Synthesis of novel 2-(4-(2-morpholinoethoxy)phenyl)-N-phenylacetamide analogues and their antimicrobial study

Article abstract of DOI:10.1007/s12039-012-0308-3

A new class of potential biologically active 2-(4-(2-morpholinoethoxy) phenyl)-N-phenylacetamides has been synthesized from hydroxyphenylacetic acid. The products were characterized through IR, ¹H NMR, mass spectral studies and elemental analys

Full text of DOI:10.1007/s12039-012-0308-3

c
J. Chem. Sci. Vol. 124, No. 5, September 2012, pp. 1019–1023. ꢀ Indian Academy of Sciences.
Synthesis of novel 2-(4-(2-morpholinoethoxy)phenyl)-N-phenylacetamide
analogues and their antimicrobial study
H P JAYADEVAPPA1,∗, G NAGENDRAPPA1, S UMESH2 and S CHANDRASHEKAR2
1Department of Studies in Chemistry, 2Department of Studies in Applied Botany and Biotechnology,
Manasagangotri, Mysore 570 006, India
e-mail: hpjayadevappa@yahoo.com
MS received 27 February 2012; revised 17 May 2012; accepted 25 May 2012
Abstract. A new class of potential biologically active 2-(4-(2-morpholinoethoxy)phenyl)-N-phenylaceta-
mides has been synthesized from hydroxyphenylacetic acid. The products were characterized through IR, 1H
NMR, mass spectral studies and elemental analysis. The compounds were screened for antimicrobial activity
by disc agar diffusion technique. The potency of compounds is tested against variety of fungal and bacte-
rial strains in comparison to clotrimazole and streptomycin, respectively. Some of the synthesized compounds
exhibit superior in vitro activity compared to the standard drugs.
Keywords. 2-(4-(2-Morpholinoethoxy)phenyl)-N-phenylacetamides; in vitro antimicrobial activity; heterocycles;
clotrimazole.
1. Introduction
and antagonist properties.11 In view of this, it was pro-
posed to synthesize novel morpholino acetamides and
to study their biological activity.12
The discovery of penicillin by Alexander Fleming in
1928 is a milestone in the history of medicine.1 It was
predicted that infectious diseases would be completely
eliminated by the discovery of more antimicrobials.
Unfortunately, the microorganisms are becoming resis-
tant more quickly than new drugs are being made avail-
able. The rapid emergence of antibacterial resistance
and the lack of novel antibiotics in the past several
decades enforce researchers to discover novel antibio-
tics to combat antimicrobial resistance.2
The design of new antimicrobial agents with reduced
toxicity and lower side effect is a continuous pro-
cess. Many heterocycles were frequently encountered in
medicinal chemistry whose derivatives represent a class
of compounds possessing a wide spectrum of antimi-
crobial activity. One such heterocycle morpholine is
a building block in many pharmaceutical prepara-
tions like the antibiotic linezolid,3 the anticancer agent
gefitinib4 and the analgesic dextromoramide.5 Certain
morpholino acetimidamide derivatives were found to
suppress hepatitis C virus replication.6 Paracetamol,
a simple acetamide is a widely used analgesic and
antipyretic agent. Acetamide derivatives show potential
biological functions. They possess excellent antimicro-
bial,7 antiinflammatory,8 antioxidant,9 tranquilizer10
2. Experimental
2.1 Materials
Chemicals used were of analytical grade. The reactions
were monitored by TLC on aluminium-backed silica
plate visualized by UV-light. Melting points were deter-
mined on a Thomas Hoover capillary melting point
1
apparatus using digital thermometer. H NMR spectra
were recorded on a Bruker 300 MHz spectrometer in
CDCl3. Chemical shifts were reported in parts per mil-
lion down field from tetramethyl silane. Mass spectra
were recorded on a VG70-70 H mass spectrometer.
2.2 Synthesis of 2-(4-hydroxyphenyl)-N-phenyl
acetamides
The synthetic sequence is outlined in scheme 1.13–17
A
mixture of 2-(4-hydroxyphenyl)acetic acid (1.10 mmol)
and corresponding amine (2a–e. 10 mmol) in few mL of
water and few drops of pyridine catalyst was stirred for
48 h at room temperature. The product was extracted
with ice cold ether (3 × 40 mL). The ether layer was
washed with 2% sodium carbonate solution (3 × 20 mL),
2% hydrochloric acid solution (3 × 30 mL) and dis-
tilled water. Then the organic layer was dried over
∗For correspondence
1019

1020
H P Jayadevappa et al.
OH
OH
NH2
+
Pyridine
H
N
OH
R
O
O
R
1
2a-e
3a-e
O
O
N
O
N
Cl
4
H
N
K2CO3
Dimethyl sulphoxide
O
R
5a-e
e: R = CH3
a: R = H,
d: R = Cl,
b: R = NO2,
c: R = Br,
Scheme 1. Synthesis of 2-(4-(2-morpholinoethoxy)phenyl)-N-phenylacetamides.
anhydrous sodium sulphate and evaporated to dryness. 9.02(br s, 1H, OH); EI-MS; m/z 272 (M+, 62), 273
The crude product was recrystallized using alcohol to (M+, 87), 274 (M+, 45), 139 (62), 104 (32). Ana. Calcd
afford 2-(4-hydroxyphenyl)-N-phenyl acetamides (3a–e). for C14H12N2O4 (272); C, 61.76; H, 4.44; N, 10.30.
Found; C, 61.75; H, 4.42; N, 10.32.
2.3 Charecterisation of compounds (3a–e)
2.3c Compound 3c. N-(4-bromophenyl)-2-(4-hydroxy-
phenyl)acetamide: Mp 169–171◦C; IR(Nujol) 1705 cm−1
(amide, C=O), 3385 cm−1 (amide, N-H), 3510–
2.3a Compound 3a. 2-(4-hydroxyphenyl)-N-phenyl-
acetamide: Mp 160–162◦C; IR(Nujol) 1695 cm−1 (amide,
C=O), 3360 cm−1(amide, N-H), 3525–3610 cm−1 (O-
1
3630 cm−1 (O-H); H NMR(CDCl3); δ 2.62(s, 2H,
1
H); H NMR(CDCl3); δ 2.6(s, 2H, CH2), 3.12(s distd,
CH2), δ 3.14(s distd, 1H, N-H), 7.2–7.8(m, 8H, Ar-H),
9.02(br s, 1H, OH); EI-MS; m/z 306 (M+, 55), 307
(M+, 92), 308 (M+,42), 173 (54), 104 (62), 124.5(78).
Anal. Calcd for C14H12BrNO2 (306); C, 54.92; H, 3.95;
Br, 26.10; N, 4.58. Found; C, 54.88; H, 3.96; Br, 26.15;
N, 4.60.
1H, N-H), 6.8–7.8(m, 9H, Ar-H), 9.0(br s, 1H, OH);
EI-MS; m/z 227 (M+, 75), 228 (M+, 84), 226 (100),
121 (43), 93 (78). Anal. Calcd for C14H13NO2 (227);
C, 73.98; H, 5.77; N, 6.17. Found; C, 74.02; H, 5.75;
N, 6.19.
2.3b Compound 3b. 2-(4-hydroxyphenyl)-N-(4-nitro- 2.3d Compound 3d. N-(4-chlorophenyl)-2-(4-hydroxy-
phenyl)acetamide: Mp 172–174◦C; IR(Nujol) 1725 cm−1 phenyl)acetamide: Mp 170–172◦C; IR(Nujol) 1705 cm−1
(amide, C=O), 3420 cm−1 (amide, N-H), 3500– (amide, C=O), 3390 cm−1 (amide, N-H), 3530–
1
3615 cm−1 (O-H); H NMR(CDCl3); δ 2.62(s, 2H, 3635 cm−1 (O-H); 1H NMR(CDCl3); δ 2.60(s, 2H,
CH2), δ 3.1(s distd, 1H, N-H), 7.1–7.8(m, 8H, Ar-H), CH2), δ 3.12(s distd, 1H, N-H), 7.12–7.82(m, 8H,

Synthesis of novel 2-(4-(2-morpholinoethoxy)phenyl)-N-phenylacetamide analogues and their antimicrobial study 1021
Ar-H), 9.02(br s, 1H, OH); EI-MS; m/z 261.5 (M+, 45), 1708 cm−1 (amide, C=O), 3425 cm−1 (amide, N-H);
262.5 (M+, 100), 260.5 (M+, 35), 128.5 (72), 104(53). 1H NMR(CDCl3); δ 1.34(t, 4H, ring 2N-CH2), 2.0(t,
Anal. Calcd for C14H12ClNO2 (261.5); C, 64.25; H, 2H, N-CH2), 2.62(s, 2H, CH2), 3.1(s distd, 1H, N-H),
4.62; Cl, 13.56; N, 5.35. Found; C, 64.22; H, 4.61; Cl, 3.62(t, 2H, O-CH2), 4.24(t, 4H, ring 2O-CH2), 7.1–
13.54; N, 5.36.
7.8(m, 8H, Ar-H); EI-MS; m/z 387 (M+, 72), 388 (M+,
42), 115 (65), 100 (45), Anal. Calcd for C20H23N3O5
(385); C, 62.33; H, 6.01; N, 10.90. Found; C, 62.31; H,
6.02; N, 10.92.
2.3e Compound 3e. 2-(4-hydroxyphenyl)-N-(4-methyl-
phenyl)acetamide: Mp 165–167◦C; IR(Nujol) 1700 cm−1
(amide, C=O), 3395 cm−1 (amide, N-H), 3525–
3640 cm−1 (O-H); 1H NMR(CDCl3); δ 2.58(s, 2H,
CH2), δ 3.08(s distd, 1H, N-H), 6.9–7.8(m, 8H, Ar-
H), 9.02(br s, 1H, OH); EI-MS; m/z 241 (M+, 67),
242 (M+, 100), 240 (M+, 38), 108 (51), 104(65). Anal.
Calcd for C15H15NO2 (241); C, 74.67; H, 6.27; N, 5.82.
Found; C, 74.64; H, 6.25; N, 5.83.
2.5c Compound 5c. 2-(4-(2-morpholinoethoxy)phenyl)-
N-(4-bromophenyl)acetamide: Mp 195–197◦C; IR(Nujol)
1710 cm−1 (amide, C=O), 3385 cm−1 (amide, N-H); 1H
NMR(CDCl3); δ 1.34(t, 4H, ring 2N-CH2), 2.0(t, 2H,
N-CH2), 2.62(s, 2H, CH2), δ 3.14(s distd, 1H, N-H),
3.6(t, 2H, O-CH2), 4.22(t, 4H, ring 2O-CH2), 7.2–
7.8(m, 8H, Ar-H; EI-MS; m/z 420 (M+, 65), 421 (M+,
80), 115 (55), 100 (38), Anal. Calcd for C20H23BrN2O3
(419); C, 57.29; H, 5.53; Br, 19.06; N, 6.68. Found; C,
57.25; H, 5.52; Br, 19.08; N, 6.70.
2.4 Synthesis of 2-(4-(2-morpholinoethoxy)phenyl)-
N-phenylacetamides
A mixture of 3a–e (2 mmol) and 1-(2-chloroethyl) mor-
pholine hydrochloride (4.2 mmol) in the presence of
anhydrous potassium carbonate (5 mmol) and dimethyl
sulphoxide (DMSO) (15 ml) was refluxed for 12 h and
then cooled. The residual mass was triturated with
ice water to remove potassium carbonate and dimethyl
sulphoxide. Then the product was extracted with chlo-
roform (3 × 20 mL). The organic layer was washed with
saturated sodium chloride-solution (3 × 20 mL) and 2%
sodium hydroxide solution (3 × 20 mL) followed by
distilled water and dried over anhydrous sodium sul-
phate. The crude product obtained by the evaporation of
organic layer on recrystallizaton using ethanol afforded
the title compounds 2-(4-(2-morpholinoethoxy)phenyl)-
N-phenylacetamides (5a–e). The compounds 3a–e and
5a–e were characterized by IR, 1H NMR, mass spectral
studies and elemental analysis.
2.5d Compound 5d. 2-(4-(2-morpholinoethoxy)phenyl)-
N-(4-chlorophenyl)acetamide: Mp 198–200◦C; IR(Nujol)
1705 cm−1 (amide, C=O), 3390 cm−1 (amide, N- H);
1H NMR(CDCl3); δ 1.34(t, 4H, ring 2N-CH2), 2.0(t,
2H, N-CH2), 2.60(s, 2H, CH2), δ 3.12(s distd, 1H,
N-H), 3.6(t, 2H, O-CH2), 4.22(t, 4H, ring 2O-CH2),
7.12–7.82(m, 8H, Ar-H); EI-MS; m/z 375.5 (M+, 78),
376.5 (M+, 90), 115 (55), 100 (32), Anal. Calcd for
C20H23ClN2O3 (374.5); C, 60.08; H, 6.18; Cl, 9.46; N,
7.47. Found; C, 60.02; H, 6.16; Cl, 9.44; N, 7.49.
2.5e Compound 5e. 2-(4-(2-morpholinoethoxy)phenyl)-
N-(4-methylphenyl)acetamide: Mp 194–196◦C; IR(Nujol)
1700 cm−1 (amide, C=O), 3395 cm−1 (amide, N-H); 1H
NMR(CDCl3); δ 1.34(t, 4H, ring 2N-CH2), 2.0(t, 2H,
N-CH2), 3.58(t, 2H, O-CH2), 4.18(t, 4H, ring 2O-CH2),
2.58(s, 2H, CH2), δ 3.08(s distd, 1H, N-H), 6.9–7.8(m,
8H, Ar-H); EI-MS; m/z 353 (M+, 70), 356 (M+, 92),
115 (42), 100 (45), Anal. Calcd for C21H26N2O3 (354);
C, 71.16; H, 7.38; N, 7.90. Found; C, 71.13; H, 7.36; N,
7.92.
2.5 Charecterization of compounds (5a–e)
2.5a Compound 5a. 2-(4-(2-morpholinoethoxy)phenyl)-N-
phenylacetamide: Mp 190–192◦C; IR(Nujol) 1698 cm−1
(amide, C=O), 3370 cm−1(amide, N-H); 1H NMR
(CDCl3); δ 1.34(t, 4H, ring 2N-CH2), 2.0(t, 2H, N-
CH2), 2.6(s, 2H, CH2), 3.12(s distd, 1H, N-H), 3.6(t,
2H, O-CH2), 4.2(t, 4H, ring 2O-CH2), 6.8–7.8(m, 9H,
Ar-H); EI-MS; m/z 341 (M+, 68), 342 (M+, 85), 115
(75), 100(38), Anal. Calcd for C20H24N2O3 (340); C,
70.56; H, 7.11; N, 8.23. Found; C, 70.54; H, 7.12;
N, 8.25.
2.6 Antimicrobial study
The in vitro antimicrobial activity of the compounds 1,
3a–e, 5a–e and morpholine were studied by disc agar
diffusion technique18 at different concentrations rang-
ing from 20 to 250 mg/mL using ethylacetate as con-
trol. The specific bacterial culture was spread uniformly
over nutrient agar in Petri plates. Then the test solu-
tion, standard and control of known similar concen-
2.5b Compound 5b. 2-(4-(2-morpholinoethoxy)phenyl)- trations were spotted in sample wells at specific dis-
N-(4-nitrophenyl)acetamide: Mp 203–205◦C; IR(Nujol) tance. The zones of inhibition19 were measured after 24 h

1022
H P Jayadevappa et al.
Table 1. Antifungal screening results of compounds 3a–e and 5a–e (IC50
values in μg/mL).
Compound
C. albicans C. parapsilosis F. moniliforme A. ochraceus
3a
3b
3c
3d
3e
70
70
60
60
70
80
80
70
70
80
110
90
90
80
100
70
40
50
70
70
5a
5b
5c
5d
5e
40
20
20
30
40
70
30
30
40
60
80
60
70
70
70
60
20
30
40
50
Control
1
Morpholine
_
80
90
_
_
_
90
120
120
40
70
80
20
100
30
Clotrimazole 30
incubation at 37◦C for antibacterial activity and 48 h synthesized acetamides 3a–e possess enhanced activity
incubation at 25◦C for antifungal activity. The half
when compared to morpholine and the compound 2-(4-
maximal inhibitory concentration (IC50) is determined
for each pathogen and the experiments were carried out
in duplicate repeatedly to get reproducible results.
hydroxyphenyl)acetic acid which is the core structure in
the series. The efficacy of title compounds 5a–e is com-
parable with that of standard drug clotrimazole. The
activity results reveal that the compounds 5b, 5c and
5d possessing nitro, bromo and chloro groups, respec-
tively exhibited maximum activity by inhibiting growth
of all the fungi to a significant level in comparison to the
standard drug. The compounds 5a and 5e are slightly
less potent due to absence of active functional groups.
All the compounds of the series are more potent to
C. albicans and C. parapsilosis and were less potent to
F. moniliforme and A. ochraceus.
3. Results and discussion
3.1 Antifungal activity
The compounds were screened against the fungi
C. albicans, C. parapsilosis, F. moniliforme and
A. ochraceus using clotrimazole as the reference stan-
dard and the results are summarized in table 1. The
Table 2. Antibacteerial screening results of compounds 3a–e and 5a–e (IC50
values in μg/mL).
Compound
P. vulgaris
P. fluorescenes
S. aureus
B. mycoides
3a
3b
3c
3d
3e
80
60
70
70
80
70
40
40
50
60
110
90
90
90
100
100
90
80
80
100
5a
5b
5c
5d
5e
60
40
40
60
60
40
30
30
40
40
80
70
70
80
80
90
80
60
70
90
Control
1
Morpholine
Streptomycin
_
_
_
_
90
120
50
90
90
30
120
120
60
120
150
70

Synthesis of novel 2-(4-(2-morpholinoethoxy)phenyl)-N-phenylacetamide analogues and their antimicrobial study 1023
3.2 Antibacterial activity
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B. mycoides along with the standard streptomycin were
summarized in table 2. Once again, the synthesized
acetamides 3a–e showed increased potency when com-
pared to morpholine and 2-(4-hydroxyphenyl)acetic
acid and the efficacy of title compounds 5a–e is com-
parable with that of standard drug streptomycin. The
compounds 5a–e were almost equipotent to P. vulgaris
and P. fluorescenes where as less potent to S. aureus and
B. mycoides when compared to the standard. The com-
pounds 5b, 5c and 5d possess excellent activity against
the bacteria. This may be due to the presence of nitro
and halo groups on N-phenyl ring.
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4. Conclusions
In conclusion, the synthesized compounds 5a–e have
remarkable antifungal and antibacterial activity. The
activity of compounds 5b, 5c and 5d with 4-
Nitrophenyl and 4-Halophenyl groups indicate the
importance of functional groups in enhancing the
antimicrobial activity of a compound. The antimicro-
bial potency of the compounds is more against Gram
negative bacteria compared to Gram positive bacteria.
The efficacy of compounds has a bright prospect for
the discovery of many new drugs used in the treat-
ment of fungal and bacterial infections. Finally, one can
conclude that the condensation of two bio-active com-
pounds may be useful to produce new compounds with
desired activity.
Acknowledgements
The authors thank the University of Mysore, Mysore for
providing laboratory facilities in Department of Stud-
ies in Chemistry, Manasagangothri for synthetic work
and Department of Applied Botony and Biotechnology,
Manasgangothri, Mysore for conducting antimicrobial
study.
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