Reactivity of β-cetoesters compounds, synthesis of nitrogenated heterocycles (derivatives of tetrahydroacridin-9-ones and pyrimidinone) and biological properties of pyrimidinone derivatives

Article abstract of DOI:10.14233/ajchem.2015.18918

Ethyl 2-oxocyclohexanecarboxylate has undergone smooth condensation with arylamines under ethanol. The corresponding β-enaminoesters compounds were obtained in good yields. These compounds were then refluxed in biphenyl ether to attain the respective subs

Full text of DOI:10.14233/ajchem.2015.18918

Asian Journal of Chemistry; Vol. 27, No. 10 (2015), 3675-3680
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.18918
Reactivity of β-Cetoesters Compounds, Synthesis of Nitrogenated Heterocycles
(Derivatives of Tetrahydroacridin-9-ones and Pyrimidinone) and
Biological Properties of Pyrimidinone Derivatives
1,2
1,2
3
4
Y. KOUADRI1,2,*, M.R. OUAHRANI , B.E. MISSAOUI , F. CHEBROUK and N. GHERRAF
1Laboratoire de Chimie Organique, Université KASDI Merbah, Ouargla, Algeria
2Laboratoire VPRS Université KASDI Merbah, Ouargla, Algeria
3Centre de Recherche Scientifique et Technique en Analyses Physico-Chimiques (CRAPC), BP 248, Alger 16004, Algeria
4Laboratoire des Ressources Naturelles et Aménagement des milieux sensibles, Université Larbi ben M'hidi, Oum Elbouaghi, Algeria
*Corresponding author: Fax: +213 32563213; Tel: +213 559103485; E-mail: hadadberini@yahoo.com
Received: 9 December 2014;
Accepted: 14 January 2015;
Published online: 22 June 2015;
AJC-17325
Ethyl 2-oxocyclohexanecarboxylate has undergone smooth condensation with arylamines under ethanol. The corresponding β-enaminoesters
compounds were obtained in good yields. These compounds were then refluxed in biphenyl ether to attain the respective substituted
tetrahydroacridin. The reaction of 2-amino-5,6-dimethylbenzimidazole with β-cetoesters gave access to an efficient synthesis of pyrimidinone
derivatives in excellent yield.A series of novel heterocycles were prepared. Biological properties of compounds 11-14 have been distinctively
evolved.
Keywords: β-Cetoesters, Tetrahydroacridin-9-ones, 2-Amino-5,6-dimethylbenzimidazole, Pyrimidinone.
Synthesis of β-enamino ester: In a three-necked 100 mL
flask equipped with a magnetic stirrer with heating and cooling,
the β-keto ester (1 eq) was placed in 10 mL of ethanol and
then one equivalent of aryl amines is added in the presence of
acetic acid. The mixture is stirred and heated under reflux for
6 h. The solvent was evaporated under reduced pressure.
Ethyl 2-(phenylamino)cyclohex-1-enecarboxylate (4):
Yield : 85 %; 1H NMR (DMSO-d6) δ ppm: 1.25 (t, J = 7 Hz,
3H, CH3); 1.69 (d, J = 6.61, 4H); 2.27-2.44 (dt, J = 5.86 Hz,
22.66 Hz, 4H); 4. 14 (q, J = 7 Hz, 2H,-CH2); 7.10-7.20 (m,
3H,Harom); 7.30-7.40 (m, 2H,Harom) 10.81 (s,1H, NH); 13C NMR
(DMSO-d6) δppm : 14,62 (CH3); 21.93 (-CH2-); 22.24 (-CH2-);
23.75 (-CH2-); 27.65(-CH2-); 58.90(-CH2-); 92.43(C); 124.20
(Carom); 129.22 (Carom) 139.37 (C); 156.51 (Carom); 170.00
(C=O).
INTRODUCTION
Nitrogen containing molecules are a group of compounds
of high importance in organic chemistry because of their
reactivity in addition to their presence in a large number of
molecules of natural and synthetic origin1. In fact, they play a
key role in various fields namely pharmacy, medicine, biology
and agronomy.
Among the molecules containing a nitrogen atom, are the
1,2,3,4-tetrahydroacridine derivatives which encompass a very
important role in the treatment of Alzheimer’s system2,3. A
variety of natural and synthetic acridine derivatives have also
been tested for antimalarial4, antiinflammatory5,6 and anal-
gesic7. Pyrimidinones derivatives possess various biological
activities including the insulin-mimetic8, antiinflammatory9
and antiproliferative10 properties.
Ethyl 2-(3-methoxyphenylamino)cyclohex-1-
enecarboxylate (5): Yield : 88 %; 1H NMR (CDCl3) δ ppm:
1.25 (t, J = 7 Hz, 3H, CH3); 1.46-1.64 (m, 4H); 2.17-2.34 (m,
4H); 4.20 (q, J = 7 Hz, 2H, -CH2); 6.75 (d, J = 2.2 Hz, 2H,
This work enrolled in this context, aims to develop tetra-
hydroacridin-9-ones and pyrimidinones derivatives synthetic
ways. For this, the reactivity of β-keto esters avers an ideal
tool.
13
Harom); 8.10 (d, J = 2.2 Hz, 2H, Harom); 9.10 (s,1H, NH); C
NMR (CDCl3) δ ppm: 14.65 (CH3); 22.25 (-CH2-); 22.69
(-CH2-); 23.82 (-CH2-); 26.01 (-CH2-); 58.64 (-CH2-); 90.14
(C); 122.45 (Carom); 127.37 (Carom); 135.49 (C); 140.99 (Carom);
152.50 (Carom); 170.88 (C=O).
EXPERIMENTAL
The nuclear magnetic resonance (1H, 13C, DEPT) were
recorded on a Bruker AC-300.

3676 Kouadri et al.
Asian J. Chem.
Ethyl 2-(3-chlorophenylamino)cyclohex-1-enecar-
boxylate (6): Yield: 86 %; 1H NMR (CDCl3) δ ppm: 1.24 (t,
J = 7 Hz, 3H, CH3); 1.40-1.70 (m, 4H); 2.05-2.40 (m, 4H);
4.10 (q, J = 7 Hz, 2H,-CH2); 6.25 (d, J = 2.2 Hz, 1H, Harom);
6.80-7.15 (m, 3H, Harom); 8.95 (s, 1H, NH); 13C NMR (CDCl3)
δppm: 14.30 (CH3); 21.61 (-CH2-); 21.92 (-CH2-); 23.43 (-CH2-);
27.33 (-CH2-); 58.58 (-CH2-); 92.11 (C); 118.88 (Carom); 123.88
(Carom); 128.90 (Carom); 133.05 (Carom); 136.95 (C); 139.05
(Carom); 156.50 (Carom); 169.68 (C=O).
Synthesis of tetrahydroacridin-9-ones derivatives: The
prepared β-enamino-esters are then left in a diphenyl ether
solution under stirring and heated under reflux (230 ° C) for
2 h. The residue is treated with a 50:50 mixture of ether and
petrol ether and the solid is filtered and dried.
5,6,7,8-Tetrahydroacridin-9(10H)-one (7):Yield: 60 %;
m.p. 240 °C; 1H NMR (DMSO-d6) δppm: 1.60-1.80 (m,4H);
2.30 (t, J = 5.4, 2H); 2.75 (t, J = 5.8, 2H); 7.20 (t, J = 7.5, 1H);
7.40-7.60 (m, 2H); 8.3 (d, J = 8.0, 1H); 11.29 (s, 1H, NH); 13C
NMR (DMSO-d6) δppm: 21.33 (-CH2-); 21.56 (-CH2-); 21.64
(-CH2-); 29.39 (-CH2-); 115.79 (Cq); 117.28 (Carom); 121.26
(Carom); 122.63 (Cq, arom); 124.89 (Carom); 133.09 (Carom); 139.26
(Cq, arom); 146.54 (Cq); 175.21 (C=O).
2.30 (s, 6H,2-CH3); 2.70-2.85 (m,4H); 7.50 (s,2H, Harom); 10.85
(s, 1H, NH); 13C NMR (DMSO-d6) δppm: 18.40 (2-CH3); 21.69
(-CH2-); 26.86 (-CH2-); 34.26(-CH2-); 101.34 (C); 114.69
(Carom); 118.59 (Carom); 122.48 (Carom); 130.43 (Carom); 145.82
(C); 151.86 (C); 159.87 (C=O).
7,8-Dimethyl-2-methylbenzo[4,5]imidazo[1,2-a]pyri-
midin-4(1H)-one (13): Yield: 74 %; m.p.: 225 °C; 1H NMR
(DMSO-d6) δppm: 1.75 (s,3H,CH3); 2.80 (s, 6H,2-CH3); 5.82
(s, 1H,=CH); 7.81 (s,2H, Harom); 11.20 (s, 1H, NH); 13C NMR
(DMSO-d6) δppm: 17.84 (2-CH3); 22.82 (CH3); 98.28 (=CH);
114.84 (Carom); 119.46 (Carom); 123.63 (Carom); 131.28 (Carom);
148.41 (C); 155.46(C); 159.95(C=O).
7,8-Dimethyl-2-methoxybenzo[4,5]imidazo[1,2-
a]pyrimidin-4(1H)-one (14): Yield: 74 %; m.p.: 240 °C; 1H
NMR (DMSO-d6) δ ppm: 2.20 (s, 6H,2-CH3); 3.75 (s,3H,
O-CH3); 5.75 (s, 1H,=CH); 7.25 (s,2H, Harom); 11.00 11.20 (s,
1H, NH); 13C NMR (DMSO-d6) δppm : 17.76 (2-CH3); 52.14
(CH3); 100.14 (=CH); 114.76 (Carom); 119.72 (Carom); 123.77
(Carom); 132.95 (Carom); 146.21(C); 158.21 (C=O); 179.28 (C).
RESULTS AND DISCUSSION
Reactivity of β-keto esters with the arylamines
5,6,7,8-Tetrahydro-3-methoxyacridin-9(10H)-one (8):
Yield: 65 %; m.p. 255 °C; 1H NMR (DMSO-d6) δppm: 1.65-
1.80 (m,4H); 2.41 (t, J = 5.4, 2H); 2.65 (d, J = 5.8, 2H); 7.10
Synthesis of tetrahydroacridin-9-ones derivatives:
Synthesis and reactivity of derivatives of tetrahydroacridin-9-
ones (I) have been particularly enriched by the work of the
teams of Elguero et al.2 and Rodriguez et al.11. Their research
permitted to clarify the notion of this chemistry compounds
class.
13
(d, J = 10, 2H); 8 (d, J = 8.7, 1H); 11.38 (s, 1H, NH); C
NMR (DMSO-d6) δppm: 22.13 (-CH2-); 22.25 (-CH2-); 22.55
(-CH2-); 27.29 (-CH2-); 55.97 (-CH3); 98.68 (Carom); 113.14
(Carom); 115.67 (Cq); 118.14 (Cq, arom); 127.25 (Carom); 141.57
(Cq, arom); 147.41 (Cq); 162.10 (C q arom); 175.74 (C=O).
2-Chloro-5,6,7,8-tetrahydroacridin-9(10H)-one (9):
Yield: 67 %; m.p. 248 °C; 1H NMR (DMSO-d6) δppm: 1.73-
1.85 (m,4H); 2.43 (t, J = 5.9, 2H); 2.71 (t, J = 5.8, 2H); 7.50
(d, J = 8.8, 1H); 7.40-7.60 (m, 2H); 7.60 (dd, J = 2, 1H); 7.97
(d, J = 2, 1H); 11.50 (s, 1H, NH); 13C NMR (DMSO-d6) δppm:
21.37 (-CH2-); 21.63 (-CH2-); 21.71 (-CH2-); 27.10 (-CH2-);
116.01 (Cq); 119.83 (Carom); 123.68 (Cq arom); 124.07(Cq, arom);
126.51 (Carom); 131.04 (Carom); 137.77 (Cq, arom); 147.32 (Cq);
174.70 (C=O).
O
R
N
H
I
For our part, having synthesized tetrahydroacridin-9-ones
derivatives, we study their reactivity toward the alkylating
agents.
Condensation of β-keto esters with 2-amino-5,6-
dimethylbenzimidazole: In a three-necked 100 mL flask
containing 30 mL of ethanol, β-keto ester (1 eq) was placed
with 2-amino-5,6-dimethylbenzimidazole (1/1 eq), the mixture
is heated under reflux. The reaction was followed by thin layer
chroma-tography TLC.After evaporation of the solvent under
reduced pressure, the resultant product is washed with ethyl
ether.
The synthesis method, we have adopted, carries out the
condensation reaction of ethyl 2-oxocyclohexanecarboxylate
with arylamines (Scheme-I).
In a first step, we have synthesized β-enamino ester deri-
vatives by condensation of these β-keto esters with arylamines
in ethanol under reflux in the presence of acetic acid. Then a
cyclization was carried out in biphenyl ether solution, thus
forming tetrahydroacridin-9-ones derivatives.
8,9-Dimethyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo-
[2,1-b]quinazolin-12(5H)-one (11): Yield: 77 %; m.p.: 255
°C; H NMR (DMSO-d6) δ ppm: 1.60-1.85 (m,4H); 2.25 (s,
We have isolated, in all cases, a single product whose
structure could match the tetrahydroacridin-9-ones derivative.
1H NMR (DMSO-d6) spectra of the obtained products,
exhibit signals in the range of 7.25-8.43 ppm corresponding
to the aromatic protons. We note the absence of the signals
corresponding to the proton’s groups (CO2C2H5).
Tetrahydroacridin-9-ones derivatives compounds: 13C
NMR spectra have, in particular, signals at 174.41-175.77 ppm,
121.26-121.92 ppm and 145.77-148.41 ppm, corresponding
respectively to the carbonyl carbon (C=O) and two ethylenic
carbons in α and β.
1
6H, 2-CH3); 2.72-2.85 (m,4H); 7.51 (s,2H, Harom); 11.25 (s,
1H, NH); 13C NMR (DMSO-d6) δ ppm: 18.01(2-CH3); 22.30
(-CH2-); 22.94 (-CH2-); 23.30 (-CH2-); 30.39(-CH2-);
103.23(C); 114.85 (Carom); 118.81 (Carom); 122.86 (Carom);
129.04 (Carom); 147.43 (C); 152.04 (C) 159.29 (C=O).
7,8-Dimethyl-2,3-dihydrobenzo[4,5]imidazo[1,2-
a]cyclopenta[d]pyrimidin-11(4H)-one) (12): Yield : 80 %;
m.p.: 250 °C; 1H NMR (DMSO-d6) δppm: 1.98-2.09 (m,2H);

Vol. 27, No. 10 (2015)
Reactivity of β-Cetoesters Compounds and Synthesis of Nitrogenated Heterocycles 3677
O
CO2Et
NH2
X
X
Biphenylether
260°C
EtOH/AcOH
reflux
+
X
N
H
R
O
N
H
R
R
CO2Et
1
2
3
R:
R:
R:
H, X H
7
8
9
R:
R:
R:
H, X H
4
5
6
R:
R:
R:
H, X H
OMe,X H
OMe,X H
OMe,X H
H,X:Cl
H,X:Cl
H,X:Cl
Scheme-I: Synthesis of tetrahydroacridin-9-ones derivatives
Reactivity of compound 9 with halogen derivatives:
For our part, we examined the alkylation reaction under the
catalysis conditions by transfer of solid-liquid phase of the
tetrahydroacridin-9-ones derivatives with various halogenated
derivatives using methyl iodomethane, bromoethane, propargyl
bromide. Potassium carbonate is used as inorganic base in
anhydrous tetrahydrofurane and bromide of tetra-n-butyl-
ammonium (BTBA) as a catalyst.
The structures of the isolated compounds were established
on the basis of spectral data, 1H NMR spectra of compounds
10a-c, recorded in DMSO-d6, present, besides the signals
corresponding to the protons of two methyl groups and
aromatic protons, signals relating to the protons of the N-alkyl
groups. The different chemical shifts are reported in Table-1.
13C NMR spectra of compounds 10 a-c, recorded in DMSO-d6,
are collected in Table-2.
It is found that, regardless of the used alkyl halide, alkyla-
tion of 2-chloro-5,6,7,8-tetrahydroacridin-9(10H)-one (9) led,
after 24 h under stirring at ambient temperature, leads to
N-alkyl compounds in good yield: 64-86 % (Scheme-II).
Reactivity of β-keto esters with 2-amino-5,6-dimethyl-
benzimidazole: We are interested in the preparation of new
heterocyclic compounds bonding pyrimidinone nuclei by
condensation, in ethanol under reflux of β-keto esters and
2-amino-5,6-dimethylbenzimidazole (Scheme-III).
O
O
Cl
Cl
RX/K2CO3/BTBA
O
O
O
R3
R1
N
Ethanol
Reflux
N
24h/T.A
N
N
H
R2
+
NH2
R1
O
R
10a-c
a:R=CH3
b:R=C2H5
N
H
N
N
H
R3
c:R=CH2-CH=CH2
Scheme-III: Synthesis of pyrimidinone derivatives
Scheme-II: Alkylation of 2-chloro-5,6,7,8-tetrahydroacridin-9(10H)-one
(9), leading after 24 h, under stirring at ambient temperature,
to N-alkyl compounds.
The condensation of 2-aminobenzimidazole with β-keto
esters was carried out in ethanol under reflux. In all cases, we
obtained pyrimidinone derivatives in good yields. The results
of the condensation of these β-keto esters with amines are
recorded on Table-3.
The structures of the isolated compounds were established
on the basis of spectral data, 1H NMR, 13C NMR and IR. 1H
NMR spectra of compounds 10a-c, recorded in DMSO-d6,
TABLE-1
1H NMR SPECTRA OF 10a-c COMPOUNDS
Products
CH2 (Caciques)
CH3
CH3
–
CH2N
–
CHVinylique CH2Vinylique
CHarom
1.65-1.85 (m, 4H)
2.60-3.00 (m, 4H)
3.26
(s, 3H)
7.6(d, J = 8.9 Hz, 1H); 7.8 (dd, J = 8.9,
2.0 Hz, 1H); 8.3 (d, J = 2.0 Hz, 1H);
–
–
–
–
10a
1.70-2.00 (m, 4H)
2.70-3.10 (m, 4H)
1.51(s, 3H) 3.25 (q, 2H)
J = 7.0 Hz
7.5(d, J = 8.9 Hz, 1H); 7.7 (dd, J = 8.9,
2.0 Hz, 1H); 8.2 (d, J = 2.0 Hz, 1H);
–
–
10b
10c
J = 7.0 Hz
1.70-2.00 (m, 4H)
2.65-2.90 (m, 4H)
5.80-6.00 5.00-5.30
(m, 1H) (m, 2H)
3.76 (m, 2H)
–
7.50-8.20 (m, 3H)
TABLE-2
13C NMR SPECTRA OF 10a-c COMPOUNDS
CH2
(Caciques)
21.72; 21.81;
21.99; 29.48
Products
10a
CH3
CH3
–
CH2N
–
CHVinylique
CH2Vinylique
CHarom
Cq
117.16; 131.89;
126.48
121. 69; 123.96 125.69;
138.96; 145.77; 175.77
44.05
–
–
–
–
21.01; 21.43;
21.86; 29. 37
118.29; 132.91;
126.94
121. 84; 123.29 125.91;
138.29; 146. 08; 174.41
–
–
18.21
–
48. 84
49.93
10b
21.14; 21.42;
21.69; 29.30
117.20; 131.66;
126.95
121. 92; 123.46 125.66;
138.46; 146.14; 175.31
136.46
119.93
10c

3678 Kouadri et al.
Asian J. Chem.
TABLE-3
RESULTS OF THE CONDENSATION OF β-KETO ESTERS WITH AMINES
2-Amino-5,6-
dimethylbenzimidazole
Conditions
operators
Entry
1
Product obtained
Yield (%)
77
β-Keto esters
O
N
O
O
Ethanol,
8 h,
reflux
OEt
N
N
H
11
O
N
N
O
O
Sans solvent,
24 h,
NH2
2
3
4
80
74
75
OMe
N
T.A.
N
N
H
H
12
O
O
O
Ethanol,
8 h,
reflux
N
OMe
N
N
H
13
O
O
O
Ethanol,
9 h,
reflux
N
MeO
OMe
O
N
N
H
14
Pyrimidinones derivatives compounds structures were
established from 1H NMR and 13C NMR spectral data.
1H NMR spectra at 300 MHz in DMSO, we observe the
characteristics of the signal pyrimidinones derivatives structure.
These spectra differ slightly in the chemical shift, depending
on the nature of the substituents, i.e. in their electronic effects.
All spectra show signals in the region 7.25-8.43 ppm
corresponding to the aromatic protons. We note that the proton
of the double bond of the compounds 13 and 14 appears in the
form of a singlet signal between 5.75-5.82 ppm.
of the ketonic function. The resultant intermediate formed by
elimination of a molecule of water, followed by esterification
reaction leads to the skeleton of the pyrimidinone derivatives.
Cyclization involves the attack of intracyclic nitrogen yielding
the pyrimidinone derivative.
This method enabled us to prepare poly and heterocyclic
compounds in one step under simple conditions. We analyzed
the biological activity of chemically synthesized molecules
by investigating their antimicrobial and antifungal effect.
Evaluation of antimicrobial and antifungal activity
of the resultant compounds: If antimicrobial activity of 2-
amino-5,6-dimethylbenzimidazole (ABDI) is nil for all of the
tested strains, it is otherwise for compounds (11, 12, 13 and
14) resulting from the condensation of the β-keto esters with
the latter.
13C NMR spectra of the pyrimidinone derivatives com-
pounds exhibit, in particular, signals at 158.21-159.87 ppm;
98.29-103.23 ppm and 145.82-169 ppm, corresponding
respectively to the carbonyl carbon (C=O) and two ethylenic
carbons in α and β.
The results obtained from this study have enabled us to
propose the mechanism of formation of pyrimidinone deri-
vatives (Scheme-IV). The formation of these latter compounds
can be explained by a nucleophilic attack of the free electron
pair of the nitrogen atom of the amino group on the carbonyl
Antifungal activity of compounds (11, 12, 13 and 14):
The antifungal activity of the products obtained from the
condensation of β-keto esters with 2-amino-5,6-dimethyl-
benzimidazole is illustrated in Fig. 1.
O
O
N
N
N
N
NH2 +
R1
R2
NH
NH
R3
O
N
H
N
R3
R1
R1
H
R3
O
O
O
R2
Scheme-IV: Formation mechanism of pyrimidinone derivatives

Vol. 27, No. 10 (2015)
Reactivity of β-Cetoesters Compounds and Synthesis of Nitrogenated Heterocycles 3679
11
12
enterica, which are more or less sensitive (the diameter of the
inhibition halo is 0.9 cm for the first and varies from 0.7 to
1.15 cm for the second).
Antimicrobial activity of compound 11: The antimicro-
bial activity of compound 11 towards the fungal flora and
bacterial flora is illustrated in Fig. 3.
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
13
14
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
Fig. 1. Antifungal activity of compounds (11, 12, 13 and 14)
It is observed that the activity varies from one compound
to another on the one hand and this activity depends on the
tested strain, on the other hand. Indeed, it seems that Aspergillus
flavus is the most sensitive to the tested compounds (the
diameter of the inhibition halo varies from 0.6 to 1.45 cm)
followed by Fusarium oxysporum sp lini species (diameter
varies from 0.4 to 1.5 cm). For the other strains, there are
always one or more compounds that are without effects. For
example: Fusarium oxysporum sp albedins and Aspergillus
carbonarius are resistant to compounds 11 and 14 (diameter
of the halo zero), Fusarium culmorum is resistant to 11, 13
and 14, Penicillium galbrum is resistant to compounds 11 and
13, Mucor ramannianus is resistant to the compound 14 and
finally Aspergillus ochraceus is resistant to the compound 11.
Antibacterial activity of compounds (11, 12, 13 and
14): Fig. 2 shows the antibacterial activity of the compounds
(11, 12, 13 and 14) on the six tested strains.
Fig. 3. Antimicrobial activity of compound 11
Two facts should be noted, first compound 11 is ineffective
against bacterial flora, except for Salmonella enterica where
there is a halo of inhibition estimated at 1.15 cm, on the other
hand only the three fungal strains, Fusarium oxysporum sp
lini, Aspergillus flavus and Mucor ramannianus, are sensitive
to the action of compound 11. This sensitivity varies from one
strain to another. It is highest for Aspergillus flavus (1.45 cm
diameter) and lowest for Fusarium oxysporum sp lini and
Mucor ramannianus the diameter of the aureole is respectively
0.7 and 0.9 cm.
Antimicrobial activity of compound 12: Fig. 4 reports
the antimicrobial effect of compound 12 on the tested microbial
strains.
1.4
1.2
11
1.0
0.8
0.6
0.4
0.2
0
12
13
14
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
Fig. 2. Antibacterial activity of compounds (11, 12, 13 and 14)
It is noticed that Bacillus subtilis has developed a resistance
towards all compounds, Pseudomonas aeruginosa is sensitive
only towards the compound 13 (equal to 0.5 cm diameter of
the zone of inhibition) and Klebsiella pneumoniae is sensitive
towards compounds 12 and 13 (the diameter of the aureole is
0.85 and 0.8 cm respectively). For other species, strains are
resistant against a single compound and that their sensitivity
varies from one compound to another. E. coli is the most
sensitive with the diameter of inhibition ranging from 0.9 to
1.05 cm; followed by Listeria monocytogenes and Salmonella
Fig. 4. Antimicrobial activity of compound 12
There are only two bacterial strains Bacillus subtilis and
Pseudomonas aeruginosa are resistant to the action of com-
pound 12. For other strains, the resistance (or sensitivity) is
variable within the bacterial group either within the fungal
group. Nevertheless, lowest resistance was observed for fungi:
Aspergillus flavus, Aspergillus ochraceus and Penicillium
galbrum, whose diameter is 1.45, 1.1 and 0.99 cm, respectively

3680 Kouadri et al.
Asian J. Chem.
and the highest resistance was observed for both fungi:
Fusarium culmorum and Aspergillus carbonarius.
Aspergillus ochraceus and Penicillium galbrum are sensitive
to the action of the compound 14 where the diameter of the
aureole is respectively 1.5, 1.1, 1.1 and 0.5 cm. The remaining
three fungal strains have developed no resistance to the 14
compounds.
Sensitivity of strains according Duraffourd: The sensi-
tivity of strains towards different compounds is reported in
Fig. 7.
Antimicrobial activity of compound 13: The antimicro-
bial activity of compound 13 on the microbial flora is reported
in Fig. 5. It is observed that only two fungi: Fusarium culmorum
and Penicillium galbrum and bacteria: Bacillus subtilis have
developed a resistance to the compound 13 that resulted in a
nil diameter. Other strains have developed resistance more or
less variable, thus Fusarium oxysporum sp lini, Aspergillus
ochraceus and E.coli have shown to be the most sensitive
(diameters of the aureole is estimated respectively at 1.05, 1.5
and 1.05 cm); the remains strains present considerable
sensitivity.
100
90
80
70
60
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
N
L
50
40
30
20
10
0
M
11
12
13
14
Fig. 7. Susceptibility frequency of strains to different compounds
The sensitivity is nil for 78.57 % of the tested strains (35.71
% for bacteria and 42.86 % for fungi) by compound 11 and
14.29 % having limited sensitivity (7.14 % for bacteria and
7.14 % for fungi). Strains tested by compounds 12 and 13
whose sensitivity is nil are estimated at 50 % (21.43 % for
bacteria 28.57 % and for fungi), 7.14 % of the strains have
limited sensitivity (3.57 % for bacteria and 3.57 % for fungi).
And for the compound 14, 64.29 % of strains have a nil
sensitivity (28.57 % for bacteria 35.72 % and for fungi); 28.57
% have limited sensitivity (14.28 % for bacteria and 14.28 %
for fungi). We also note that the average sensitivity is 7.14 %
(for all fungi) by the four compounds.
Fig. 5. Antimicrobial activity of compound 13
Antimicrobial activity of compound 14: Fig. 6 shows
the antimicrobial activity of compound 14 against bacterial
and fungal strains.
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
REFERENCES
1. R.N. Salvatore, C.H. Yoon and K.W. Jung, Tetrahedron, 57, 7785
(2001).
2. A. Frideling, R. Faure, J.-P. Galy, A. Kenz, I. Alkorta and J. Elguero,
Eur. J. Med. Chem., 39, 37 (2004).
3. D. Santos Pisoni, J. Sobieski da Costa, D. Gamba, C.L. Petzhold, A.
César de Amorim Borges, M.A. Ceschi, P. Lunardi and C.A. Saraiva
Gonçalves, Eur. J. Med. Chem., 45, 526 (2010).
4. A.M. AbdelHalim, A.M. Tawfik, S. S. Ibrahim, A.M. ElKazak, Indian
J. Heterocycl. Chem., 3, 165 (1994).
5. Y.L. Chen, C.M. Lu, I.L. Chen, L.T. Tsao and J.P.J. Wang, Med. Chem.,
45, 4689 (2002).
6. Y.-L. Chen, I.-L. Chen, C.-M. Lu, C.-C. Tzeng, L.-T. Tsao and J.-P.
Wang, Bioorg. Med. Chem., 11, 3921 (2003).
7. J.S. Skotnicki and S.C. Gilman, Chem. Abstr., 112, 118 (1990).
8. M. Yamaguchi, K. Wakasugi, R. Saito, Y. Adachi, Y. Yoshikawa, H.
Sakurai and A. Katoh, J. Inorg. Biochem., 100, 260 (2006).
9. Y.S. Sadanandam, M.M. Shetty and P.V. Diwan, Eur. J. Med. Chem.,
27, 87 (1992).
10. C.M. Wright, R.J. Chovatiya, N.E. Jameson, D.M. Turner, G. Zhu, S.
Werner, D.M. Huryn, J.M. Pipas, B.W. Day, P. Wipf and J.L. Brodskya,
Bioorg. Med. Chem., 16, 3291 (2008).
Fig. 6. Antimicrobial activity of compound 14
It seems clear that the compound 14 may effective against
bacterial strains where the diameter of the aureole is nil, except
for E. coli and Listeria monocytogenes where the diameter is
0.95 and 0.9, respectively. For fungi, we observed that four
strains: Fusarium oxysporum sp lini, Aspergillus flavus,
11. A.C. Rodriguez, R.G. Cañas and A.M. Bernardo, An. Quim. Ser. C, 83,
24 (1987).