Chapter 12
Quantitative Structure—Activity Relationship Study of Aromatic Trifluoromethyl Ketones In Vitro Inhibitors of Insect Juvenile Hormone Esterase 2
2
András Székács1,2, Barna Bordás , György Matolcsy , and Bruce D. Hammock Downloaded by EAST CAROLINA UNIV on November 13, 2016 | http://pubs.acs.org Publication Date: November 14, 1989 | doi: 10.1021/bk-1989-0413.ch012
1
2
1Department of Entomology and Department of Environmental Toxicology, University of California, Davis, CA 95616 Plant Protection Institute of the Hungarian Academy of Sciences, Budapest, Post Office Box 102, 1525 Hungary The in vitro inhibitory activity of 41 aryl substituted 3-phenyl-1,1,1-trifluoro-2-propanones against insect juvenile hormone esterase has been related to various electronic, hydrophobic and steric parameters using linear stepwise regression analysis. The pI50 values were found to be significantly correlated to the total l i p o p h i l i c i t y of the molecule and the corrected molar volume (partial molar refractivity) of the substituents at the different substituent positions. Trifluoromethyl ketones (TFKs) have been found to inhibit various hydrolytic enzymes (1-6), Series of aliphatic and aromatic trifluoromethyl ketone sulfides (7-10) proved to be exceptionally powerful inhibitors of insect juvenile hormone esterase (JHE), an enzyme of key importance in insect metamorphosis. The trifluoroketone moiety is believed to behave as a transition state mimic (11.12) of juvenile hormones (JHs), substrates of the enzyme. The f$ sulfur atom is anticipated to mimic the a-fi double bond present in a l l natural JH substrates. In earlier structureactivity relationship (SAR) studies (7.11) clear correlation was found among the molar Iso values of these compounds against JHE and the calculated molar refractivity of the inhibitors. Examining 18 substituted 3-phenylthio-l,1,1-trifluoro-2propanones, regression equations were obtained between the inhibitory activities and the Hammett (a), Taft (E ) steric and Hansch (it) hydrophobicity constants (11). In the nope of increasing the significance of these equations and to better distinguish between the importance of various substituent positions, several new compounds of the related structure were synthesized, a much larger set of substituent parameters was applied, and instead of the arbitrary choice of these values, the variables were selected into the equations by a more sophisticated tool, linear stepwise regression analysis. OW7-6156/89/0413- 10' 3 .0x10" > 10" > 10' > 10"
J H I I I was u s e d as a s u b s t r a t e f o r JHE from Trichoplusia (cabbage l o o p e r ) . D a t a from Hammock et al. ( 2 ) .
8
6
6
7
9
9
8
6
6
6
6
6
4
6
8
4
4
8
4
4
4
ni
As i t has been p o i n t e d o u t b y T o p l i s s and Edwards ( 3 7 ) , t h e h i g h e r t h e number o f t h e p o s s i b l e i n d e p e n d e n t v a r i a b l e s t o c o n s i d e r i n a QSAR s t u d y , t h e more p r o b a b l e t h e o c c u r r e n c e o f chance c o r r e l a t i o n s . T h e r e f o r e , i n o r d e r t o e n t e r a l a r g e number
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
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12.
SZEKACS E T A L .
Aromatic Trifluoromethyl Ketones
173
o f p a r a m e t e r s i n t o t h e SRA, t h e number o f compounds needed t o be increased. Thus, 23 more compounds o f S t r u c t u r e A were synthesized. T h i r t y - f i v e compounds p r o v i d e d e x a c t n u m e r i c a l I s o v a l u e s w h i c h c o u l d be u s e d i n t h e c o m p u t a t i o n s . T h e r e a r e 15 v a r i o u s substituents appearing i n f i v e p o s s i b l e substituent p o s i t i o n s (numbered I-V i n S t r u c t u r e A) i n t h e s e compounds. I n a program, w r i t t e n i n BASIC, a d e s c r i p t o r m a t r i x was c r e a t e d b y c o p y i n g t h e a p p r o p r i a t e s u b s t i t u e n t parameters i n t o the corresponding s u b s t i t u t i o n position-compartments o f the d e s c r i p t o r matrix i f the a c t u a l s u b s t i t u e n t i s present i n the molecule i n the a c t u a l position. From t h e Hammett c o n s t a n t s , t h e e q u a t i o n O - a was assumed (31,28,39), thus a was a p p l i e d f o r p o s i t i o n s I , I I I and V, and a f o r p o s i t i o n s I I and IV. T h e r e f o r e , 10 p a r a m e t e r s were used t o enter the d e s c r i p t o r m a t r i x f o r each s u b s t i t u e n t p o s i t i o n . Two a d d i t i o n a l p a r a m e t e r s , t h e t o t a l l i p o p h i l i c i t y [JV] and i t s s q u a r e v a l u e [ ( J V ) ] were a l s o c a l c u l a t e d f o r each compound and were added t o the d a t a - s e t . F i v e p a r a m e t e r s i n t h e d a t a - s e t were f o u n d t o be unchanged f o r a l l 35 compounds and removed from t h e m a t r i x . These p a r a m e t e r s a r e H-DO f o r p o s i t i o n s I I , IV and V and H-AC f o r p o s i t i o n s IV and V. A f t e r t h e redundant elements h a d been removed, t h e r e s u l t i n g [35x47] m a t r i x was c o r r e l a t e d t o t h e v e c t o r of the b i o l o g i c a l a c t i v i t y . To p e r f o r m t h e l i n e a r s t e p w i s e r e g r e s s i o n a n a l y s i s , t h e STEPWISE p r o c e d u r e o f t h e SAS s t a t i s t i c a l package (40) and BASIC programs were u s e d . Q
a
2
Running SRA on the f u l l
sample gave t h e f o l l o w i n g
- p l s o - 0.910(±0.390) H-DOj + 0.153(10.046) MR - 1.653(10.720) a + 0.088(10.020) MR + 1.561(10.900) a" + 0.169(10.084) MR + 0.712(10.143) + 4.885 n - 35 r - 0.888 s - 0.51
equation:
n
m
y
(2) F - 14.41
( I n t h e e q u a t i o n s , n r e p r e s e n t s t h e number o f datum p o i n t s u s e d t o d e r i v e the equation, r i s the m u l t i p l e c o r r e l a t i o n c o e f f i c i e n t , s i s t h e s t a n d a r d d e v i a t i o n from r e g r e s s i o n , F i s t h e F s t a t i s t i c f o r v a r i a n c e o f each a d d i t i o n a l v a r i a b l e , t h e v a l u e s i n parentheses a f t e r the equation c o e f f i c i e n t s a r e f o r c o n s t r u c t i o n o f c o n f i d e n c e i n t e r v a l s and t h e Roman numbers i n s u b s c r i p t r e f e r to the s u b s t i t u e n t p o s i t i o n . ) The p a r t i a l r v a l u e i s t h e h i g h e s t f o r Jn and M R (0.739 and 0.325, r e s p e c t i v e l y ) and does n o t e x c e e d 0.183 f o r any o f the o t h e r v a r i a b l e s i n the e q u a t i o n . T h i s means t h a t t h e t o t a l l i p o p h i l i c i t y a l o n e e x p l a i n s o v e r 54% o f t h e t o t a l v a r i a n c e ( F i g u r e 1 ) . The p r e d i c t e d p l s o v a l u e s and t h e s t a n d a r d e r r o r o f the p r e d i c t i o n a r e l i s t e d i n T a b l e I I . and shown i n F i g u r e 2. The f a c t t h a t a has o p p o s i t e s i g n s i n p o s i t i o n s I I and IV i s seemingly c o n t r a d i c t o r y , but the weight o f a and MR i s v e r y low i n t h e e q u a t i o n , t h e r e f o r e t h e y c a n be o m i t t e d r e s u l t i n g i n E q u a t i o n 3. m
m
mIV
y
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
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174 PROBING BIOACTIVE MECHANISMS
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
Downloaded by EAST CAROLINA UNIV on November 13, 2016 | http://pubs.acs.org Publication Date: November 14, 1989 | doi: 10.1021/bk-1989-0413.ch012
12.
SZEKACS E T A L .
Aromatic Trifluoromethyl Ketones
~i
5
1
1
1
i
6
7
8
9
pi
5
0
calculated
F i g u r e 2. C o r r e l a t i o n between the c a l c u l a t e d and plso values.
measured
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
176
PROBING BIOACTIVE MECHANISMS
-pl
n - 35
5 0
- 0.796(10.412) H-DOj + 0.108(10.046) - 1.292(10.702) a + 0.842(10.140) $ r - 0.862
+ 0.071(10.020) + 5.220 s - 0.54
MR MR
n
m
(3) F - 16.79
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Requirements f o r good a c t i v i t y ( r a n k e d a c c o r d i n g t h e absolute value o f the corresponding path c o e f f i c i e n t s given i n brackets): L a r g e o v e r a l l h y d r o p h o b i c i t y (£*) [0.626]; i n p o s i t i o n I I I ; l a r g e volume (MR) [0.368]; in position I I : l a r g e volume (MR) [0.263]; in position I I : electron-donating substituent [-0.194]; in position I: proton-donor s u b s t i t u e n t [0,189]. Compounds 9, 17, 22 and 23 a r e o u t l i e r s because t h e r e s i d u a l o f t h e i r measured and c a l c u l a t e d p i 5 0 v a l u e d e v i a t e most. O m i s s i o n o f t h e f o u r o u t l i e r s i n t r o d u c e d more p a r a m e t e r s and s i g n i f i c a n t l y improved t h e s t a t i s t i c s o f t h e new e q u a t i o n , E q u a t i o n 4. - p l s o - 0.960(10.296) H-D0 + 0.165(10.034) M R - 1.633(10.529) a - 0.608(10.300) * + 0.117(10.026) M R + 0.115(10.064)MR + 0.984(10.141) J > + 4.803 n - 31 r - 0.943 s - 0.38 x
m I I
n
m
m
y
(4) F - 26.42
Requirements f o r good a c t i v i t y ( r a n k e d a c c o r d i n g t h e absolute value o f the corresponding path c o e f f i c i e n t s given i n brackets): L a r g e o v e r a l l h y d r o p h o b i c i t y (JV) [0.754]; i n p o s i t i o n I I I : l a r g e volume (MR) [0.627]: in position I I : l a r g e volume (MR) [0.403]: i n position I I I : hydrophilic substituent [-0.341]; in position I I : electron-donating substituent [-0.252]; in position I: proton-donor s u b s t i t u e n t [0.189]; i n p o s i t i o n V: l a r g e volume (MR) [0.138]. The p a r t i a l r v a l u e i s s t i l l t h e h i g h e s t f o r Jn and M R , the t o t a l l i p o p h i l i c i t y a l o n e e x p l a i n s o v e r 60% o f t h e t o t a l v a r i a n c e and i t i s a l s o v i s i b l e t h a t i t has a p a r t i c u l a r i m p o r t a n c e i n t h e para p o s i t i o n . S i n c e o has a n e g a t i v e c o e f f i c i e n t , e l e c t r o n donating substituents are p r e f e r r e d i n the meta p o s i t i o n . MR has a l m o s t t h e same c o e f f i c i e n t s f o r p o s i t i o n s I I , I I I and V, t h e l a t e s t , however, h a s t h e l o w e s t a b s o l u t e p a t h c o e f f i c i e n t [0.138]. T h e r e f o r e , compounds 3 , 4 - d i s u b s t i t u t e d w i t h l i p o p h i l i c s u b s t i t u e n t s a r e e x p e c t e d t o be h i g h l y a c t i v e . m
m
Test o f S i g n i f i c a n c e A way t o a v o i d chance c o r r e l a t i o n s i s t o i n c r e a s e t h e s i z e o f t h e sample. The p a r t i a l F v a l u e , however, i s a l s o i n f o r m a t i v e , i n
Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
12.
Aromatic TriJIuoromethyl Ketones
SZEKACS ET AL.
Table I I .
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compd. p l s o number obs.
1 2 3 4 5 6 7 8 9
5..09 6,.17 6..06 6,.39 5,.68 6,.40 5,.89 5,.08 7..64 7,.11 7,.70 7,.50 5,.91 4,.97 5,.37 6,.89 6..96 6,.04
d
10 11 12 13 14 15 16 17 18
d
a
b
0
d
O b s e r v e d and p r e d i c t e d p l s o v a l u e s s t a t i s t i c s of prediction
b
plso* predicted
pIso pred.
± ±
5,.33 5..90 8.,39 6,.63 6,.21° 5..87 6..28 5,.43 7.,09 6,.54 6,.77° 8..58 5,.39° 4,.79 5..74 6,.09 5..91 6,.89
5..31 5..92 6..48 6..61 5..81 6..00 6,.25 5..40 6.,90 7,.17 7..21 7..84 5,.64 5..53 5..71 6..53 6.,11 6..51
±
± ± ± ± +
± ±
± ± ±
± ± ± ± ±
0. 16 0. 27 0.,27 0.,13 0.,15 0.,22 0..12 0.,15 0. 30 0..38 0.,24 0..31 0..28 0.,28 0..14 0.,22 0. 12 0..13
c
c
compd. p l s o number obs.
19 20 21 22 23 24 25 26 27 28 29 30 31 32 34 35 38
d
d
6..77 6..94 7..95 5..75 5.,54 6, .47 8..13 8..52 7..89 5,.70 5..89 5..89 5,.60 5,.22 5,.16 7,.05 7..52
177 and
a
b
pIso predicted
pIso pred.
6..10 ± 0..21 6..89 ± 0..35 7.,34 ± 0. 21 6,,82 ± 0.,22 6..03 ± 0.,16 6,.40 ± 0..21 8,.36 ± 0,.29 8,.76 ± 0,.31 7..83 ± 0, 23 5..29 ± 0,.16 6..14 ± 0..26 5.,90 + 0..18 5..83 ± 0,,26 4,.99 + 0..22 5..48 ± 0..40 6,.72 ± 0,.28 7..19 ± 0.,40
4..40° 6..06° 6.,70 8.,20 6,,31 6,.38 8,.47 8,.89 7.,82 5,.20 6..23 5..90 6.,41 5,.90° 3,.46° 5 .42 6,.19 c
c
P r e d i c t i o n by E q u a t i o n 2. P r e d i c t i o n by the " l e a v e one o u t " method. Parameters, n o t i n v o l v e d i n E q u a t i o n 2, were i n t r o d u c e d i n t o the " l e a v e one o u t " e q u a t i o n a t r-0.900 t o t a l confidence l e v e l . Compounds have been o m i t t e d from E q u a t i o n 4.
t h i s r e s p e c t i t i s the most i m p o r t a n t s t a t i s t i c a l p a r a m e t e r . It t a k e s a u t o m a t i c a l l y i n t o a c c o u n t the number o f o b s e r v a t i o n s and v a r i a b l e s (degrees o f freedom). A c c o r d i n g t o t h i s p a r a m e t e r , the s i g n i f i c a n c e s o f E q u a t i o n 3 and E q u a t i o n 4 a r e v e r y h i g h (p
