9 Structure-Activity Relations
Downloaded by IMPERIAL COLLEGE LONDON on February 18, 2015 | http://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.ch009
II. Antibacterial Activity of 3-Benzoylacrylic Acids and Esters
KEITH BOWDEN and M. P. HENRY The University of Essex, Colchester, Essex, England
The bacteriostatic activity of a series of substituted trans-3benzoylacrylic acids has been successfully correlated by Hansch linear free energy relations involving polar and par tition substituent constants. The activity-lipophilicity rela tions for this series closely parallel those found previously for other antibacterial agents, with an ideal lipophilic character for gram-positive cells of 6.1 and, for linear dependence, a slope of 0.7. A polar reaction constant,ρ,of about —0.6 to —0.7 is given. A possible mode of action for these acids and their related substituted cis- and trans-3-benzoyl acrylic acids and esters is discussed as an enzyme-inhibitor interaction.
' " p h e presence of the k e t o v i n y l groups has b e e n i m p l i c a t e d i n t h e a n t i ·*- b a c t e r i a l a c t i v i t y of a n u m b e r of substances s y n t h e t i c (1-7).
( I ) , both natural a n d
A n e x a m p l e is p e n i c i l l i c a c i d w h i c h exists m a i n l y i n t h e
c y c l i c f o r m ( I ) whereas, at h i g h e r p H , t h e a n i o n of t h e c h a i n f o r m ( I I ) occurs (6, 8).
A d d i t i o n to or loss of the reactive d o u b l e - b o n d
c o m p o u n d s m a r k e d l y reduces t h e i r a c t i v i t y (1, 6, 7). MeO
H
\
S
7
Η
C = C
C
'
Ή
N
H - C > = 0
N
x
MeO
I
c=C
IK) Η
H
/
Z = >
0 /
i n these
T h e bacteriostatic
/
C = C
V c Me
V o
7
°
HO
Me I
II 130
In Biological Correlations—The Hansch Approach; Van Valkenburg, W.; Advances in Chemistry; American Chemical Society: Washington, DC, 1974.
9.
3-Benzoylacrylic
BOWDEN AND HENRY
and
Acids
131
and Ester
f u n g i c i d a l activities of m a n y s y n t h e t i c c o m p o u n d s
k e t o v i n y l g r o u p i n g h a v e b e e n i n v e s t i g a t e d (1-7).
c o n t a i n i n g the
A systematic s t u d y
of the bacteriostatic a c t i v i t y of a series of s u b s t i t u t e d f r a n s - 3 - b e n z o y l a c r y l i c acids ( I I I , R =
R
1
=
R
1 1
=
H ) has b e e n m a d e b y K i r c h n e r ,
Downloaded by IMPERIAL COLLEGE LONDON on February 18, 2015 | http://pubs.acs.org Publication Date: August 1, 1974 | doi: 10.1021/ba-1972-0114.ch009
Bailey, and Cavallito (7).
H a n s c h et al. (9, 10)
have developed
l i n e a r free energy relations
w h i c h c a n correlate b i o l o g i c a l a c t i v i t y a n d c h e m i c a l structure. E q u a t i o n s 1 a n d 2, together w i t h s i m p l i f i e d versions, h a v e b e e n p r o p o s e d to relate the m o l a r c o n c e n t r a t i o n , C , of a s u b s t i t u t e d c o m p o u n d of a series, w h i c h a l l x
cause a n e q u i v a l e n t b i o l o g i c a l response, to the h y d r o p h o b i c b o n d i n g or p a r t i t i o n constant, ττ, a n d the H a m m e t t constant, σ. T h e constants a, b, log ( 1 / C ) =
-αχ
X
2
+ 6x +
log ( 1 / C , ) = 6x +
ρj + c
(1)
ps + c
(2)
p, a n d c are o b t a i n e d f r o m the regression analysis a n d define the response of the b i o l o g i c a l system to s t r u c t u r a l features.
H a n s c h et al. (11)
s t u d i e d the bacteriostatic a c t i v i t y of diverse c o m p o u n d s .
have
T h e s e activities
w e r e n o r m a l l y w e l l c o r r e l a t e d b y E q u a t i o n 1 or 2, u s u a l l y w i t h o u t a p o l a r c o n t r i b u t i o n . T h e i d e a l p a r t i t i o n character for o p t i m u m a c t i v i t y , l o g P , was f o u n d to b e about 4 for g r a m - n e g a t i v e a n d a b o u t 6 for g r a m 0
positive bacteria ( E q u a t i o n 1 ) ; however, where a linear relation ( E q u a t i o n 2 ) r e s u l t e d , a slope of b e q u a l to a b o u t 0.7 was observed. results
were
related
to
the
cell wall
H a n s c h has m a d e t w o studies (12, tions
in penicillin
derivatives.
An
13)
of
the
These
bacteria.
of the s t r u c t u r e - a c t i v i t y r e l a
earlier attempt
u s i n g the s i m p l e H a m m e t t r e l a t i o n (14). (12)
composition
had
been
made
T h e first of H a n s e n ' s studies
gave g o o d correlations for the in vivo testing of a series of s u b s t i
t u t e d p e n i c i l l i n s h a v i n g the side c h a i n P h O C H ( C H ) C H 2
correlations for in vitro
n
a c t i v i t y w e r e less satisfactory.
3
w h i l e those
The lipophilic
character of the substituent a p p e a r e d to be m o r e i m p o r t a n t a n d gave a linear r e l a t i o n b e t w e e n p a r t i t i o n factors a n d a c t i v i t y ( E q u a t i o n 2 ) i n g b e q u a l to a b o u t —0.4->. T h e second s t u d y (13)
hav
reported a correlation
of the a c t i v i t y of s u b s t i t u t e d 2 , 6 - d i a l k o x y p h e n y l p e n i c i l l i n s against a r e -
In Biological Correlations—The Hansch Approach; Van Valkenburg, W.; Advances in Chemistry; American Chemical Society: Washington, DC, 1974.
132
BIOLOGICAL CORRELATIONS
Table I.
T H E HANSCH APPROACH
Bacteriostatic Activities and Substituent Constants for Substituted £r*ws-3-Benzoylacrylic Acids" log (I/O
b
Substituent
v. S t a p h y lococcus aureus 209
2
7
0.12 0.30i l.OOo 1.30i 2.00ο 2.12 2.30 2.60 3.12
2
8
2.6Ο2
2
9
5
Me CH Me
