o l a t e d c h l o r o p l a s t s were a s s a y e d i n t h e r e s u s p e n s i o n b u f f e r i n a 1 cm f l u o r e s c e n c e c u v e t t e a t a f i n a l c o n c e n t r a t i o n o f 130 μgs C h l / m l ; measurements were made w i t h t h e probe p l a c e d d i r e c t l y a g a i n s t t h e s u r f a c e o f t h e c u v e t t e . H e r b i c i d e s were added from a c e t o n e s t o c k s t o a f i n a l s o l v e n t c o n c e n t r a t i o n o f 0.1% ( v / v ) . Cucumber c o t y l e d o n s were h a r v e s t e d from t h e g r e e n e d s e e d l i n g s b y hand and r i n s e d t h r e e t i m e s i n 20 ml volumes o f 1 mM C a C l and 2.0 mM K P i (pH 6.5) . The c o t y l e d o n s were i n c u b a t e d by f l o a t i n g a b a x i a l s i d e up i n 3 mis o f t h e same b u f f e r i n 35 mm p e t r i d i s h e s . C o n t r o l s were t r e a t e d w i t h i d e n t i c a l concentrations o f acetone. The t r e a t e d c o t y l e d o n s were h e l d i n t h e d a r k f o r s i x h o u r s t o a l l o w uptake o f t h e h e r b i c i d e s , t h e f l o a t i n g c o t y l e d o n s were s w i r l e d t h r o u g h o u t t h e i n c u b a t i o n p e r i o d by s h a k i n g t h e p e t r i d i s h e s a t 90 rpm on t h e s u r f a c e o f a g y r o t o r y s h a k e r . A t t h e e n d o f t h e uptake p e r i o d , t h e c o t y l e d o n s were removed f r o m t h e t r e a t m e n t s o l u t i o n and c h l o r o p h y l l f l u o r e s c e n c e was measured by p l a c i n g t h e probe a g a i n s t t h e a b a x i a l s u r f a c e . 2

Lead

Analysis

The s e c o n d s t e p i n t h e o p t i m i z a t i o n p r o c e s s i n v o l v e d t h e i d e n t i f i c a t i o n o f p o s i t i o n s i n t h e l e a d t h a t c o u l d be s u b s t i t u t e d



240


without loss of a c t i v i t y or with substantial increases i n a c t i v i t y . This involved the synthesis of analogs of 1_ which were substituted with chlorine and/or methyl i n a l l nonequivalent positions. These compounds were tested i n the invitro assay, an assay that i s devoid of uptake and metabolism b a r r i e r s , so as to measure t h e i r true i n t r i n s i c potency. From the observed responses (Table II) i t was apparent that substitution i n the 3-position of the aromatic ring resulted i n a general loss of a c t i v i t y . The importance of the other positions was not so obvious and probes i n the 6-position never yielded to synthesis (intermediates f a i l e d to ring close). Of the positions probed, the 5'-position appeared to be a reasonable place to start since substitution there afforded compounds that were equally active or more active than the parent compound.

I n i t i a l Set Design A set of compounds substituted i n the 5'-position was designed to explore the physiochemical parameter space represented by π, F, R and MR. This i n i t i a l compound set was r e s t r i c t e d to cover these minimum parameters i n the interest of e f f i c i e n c y . Later, i f the l e v e l of a c t i v i t y warranted i t , the i n i t i a l set could be expanded to more f u l l y explore parameter space. In order to adequately cover the chosen parameter space, a 2 f a c t o r i a l design was u t i l i z e d . (5.) The 16 required compounds were selected v i a c l u s t e r analysis from our substituent physical-chemical database. (j5) Marker points which represented the f a c t o r i a l design were included i n the data set p r i o r to c l u s t e r i n g . (2) In t h i s way substituents which best represented the f a c t o r i a l design were those that were n

Table I I .

Invitro potency of i n i t i a l substitution probe set f o r 1,.

Compound

Y

χ

1 2

H 3-CH

3

3-C1

4

4-C1

5

5-CH3

6 7

H H

3

H H H H

Chloroplast P*sn

5.8 4.6

4.9 6.0

H CH3

5.9 5.9

Cl

6.0


19. SIMMONS ET AL.

2-(2'-NUwphenyl)-l,3,4-oxudiaz0les

241

closest to these marker points i n the output from the c l u s t e r i n g program. The selected compounds, presented i n Table I I I , were confirmed as adequately representing the chosen parameter space using factor analysis. (8_) In t h i s method an orthogonally arranged set w i l l a f f o r d as many factors (Eigenvectors) as there are properties represented. While the set a c t u a l l y chosen afforded only three factors, i t s u f f i c e d to represent a s y n t h e t i c a l l y accessible set (Table IV).

F a c t o r i a l l y designed analog set f o r 1.


Table I I I .

Phvsiochemical Data Compound Number

Χ

7

H CH CI

8

C

1

6

3

H

2 5

iPr

9 10 11 12

C F

3 CC1 NH2

13 14 15 16 17 18 19

3

CC H NHnC H9 NHC H 3

5

4

2

5

OCH3 NHCH3 SCH3

NHCONHC H ; OnC H OnC H 2

20 21

5

1;L

3

7

5

High Low

Table IV.

π

F

R

0. 00 0. 56 0. 71 1. 02 1. 53 0. 88 1. 31 - 1 . 23 1. 14 1. 45 0. 08 - 0 . 02 - 0 . 47 0. 61

- 0 - 50 2.,04 1.,05

0 .00 -0 .04 0 .41 -0 .05 -0 .05 0 .38 0 .31 0 .02 -0 .03 -0 .28 -0 .11 0 .26 -0 .11 0 .20 0 .14 0 .25 0 .22

0. 00 - 0 . 13 - 0 . 15 - 0 . 10 - 0 . 10 0. 19 0. 05 - 0 . 68 - 0 . 19 - 0 . 25 - 0 . 51 - 0 . 51 - 0 . 74 - 0 . 18 - 0 . 39 - 0 . ,57 - 0 . ,45

2.,04 - 1 . ,23

0 .41 -0 .28

0.,19 - 0 . ,74

MR 1,.03 5,.65

6,.03 10, .30

14,.98 5,.02 20 .12 .5 .42 13 .53

24 .26 14 .98 7 .87 10 .33

13 .82 23 .19 26 .26 17 .06 26 .26 1 .03

Factor analysis of analog set for 1. Factor

Factor

Factor

0.00 0.00

0. 00 0. 63 0. 95 0. 00

0 .00 0 .00 0 .00 0 .99

1.42

1. 35

1 .01

MR π R F

0.95

Eigen values

0.71


242


Synthesis


The target compounds were synthesized v i a the standard procedures outlined i n Scheme I. Acylation of the arylhydrazide, which was obtained from the ester through reaction with hydrazine i n ethanol, occurred smoothly with the appropriate acid chloride i n toluene at reflux to a f f o r d the desired compounds i n y i e l d s of 50-95%. These intermediates could be c y c l i z e d by two procedures. (9) For the targets where R was not an amine or substituted amine, c y c l i z a t i o n occurred smoothly i n polyphosphoric acid. For those targets where R was an amine or substituted amine, c y c l i z a t i o n occurred reasonably well i n refluxing phosphorous oxychloride. Scheme I. Synthesis of Substituted -2'(2'-Nitrophenyl)-1,3,4-oxa diazoles Ο

R

=

N

R

,

2

100 C 8 hr 50-85%

Since these compounds were functioning as photosystem I electron acceptors, and the need f o r a proper reduction p o t e n t i a l i s well documented, reduction potentials were measured f o r these targets. Reduction potentials were determined i n 50% ethanol/water with a dropping mercury electrode and are reported r e l a t i v e to the standard calomel electrode. (We are indebted to Manny Alvarez of FMC Corporation f o r these determinations.) Without exception, the reduction potentials were i n the range expected f o r compounds serving as photosystem I electron acceptors (-300 to -714 mV) (Table V). The set of compounds were then tested i n the i s o l a t e d chloroplast and excised cotyledon assays. In both assays the most potent of the oxadiazoles were approaching the l e v e l of a c t i v i t y seen with paraquat (Table V). These b i o l o g i c a l data were analyzed v i a multiple l i n e a r regression against the substituent parameters π, F, R, MR, and the E /2 values. For the chloroplast data no s i g n i f i c a n t c o r r e l a t i o n between a c t i v i t y and π, F, R and MR could be found ( a l l r values < 0.03). However, a reasonably good c o r r e l a t i o n existed between a c t i v i t y and the reduction p o t e n t i a l for the n i t r o group, that i s compounds with the most e a s i l y reduced Ν0 were i n fact the most active electron acceptors (Figure 2 ) . However, t h i s dependence on reduction potential was no longer seen when attempts were made to s i m i l a r l y correlate the observed a c t i v i t y i n the excised cotyledons with these same parameters. In fact, the best equation showed a parabolic dependence of b i o l o g i c a l a c t i v i t y on the π value of the substituent at the 5'-position (Figure 3 ) . In t h i s analysis the 5'-CI analog, 1_, was excluded since nucleophilic displacements of chlorine i n t h i s position are known to occur f a i r l y e a s i l y (JL0) and the low l e v e l of a c t i v i t y f o r t h i s analog might be due to f a c i l e metabolism. This analysis suggested that the overriding e f f e c t operating i n the in vivo assay 1

2

2


19. SIMMONS ET AL.

2-(2'-Nitrophenyl)-l,3,4-oxadiazoles

243

was uptake and transport of the herbicide to the active s i t e . Presumably, once at the active s i t e , b i o l o g i c a l a c t i v i t y would be dependent upon the reduction p o t e n t i a l of the n i t r o group based upon the response observed i n the invitro assay.


Conclusion We were not the f i r s t to observe reduction p o t e n t i a l dependent b i o l o g i c a l a c t i v i t y of nitrobenzenes. In 1984 G i l l e s Klopman reported on the mutagenicity of nitroarenes. (11) He observed a d i r e c t c o r r e l a t i o n between mutagenicity i n Salmonella cyphimurium strains and the reduction p o t e n t i a l of the n i t r o group. For the nitroarenes studied, there was an excellent c o r r e l a t i o n , s p e c i f i c a l l y , the more e a s i l y reduced nitroarenes were the more mutagenic. Table V.

B i o l o g i c a l a c t i v i t i e s of 2-(2'-nitrophenyl)-1,3,4oxadiazoles

Chloroplast pl

Compound

R

9 19 20 12 1 6 13 17 8 11 21 18 10 14 7 16 15

iPr NHCONHC H OnC H

5 0

2

5

N H

l:L

2

Η CH CC H NHCH 3

3

5

3

C

H

2 5 cci 3

OnC H SCH 3

7

3

C F

3

NHnC H CI OCH NHC H 4

g

3

2

5

Paraquat

5

Cotyledon pl 0 5

1

E /

2

5. 6 5. 6 5. 6 5.,7 5.,8 5..9 5.,9 5..9 6..0 6..0 6..0 6,.1 6,.2 6,.3 6.3 6.4 6.6

5. 6 5. 0 5.,0 4.,5 5.,4 5.,7 5.,7 5..0 5..9 5..4 5..3 5,.6 5,.7 4,.9 5,.8 5 .4

-610 -560 -560 -520 -560 -590 -500 -460 -460 -600 -500 -450 -480 -430 -480 -470

6.8

6.3

-460

-, .-


mV

< )


244


The reduction p o t e n t i a l of n i t r o groups* i n substituted nitrobenzenes i s well correlated to the e l e c t r o n i c c h a r a c t e r i s t i c s of the substituents. (12) In general, the more electron withdrawing i s the substituent, the more e a s i l y reduced i s the r e s u l t i n g nitrobenzene. If the n i t r o group i s twice ortho substituted, as i n compounds 2 and 3,, the reduction p o t e n t i a l i s s h i f t e d to outside the expected range f o r PSI electron acceptors ( t y p i c a l l y -300 to -714 mV), hence the poor potency of these compounds i s explained. In 1986 Claus Kramer reported on the a l g i c i d a l a c t i v i t y of simple nitrobenzenes against C h l o r e l l a v u l g a r i s . (13) For these substituted nitrobenzenes we observed through our analysis of the reported b i o l o g i c a l a c t i v i t y a l i n e a r relationship between a l g i c i d a l a c t i v i t y and an e l e c t r o n i c parameter.

β.8

T

η « 16

r - 0.67 Figure 2»

s - 0.24

F «

Chloroplast ϊ>Ι

ςη

11.2

vs E l / 2


245

19. SIMMONS ET AL. 2'(2'Nitwphenyl)'l 3 4^xaJiazoles y

Equation 1

- l o g ( L C Q ) « 3.0 F - 2.9 B l + 7.6 s=0.35

F=18.2

n=8

- l o g (LC50) - 2.3 σ + 3.5 r=0.96


ortho substituted

5

r=0.94

Equation 2

f

s=0.20

F=93

meta substituted n=ll

The more electron withdrawing analogs showed the highest l e v e l of a l g i c i d a l a c t i v i t y . The implication i s that the a l g i c i d a l a c t i v i t y involves n i t r o group reduction, and s p e c i f i c a l l y , more e a s i l y reduced compounds are the more a c t i v e . Since nitroarenes seem to be able to e l i c i t a b i o l o g i c a l response i n several systems (bacteria, algae, plants) and the potency of the response i s uniformly dependent on the ease of reduction of the n i t r o group, the 2-(2'-nitrophenyl)-1,3,4oxadiazoles were dropped from further consideration, since they would not be expected to exhibit s e l e c t i v e a c t i v i t y .

1*50 c ο t

5.9

τ

5/7

+

•

•

5.5

/on

y

5.3

e d ο η

5.1

1

4.9

+

4.7

+

• (5*-Cl)

"Η 1 1 -l.O O.O

4.5

l.O

1

2 . 0

PI pl η - 15

5 0

= -0.32π^ + 0.49π + 5.47 r - 0.87

s = 0.20

F = 19.4

Figure 3. Cotyledon p l ^ vs w (5'-position)


246

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS II


Literature Cited 1. Mohanty, P. Govindjee, Plant Biochem J , 1974, 1, 78-106. 2. Black, C . C . , Effects of herbicides on photosynthesis, In SO Duke, ed, Weed Physiology Volume II Herbicide Physiology. CRC Press: Boca Raton, Florida, 1985, p 1-36. 3. Leegood, R.C., Walker, D.A., Chloroplasts, In JL Hall, AL Moore, eds, Isolation of Membranes and Organelles from Plant Cells; Academic Press: New York, 1983, p 185-210. 4. Brewer, P . E . , Arntzen, C . J . , Slife, F.W., Weed Sci, 1979, 27, 300-308. 5. Austel, V . , Eur J Med Chem Chim Ther, 1982, 17, 9. 6. Hansch, C. and Unger, S., J Med Chem, 1973, 16, 1217. 7. Austel, V., Eur J Med Chem Chim Ther, 1982, 17, 339. 8. Martin, Y.C. and Panas, H.N., J Med Chem, 1979, 22, 784. 9. Behr, L . C . , in The Chemistry of Heterocyclic Compounds; Wiley, R., Ed.; Interscience Publishers: New York, 1962; Vol. 17, p 263. 10. Potts, K.T. and R.M. Huseby, J Org Chem, 1966, 31, 3528. 11. Klopman, G., Mutation Research, 1984, 126, 139. 12. Zuman, P., Substituent Effects in Organic Polarography, Plenum Press: 1967, p 114. 13. Kramer, C . , Biochem Physiol Pflanzen, 1986, 181, 411. Received December 15, 1989


(2'-Nitrophenyl)-1,3,4-oxadiazoles - American Chemical Society

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