Photosynthesis - Inhibiting efficiency of 4-chloro-2- (chlorophenylcarbamoyl)phenyl alkylcarbamates

Article abstract of DOI:10.1016/j.bmcl.2011.05.118

A series of photosynthetic electron transport (PET) inhibitors from the group of salicylanilide alkylcarbamates was investigated. The compounds were analyzed using RP-HPLC to determine lipophilicity, and their PET inhibition was determined in spinach (Spinacia oleracea L.) chloroplasts. The site of action of the studied compounds is situated at the donor site of photosystem 2 (PS 2). Compounds substituted by chlorine in C′-3 and C′-4 of the aniline ring and the optimal length of the alkyl chain pentyl-heptyl in the carbamate moiety provided the most active PET inhibitors (IC₅₀ inhibition <10 μmol/L). Disubstitution in C′-3,4 by chlorine caused significant PET inhibiting activity decrease. Nevertheless, for all three series of C′-3, C′-4, C′-3,4 compounds, the dependence of PET activity on lipophilicity showed to be quasi-parabolic.

Full text of DOI:10.1016/j.bmcl.2011.05.118

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4564–4567
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Photosynthesis—Inhibiting efficiency
of 4-chloro-2-(chlorophenylcarbamoyl)phenyl alkylcarbamates
Ales Imramovsky a, , Matus Pesko b, Juana Monreal Ferriz c, Katarina Kralova d, Jarmila Vinsova c,
⇑
Josef Jampilek e
a Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic
b Department of Ecosozology and Physiotactics, Faculty of Natural Sciences, Comenius University, Mlynska dolina Ch-2, 842 15 Bratislava, Slovakia
c Department of Inorganic and Organic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic
d Institute of Chemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina Ch-2, 842 15 Bratislava, Slovakia
e Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1/3, 612 42 Brno, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of photosynthetic electron transport (PET) inhibitors from the group of salicylanilide alkylcarba-
mates was investigated. The compounds were analyzed using RP-HPLC to determine lipophilicity, and
their PET inhibition was determined in spinach (Spinacia oleracea L.) chloroplasts. The site of action of
the studied compounds is situated at the donor site of photosystem 2 (PS 2). Compounds substituted
by chlorine in C0-3 and C0-4 of the aniline ring and the optimal length of the alkyl chain pentyl-heptyl
Received 26 April 2011
Revised 30 May 2011
Accepted 30 May 2011
Available online 12 June 2011
in the carbamate moiety provided the most active PET inhibitors (IC50 inhibition <10 lmol/L). Disubsti-
Keywords:
tution in C0-3,4 by chlorine caused significant PET inhibiting activity decrease. Nevertheless, for all three
series of C0-3, C0-4, C0-3,4 compounds, the dependence of PET activity on lipophilicity showed to be quasi-
parabolic.
4-Chloro-2-(chlorophenylcarbamoyl)phenyl
alkylcarbamates
Lipophilicity
Ó 2011 Elsevier Ltd. All rights reserved.
PET inhibition
Spinach chloroplasts
Structure–activity relationships
Salicylanilides (2-hydroxy-N-phenylbenzamides) and/or their
substituted N-alkylcarbamates show manifold pharmacological
activities.1–7 The presence of amide (–NHCO–) groups in the struc-
ture of phenylcarbamoylphenyl N-alkylcarbamates can also cause
interaction with various enzymes or enzymatic systems, for exam-
ple, a carbamate moiety is characteristic for a number of herbicides
acting as photosynthetic electron inhibitors.8–12
The Hill reaction is a basic redox reaction of photosystem 2 (PS
2). Herbicides which inhibit the Hill reaction belong to the group
of PS 2 herbicides. Experimental studies have established that many
PS 2 herbicides bind non-covalently to a 32 kDa protein in the PS 2
complex and inhibit electron transfer between the primary electron
acceptor—quinone QA and the secondary electron acceptor—qui-
none QB on the reducing side of PS 2.13 The herbicides contain
hydrophobic components as well as a flat polar component. The
function of the hydrophobic components is to increase the lipid sol-
ubility of the entire herbicide molecule and to fit the hydrophobic
surface of the herbicide binding site. It is assumed that the flat polar
component binds electrostatically at a highly polar protein site.13
Tischer and Strotmann14 and Moreland15 suggested QB as the site
of action of phenylcarbamates. On the other hand, Sersen et al.
determined the intermediate D+ on the donor side of PS 2 as the site
of action of alkyl-N-phenylcarbamates (alkyl = methyl-octyl).16
However, after addition of an artificial electron donor 1,5-diphe-
nylcarbazide (DPC) to chloroplasts treated with these compounds,
complete restoration of photosynthetic electron transport (PET) in
chloroplasts was observed.16 Because the site of DPC action is Z+/
D+ intermediate on the donor side of PS 2,17 it can be assumed that
the part of the PET chain from the intermediate Z+/D+ through P680,
pheophytin, QA and QB to the plastoquinone pool was not damaged
by studied phenylcarbamates.
As mentioned above, reaching the inhibitory site of action
and binding to QB-binding niche or to Z+/D+ intermediate on
the donor side of PS 2 would be influenced by hydro/lipophilic
properties of the compounds. It is evident from the aforesaid
that lipophilicity is an important physical property, and direct
relations between lipophilicity and herbicidal activity should be
expected. Therefore lipophilicity of the prepared compounds
was determined using RP-HPLC. Relationships between the struc-
ture/physico-chemical parameters and in vitro inhibitory activity
related to PET inhibition in spinach chloroplasts of the com-
pounds are discussed.
The synthesis of the carbamates is shown in Scheme 1. The syn-
thetic pathway was discussed in Imramovsky et al.5,18 and all the
prepared compounds were characterised and published recently.6
⇑
Corresponding author.
E-mail address: ales.imramovsky@upce.cz (A. Imramovsky).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.118

A. Imramovsky et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4564–4567
4565
O
O
R1
R1
Cl
R2
N
Cl
a
N
N
H
O C
+
H
OH
O
R1 = 3-Cl = comp. 1
R2 = alkyl: C2 - C11
(except alkyl C3)
R1 = 3-Cl = comp. 4
R1 = 4-Cl = comp. 5
R1 = 3,4-diCl = comp. 6
R2
O
N
H
R1 = 4-Cl = comp. 2
R1 = 3,4-diCl = comp. 3
Scheme 1. Synthesis of target 4-chloro-2-(chlorophenylcarbamoyl)phenyl alkylcarbamates 4, 5 and 6: (a) TEA, ACN, ambient temperature.5,6
The compounds under investigation could be divided into three
groups based on their substitution: Group 1 includes 3-Cl substi-
tuted carbamates 4a–4i; Group 2 contains 4-Cl derivatives 5a–5i;
and Group 3 is composed of 3,4-Cl compounds 6a–6i, see Table 1.
Most frequently drugs cross biological membranes through the
passive transport, which strongly depends on their lipophilicity,
therefore it has been studied and applied as an important drug
property for decades.19 Different lipophilicity descriptors such as
log kw, log P, log D, etc. are used for SAR description and prediction.
However, the algorithms used in their calculation do not take into
account configuration specificity and sometimes even intramolec-
ular interactions of these N-substituted carbamoyl derivatives.
Hydrophobicities (log P/Clog P) of compounds 4, 5 and 6 were cal-
culated using two commercially available programs (ChemOffice
Ultra 10.0 and ACD/LogP) and also measured by means of the RP-
HPLC determination of capacity factors k expressed as log k. The
procedure was performed under isocratic conditions with metha-
nol as an organic modifier in the mobile phase using an end-
capped non-polar C18 stationary RP column. The results are shown
in Table 1.
PET inhibitor diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea;
DCMU), that is, the studied compounds strongly inhibited photore-
duction of artificial electron acceptor 2,6-dichlorophenol-indophe-
nol (DCPIP) in spinach chloroplasts. The IC50 values, the molar
concentrations of inhibitors that caused a 50% decrease in biologi-
cal activity in comparison with the untreated control, are summa-
rized in Table 1.
The most active inhibitors that provided the lowest IC50 are
compound with C0-3 and C0-4 substitution. The comparison of the
activity and lipophilicity of prepared compounds is shown in Fig-
ure 1. The dependencies of PET-inhibiting activity [log(1/IC50)] on
compound lipophilicity expressed as log k showed that activity of
3- and 4-chloro substituted compounds, Group 1 (4) and Group 2
(5), is approximately by one or two orders higher than that of
3,4-dichloro substituted analogues, Group 3 (6).
The relationship between PET activity expressed as [log(1/IC50)]
and lipophilicity (log k) showed quasi-parabolic dependences in
each investigated series (R1 = 3-Cl, 4-Cl or 3,4-diCl). However, for
the set of 25 investigated compounds the dependence of biological
activity on compound lipophilicity was linear:
All the discussed compounds were tested for their PET-inhibit-
ing activity in spinach (Spinacia oleracea L.) chloroplasts,20 and they
expressed good herbicidal activity compared with a commercial
logð1=IC50Þ ¼ 8:528ðꢀ0:297Þ ꢁ 4:460ðꢀ0:342Þ log k
ð1Þ
r ¼ 0:939; s ¼ 0:216; F ¼ 170:5; n ¼ 25
Table 1
IC50 values of photosynthetic electron transport (PET) inhibition in spinach chloroplasts in comparison with 3-(3,4-dichlorophenyl)-1,1-dimethylurea (diuron; DCMU) and
comparison of calculated lipophilicities (log P/Clog P) with determined log k values.
Compd.
R1
R2
log k
log P/Clog P
log P
PET IC50 [lmol/L]
ChemOffice22–27
ACD/LogP28
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
6g
6h
6i
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
C2H5
C4H9
0.7523
0.7611
0.7732
0.7758
0.7772
0.7831
0.7837
0.7873
0.7902
0.7695
0.7759
0.7838
0.7859
0.7872
0.7899
0.7919
0.7942
0.7947
1.0234
1.0457
1.0601
1.0611
1.0667
1.0845
1.0880
1.0894
1.0903
0.47021
(0.680 0.20)a
3.79/4.1919
4.69/5.2499
5.11/5.7789
5.53/6.3079
5.94/6.8369
6.36/7.3659
6.78/7.8949
7.19/8.4239
7.61/8.9529
3.79/4.1919
4.69/5.2499
5.11/5.7789
5.53/6.3079
5.94/6.8369
6.36/7.3659
6.78/7.8949
7.19/8.4239
7.61/8.9529
4.35/4.8194
5.25/5.8774
5.67/6.4064
6.08/6.9354
6.50/7.4644
6.92/7.9934
7.34/8.5224
7.77/9.0514
8.17/9.5804
2.76/2.69124
4.02 0.40
5.08 0.40
5.61 0.40
6.14 0.40
6.67 0.40
7.20 0.40
7.74 0.40
8.27 0.40
8.80 0.40
3.98 0.39
5.04 0.39
5.57 0.39
6.10 0.39
6.63 0.39
7.16 0.39
7.70 0.39
8.23 0.39
8.76 0.39
4.88 0.41
5.94 0.41
6.47 0.41
7.01 0.41
7.54 0.41
8.07 0.41
8.60 0.41
9.13 0.41
9.66 0.41
2.78 0.38
15.6
13.4
5.4
5.3
4.9
10.1
15.4
15.8
18.3
9.7
9.6
6.3
6.3
7.1
7.4
8.0
8.4
10.5
82.3
56.4
99.2
143.5
169.08
431.6
505.5
N.D.
N.D.
1.9
C5H11
C6H13
C7H15
C8H17
C9H19
C
C
10H21
11H23
C2H5
C4H9
C5H11
C6H13
C7H15
C8H17
C9H19
4-Cl
4-Cl
C
C
10H21
11H23
3,4-Cl
3,4-Cl
3,4-Cl
3,4-Cl
3,4-Cl
3,4-Cl
3,4-Cl
3,4-Cl
3,4-Cl
–
C2H5
C4H9
C5H11
C6H13
C7H15
C8H17
C9H19
C
C
–
10H21
11H23
DCMU
N.D. = not determined.
a
Mathematically approximated to applied experimental conditions.

4566
A. Imramovsky et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4564–4567
5.4
5.2
5.0
4.8
4.6
4.4
4.2
4.0
3.8
3.6
3.4
3.2
4d 4e
4c
5d
5e
5c
5f
5g
5h
5i
5a
4f
4g
5b
4a
4b
4h
4i
6b
6c
6a
6d
6e
Group 1 (4a-i) Group 2 (5a-i) Group 3 (6a-g)
6f
6g
0.75
0.76
0.77
0.78
0.79
0.80 1.02
1.03
1.04
1.05
1.06
1.07
1.08
1.09
log k
Figure 1. Dependences of PET-inhibiting activity (log 1/IC50 [mol/L]) on lipophilicity expressed as log k.
Similarly, the dependence of PET-inhibiting activity on the Ha-
mett’s constant of R1 substituent was also linear:
(alkyl = methyl-octyl) and alkyl-N-phenylthiocarbamates, the
intermediate D+ on the donor side of PS 2 was determined, where-
by the part of the PET chain from the intermediate Z+/D+ through
P680, pheophytin, QA and QB up to plastoquinone pool was not
damaged.16 After addition of DPC to chloroplasts treated with com-
pounds 4e and 5a (activity of chloroplasts reached only 20% of the
activity of untreated chloroplasts), practically complete PET resto-
ration (up to 94% related to the untreated control) was observed.
Based on these results it can be assumed that similarly to above
mentioned N-phenylcarbamates,16 the site of action of the studied
compounds will be situated on the donor side of PS 2 and not in QB,
which is located at the acceptor side of PS 2. On the other hand, the
site of action of piperidinoethyl alkoxyphenyl-carbamates was
found to be Z+/D+ intermediate on the donor side of PS 2 and the
oxygen evolving complex as well.31
The loss of biological activity observed for amphiphilic com-
pounds upon elongation of their hydrophobic (hydrocarbon) part
is called ‘cut-off’ effect.36 These hydrophobic parts (e.g. alkyl
substituents) of membrane active compounds interact with lipi-
dic parts of biological membranes (including thylakoid). How-
ever, water solubility of compounds with a longer alkyl chain
is limited, and too large values of compound partition coefficient
did not enable the penetration of such molecules through hydro-
philic (aqueous) regions of biological membranes. Consequently,
the final concentration of long-chain compounds in the mem-
brane will be lower than that of compounds with shorter alkyl
chain, which results in the loss of biological activity. The qua-
si-parabolic dependence of biological activity (bactericidal activ-
ity against Staphylococcus aureus, algicidal activity in Chlorella
vulgaris and PET-inhibiting activity in spinach chloroplasts) on
the length of alkyl substituent was found for piperidinoethylest-
ers of 2-, 3- and 4-alkoxy substituted phenylcarbamic acids.31
Similar behaviour was observed for antifungal activity against
Candida albicans as well as antialgal activity against C. vulgaris
of piperidinopropyl esters of alkoxy substituted phenylcarbamic
acids.37
logð1=IC50Þ ¼ 6:055ðꢀ0:171Þ ꢁ 3:541ðꢀ0:414Þ
r
ð2Þ
r ¼ 0:872; s ¼ 307; F ¼ 73:0; n ¼ 25
The use of both above mentioned descriptors (log k and
r
) im-
proved the results of statistical analysis:
logð1=IC50Þ ¼ ꢁ16:978ðꢀ7:241Þ þ 52:207ðꢀ16:082Þ
ꢁ 30:736ðꢀ8:722Þ
r
ð3Þ
r ¼ 0:961; s ¼ 17:690; F ¼ 133:80; n ¼ 025
The correlation coefficient r = 0.939 (Eq. 1) calculated for the
dependence of biological activity on log k of all the evaluated com-
pounds (n = 25) indicates that the lipophilicity is a determinant
parameter for PET-inhibiting activity of all the discussed N-alkylc-
arbamates. This is consistent with the respective literature, be-
cause it was found that the efficiency of the studied compounds
was inversely proportional to the hydrophobicity of molecules,
that is, the effectiveness decreased with the increase of their
hydrophobicity.16 However, PET-inhibiting activity is also signifi-
cantly depended on the electronic properties (Hammett’s
r param-
eters) of R1 substituents (r = 0.872, Eq. 2), and with the increase of
electron-withdrawing effect of individual substituents in the ani-
lide part of the molecule (Group 2 (R1 = 4-Cl;
r
= 0.227) P Group
1 (R1 = 3-Cl;
r r
= 0.373) o Group 3 (R1 = 3,4-Cl; = 0.600)29 PET-
inhibiting activity decreased. While in the present experiment
the compounds of Group 3 were the least active, the majority of
these compounds were found to be considerably more effective
against Mycobacterium tuberculosis 331/88 than the compounds
of Group 1 and Group 2.6
The chemical hydrolysis (carbamate bond decomposition and
the release of the parent salicylanilide) of the discussed com-
pounds were studied in aqueous buffer solutions at pH 3–8 at
37 °C by HPLC.6 The compounds were stable at acidic pH values,
but they were decomposed in alkaline environment, approx. T1/
2 64 h at pH 7.0 and approx. T1/2 43 h at pH 7.4 were shown.6 Be-
cause spectrophotometric measurements of DCPIP photoreduction
were performed within 2 min after addition of the carbamate solu-
tion (in DMSO) into chloroplast suspension with pH 7.2, decompo-
sition of the studied carbamate compounds during experiment
could be excluded.
The mechanism of PET inhibition in alkyl substituted mem-
brane-active compounds may be connected with their ability to
penetrate their hydrophobic tail into the lipid membrane and
change the orientation of electron donor and acceptor complexes
relative to one another. Due to direct interaction of such mem-
brane-active compounds with membrane proteins, conformational
changes in these proteins occur. Since PS 2 and its accessory pig-
ments are bound in the membrane protein complex, it could be
supposed that alteration of the membrane structure would induce
organizational changes in the associated peptides resulting in inhi-
bition charge separation between electron donor and acceptor
complexes.38
The data described above can be supported by previously stud-
ies and published results of various series of substituted N-carba-
mate-like compounds.7,16,30–35 As discussed above, QB as the site
of action of phenylcarbamates was suggested.14,15 Using EPR
spectroscopy as the site of action of alkyl-N-phenylcarbamates

A. Imramovsky et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4564–4567
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.05.118.
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