Synthesis and antimicrobial activities of Diphenyl(Arylamino)(1-Phenyl-3- (Pyridin-2-Yl)-1 H -Pyrazol-4-Yl)Methylphosphonates

Article abstract of DOI:10.1080/10426507.2012.690117

A series of novel diphenyl(arylamino)(1-phenyl-3-(pyridin-2-yl)-1H-pyrazol- 4-yl)methylphosphonates have been synthesized in high yields. They were screened for their antibacterial activities against Escherichia coli (NCIM2065) as a Gram-negative bacterium, Bacillus subtilis (PC1219) and Staphylococcus aureus (ATCC25292) as Gram-positive bacteria, and Schccaromycies cerevisiae as a fungus. The minimum inhibitory concentrations (MICs) of the synthetic compounds showed moderate antibacterial and antifungal activities at low concentrations (10-1000g/mL). Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426507.2012.690117

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Synthesis and Antimicrobial Activities
of Diphenyl(Arylamino)(1-Phenyl-3-
(Pyridin-2-Yl)-1H-Pyrazol-4-
Yl)Methylphosphonates
Mohamed F. Abdel-Megeed a , Badr E. Badr b , Mohamed M. Azaam a
& Gamal A. El-Hiti a c
a Department of Chemistry, Faculty of Science, Tanta University,
Tanta, Egypt
b Department of Botany, Faculty of Science, Tanta University, Tanta,
Egypt
c School of Chemistry, Cardiff University, Cardiff, UK
Accepted author version posted online: 09 May 2012.Version of
record first published: 10 Sep 2012.
To cite this article: Mohamed F. Abdel-Megeed, Badr E. Badr, Mohamed M. Azaam & Gamal A. El-Hiti
(2012): Synthesis and Antimicrobial Activities of Diphenyl(Arylamino)(1-Phenyl-3-(Pyridin-2-Yl)-1H-
Pyrazol-4-Yl)Methylphosphonates, Phosphorus, Sulfur, and Silicon and the Related Elements, 187:12,
1462-1468
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Phosphorus, Sulfur, and Silicon, 187:1462–1468, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.690117
SYNTHESIS AND ANTIMICROBIAL ACTIVITIES
OF DIPHENYL(ARYLAMINO)(1-PHENYL-3-(PYRIDIN-2-YL)-
1H-PYRAZOL-4-YL)METHYLPHOSPHONATES
Mohamed F. Abdel-Megeed,1 Badr E. Badr,2 Mohamed M.
Azaam,1 and Gamal A. El-Hiti1,3
1Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt
2Department of Botany, Faculty of Science, Tanta University, Tanta, Egypt
3School of Chemistry, Cardiff University, Cardiff, UK
GRAPHICAL ABSTRACT
N
N
N
N
P(OPh)3, LiClO4
NHAr
Ar NH2
+
DCM, RT, 24-30 h
CHO
HC OPh
P
N
N
O
OPh
Ph
Ph
2-7
)
1
(70-84%
Ar = Ph, 4-ClC6H4, 4-MeC6H4, 4-Me2NC6H4, 4-HO2CC6H4, 4-MeOC6H4
Abstract A series of novel diphenyl(arylamino)(1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-4-
yl)methylphosphonates have been synthesized in high yields. They were screened for their
antibacterial activities against Escherichia coli (NCIM2065) as a Gram-negative bacterium,
Bacillus subtilis (PC1219) and Staphylococcus aureus (ATCC25292) as Gram-positive
bacteria, and Schccaromycies cerevisiae as a fungus. The minimum inhibitory concentrations
(MICs) of the synthetic compounds showed moderate antibacterial and antifungal activities at
low concentrations (10–1000 µg/mL).
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords α-Aminophosphonates; antimicrobial; Gram-negative and Gram-positive bacteria;
fungi; minimum inhibitory concentrations
INTRODUCTION
Organophosphorus derivatives are an important class of biologically active com-
pounds.1 α-Aminophosphonates are among the most common organophosphorus deriva-
tives and have been used as enzyme inhibitors, inhibitors of serine hydrolase, peptide
Received 26 February 2012; accepted 21 April 2012.
Address correspondence to Gamal A. El-Hiti, School of Chemistry, Cardiff University, Main Building, Park
Place, Cardiff CF10 3AT, UK. E-mail: el-hitiga@cardiff.ac.uk; gelhiti@yahoo.co.uk
1462

SYNTHESIS AND ANTIMICROBIAL ACTIVITIES
1463
mimics, antiviral, antibacterial, antifungal, anticancer, anti-HIV, antibiotics, herbicidal, and
in other various applications.2–20 Also, α-aminophosphonates having heterocyclic moieties
have shown interesting biological activities.21–24
Various methods for the synthesis of α-aminophosphonates were reported.25–31 How-
ever, one pot Mannich-type32 process of carbonyl compounds, amines, and diphenyl phos-
phite in the presence of a Lewis acid catalyst remains the most efficient, simple, general,
and high yielding method.33–36
We have reported efficient syntheses of various heterocycles37–50 as part of our re-
search in organic chemistry. As part of continuing work in the area of biologically active
heterocycles, we have recently reported the synthesis, antimicrobial, and anticancer activi-
ties of a novel series of α-aminophosphonates.51 The present work was aimed to synthesize
novel α-aminophosphonates containing pyridine and pyrazole moieties with the hope that
new antimicrobial agents could be developed. We now report the successful synthesis of a
novel α-aminophosphonates and their antimicrobial properties.
RESULTS AND DISCUSSION
Chemistry
Reactions of 1-phenyl-3-pyridine-2-yl-1H-pyrazole-4-carboxaldehyde (1; 2 molar
equivalents) with aryl amines (aniline, 4-chloroaniline, 4-toluidine, 4-(N,N-dimethylamino)
aniline, 4-aminobenzoic acid, and 4-anisidine; 4 molar equivalents) and triphenylphosphite
(3 molar equivalents) in the presence of lithium perchlorate, as a Lewis acid, were carried
out in dichloromethane (DCM) at room temperature for 24–30 h under identical condi-
tions. The crude products obtained were purified by crystallization from ethanol to give
the corresponding α-aminophosphonates 2–7 in 70–84% yields (Scheme 1). The reaction
represented in Scheme 1 is general, simple, high yielding, involves easy work-up, and ac-
commodates various substituents to produce substituted α-aminophosphonates efficiently.
N
N
N
N
P(OPh)3, LiClO4
NHAr
Ar NH2
+
DCM, RT, 24-30 h
CHO
HC OPh
P
N
N
O
OPh
Ph
Ph
2-7
)
1
(70-84%
Ar = Ph, 4-ClC6H4, 4-MeC6H4, 4-Me2NC6H4, 4-HO2CC6H4, 4-MeOC6H4
Scheme 1
1
The structures of α-aminophosphonates 2–7 were confirmed by infrared (IR), H
NMR, mass spectroscopy, and elemental analyses. The IR spectra of 2–7 are characterized
by the presence of absorption bands within the 3425–3400 cm−1 region corresponding
to the stretching vibrations of the NH groups. The bands within the 1628–1596 cm−1
region are due to the stretching vibration of the C N groups of the 1H-pyrazole ring while
the absorption bands in the 1321–1310 cm−1 region are due to the symmetric stretching
vibrations of the P O groups and those within the 821–810 cm−1 region are attributed to
the P–O–C groups.

1464
M. F. ABDEL-MEGEED ET AL.
The 1H NMR spectra of α-aminophosphonates 2–7 showed a characteristic exchange-
able singlet within the 10.00–8.01 ppm region due to the NH proton while the CH protons
resonated as doublets (J = 12–15 Hz) within the 6.66–5.43 ppm region. The structures
of compounds 2–7 were confirmed further by electron impact (EI) and electrospray (ES)-
mass spectral and showed either a molecular or pseudomolecular (MH+) ion. Moreover,
the elemental analyses of 2–7 were consistent with the suggested structures.
Antimicrobial Activities
The antimicrobial agents available in the market have various drawbacks such as
toxicity, narrow spectrum of activity, and some also exhibit drug–drug interactions.52 In
view of the high incidence of infections in immunocompromised patients, demands for new
antimicrobial agents with a broad spectrum of activity and good pharmacokinetic properties
have increased.53
α-Aminophosphonates 2–7 along with the starting material 1 were screened for
their in vitro antibacterial and antifungal activities against Escherichia coli (NCIM2065)
as a Gram-negative bacterium, Bacillus subtilis (PC1219) and Staphylococcus aureus
(ATCC25292) as Gram-positive bacteria, and Schccaromycies cerevisiae as a fungus. The
inhibition zones were measured in triplicates and the results are reported in Table S1
(available online in Supplemental Materials).
The results showed that compounds 2–7 showed moderate antimicrobial activities
against the tested organisms. It is also clear that α-aminophosphonates 2–7 are more active
compared to the starting material 1.
Minimum Inhibitory Concentrations (MICs)
The MICs of compound 1 and α-aminophosphonates 2–7 were determined for each
antimicrobial agent by using the agar diffusion method. The inhibition zone was measured in
triplicates in four different concentrations (10–1000 µg/mL) and the mean value standard
deviation (SD) is recorded in Table S2 (available online in Supplemental Materials).
Table S2 (available online in Supplemental Materials) showed that all compounds
exhibit high antimicrobial activities at a concentration of 10–1000 µg/mL for all mi-
croorganisms. Compounds 1–7 showed high antimicrobial activities at a concentration of
1000 µg/mL.
The Lethal Dose
The cytotoxicity lethal dose (LD50) of compounds 1–7 was determined from the
larvae of Artemia salina using the brine shrimp lethality bioassay. The lethal doses for
compounds 1–7 are shown in Figures S1–S7 (available online in Supplemental Materials).
The lethal dose for compounds 2, 5, and 6 were found to be 915, 1000, and
2045 µg/mL, respectively while the lethal dose for compound 3 was 544 µg/mL. Clearly,
compound 6 is the safest compound to be used followed by compounds 2 and 5. On the
other hand, the starting material 1 and compounds 4 and 7 were the least safe compounds.
CONCLUSION
A convenient high yielding process for the synthesis of α-aminophosphonates, having
pyridine and pyrazole moieties, has been developed. The antimicrobial activities of the
newly synthesized compounds exhibit Gram-positive, Gram-negative bacteria and fungi

SYNTHESIS AND ANTIMICROBIAL ACTIVITIES
1465
show moderate activities at low concentrations. The lethal dose of the synthetic compounds
indicated that the synthesized compounds are safe and are promising for their use as in
vivo antimicrobial reagents. Clearly, the introduction of the phosphonate group improved
the biological activities and the safety of products for use was comparable to that of the
starting material.
EXPERIMENTAL
General Experimental
Melting point determinations were performed by the open capillary method using
an Electrothermal MEL-TEMP II apparatus (Tanta, Egypt) and are reported uncorrected.
IR spectra were recorded on a PerkinElmer 1430 Spectrophotometer (Tanta, Egypt) using
the KBr disc technique. 1H NMR spectra were recorded on a Bruker AC400 spectrometer
(Cardiff, United Kingdom) operating at 400 MHz. The spectra were recorded in DMSO-
d6. Chemical shifts δ are reported in parts per million (ppm) relative to tetramethylsilane
(TMS). Assignments of signals are based on integration values and expected chemical shift
values, and have not been rigorously confirmed. EI mass spectra were recorded at energy
70 eV with a 7070 EQ mass spectrometer (Cardiff, United Kingdom). ES analyses were
performed on a ZQ4000 spectrometer (Cardiff, United Kingdom) in the positive ionization
mode. Microanalysis was performed by analytical service at both the Universities of Tanta
and Cairo, Egypt. Reagents and solvents were obtained from commercial sources and used
without purification.
1-Phenyl-3-(pyridin-2-yl)-1H-pyrazole-4-carbaldehyde (1) was prepared according
to the literature procedure, mp 190–192 ◦C; lit. 190–192 ◦C.54
Chemistry
General Procedure for the Synthesis of Diphenyl(arylamino)(1-phenyl-3-
(pyridin-2-yl)-1H-pyrazol-4-yl)methylphosphonates 2–7. A mixture of 1 (0.50 g,
2.0 mmol) and a solution of LiClO4 in DCM (3 mL, 5.0 M; 15.0 mmol) in DCM (10 mL)
was stirred for 2 min and aromatic amine (4.0 mmol) was then added. The mixture was
stirred for 10 min and triphenylphosphite (0.93 g, 3.0 mmol) was then added. The mixture
was stirred at room temperature for 24–30 h during which the progress of the reaction was
monitored by thin-layer chromatography (TLC). Water (10 mL) was added to the reaction
mixture and the organic phase was separated and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure to give the crude product that recrystallized
from ethanol to give the pure products 2–7.
Diphenyl(1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)(phenylamino)meth-
ylphosphonate (2). White crystal; yield: 75%; mp 153–156 ◦C; IR (KBr): 3420 (NH),
1
1620 (C N), 1310 (P O), and 810 (P–O–C) cm−1. H NMR (DMSO-d6): δ 8.70 (br s,
exch., 1H, NH), 8.49–6.97 (m, 25H, Ar–H) and 6.66 (d, J = 15 Hz, 1H, CH). EI–MS: m/z
(%) 558 (M+, 2), 357 (81), 232 (91), 170 (15), 94 (100), and 65 (87). ES+–MS: m/z (%)
558 (M+, 7), 465 (100), 428 (10), 390 (24), and 372 (22). Anal. calcd for C33H27N4O3P
(558.57 g mol−1): C, 70.96; H, 4.87; N, 10.03; P, 5.55. Found: C, 71.02; H, 4.88; N, 10.07;
P, 5.52.
Diphenyl(4-chlorophenylamino)(1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-4-
◦
yl)methylphosphonate (3). White crystal; yield: 70%; mp 170–172 C; IR (KBr):
3425 (NH), 1628 (C N), 1320 (P O), and 816 (P–O–C) cm−1. H NMR (DMSO-d6):
1

1466
M. F. ABDEL-MEGEED ET AL.
δ 8.01 (br s, exch., 1H, NH), 8.86–6.63 (m, 24H, Ar–H), and 5.43 (d, J = 14 Hz, 1H, CH).
EI–MS: m/z (%) 594 ([M37Cl]+, 1), 592 ([M35Cl]+, 3), 531 (2), 455 (3), 357 (16), 232
(10), and 95 (100). Anal. calcd for C33H26ClN4O3P (593.01): C, 66.84; H, 4.42; N, 9.45;
P, 5.22. Found: C, 66.90; H, 4.45; N, 9.44; P, 5.25.
Diphenyl(1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)(4-tolylamino)methyl
◦
phosphonate (4). White crystal; yield: 81%; mp 141–143 C; IR (KBr): 3424 (NH),
1596 (C N), 1320 (P O), and 811 (P–O–C) cm−1. 1H NMR (DMSO-d6): δ 10.00 (br s,
exch., 1H, NH), 8.95–6.78 (m, 24H, Ar–H), 5.81 (d, J = 15 Hz, 1H, CH), and 2.10 (s, 3H,
CH3). EI–MS: m/z (%) 357 (5), 338 (34), 232 (82), 94 (100). ES+–MS: m/z (%) 636 ([M
+ MeCNNa]+, 51), 595 ([M + Na]+, 9), 573 (MH+, 100), 466 (10), 401 (7), 277 (12),
and 229 (11). Anal. calcd for C34H29N4O3P (572.59): C, 71.32; H, 5.10; N, 9.78; P, 5.41.
Found: C, 71.51; H, 4.91; N, 9.35; P, 5.39.
Diphenyl(4-(dimethylamino)phenylamino)(1-phenyl-3-(pyridin-2-yl)-1H-
pyrazol-4-yl)methylphosphonate (5). White solid; 84%; mp 153–155; IR (KBr):
3412 (NH), 1611 (C N), 1321 (P O), and 821 (P–O–C) cm−1; 1H NMR (DMSO-d6): δ
9.04 (br s, exch., 1H, NH), 8.78–6.75 (m, 24H, Ar–H), 6.01 (d, J = 12 Hz, 1H, CH), and
3.00 (s, 6H, 2 CH3). EI–MS: m/z (%) 601 (M+, 5), 524 (43), 447 (70), 370 (34), 338 (100).
Anal. calcd for C35H32N5O3P (601.63): C, 69.87; H, 5.36; N, 11.64; P, 5.15. Found: C,
69.68; H, 5.27; N, 11.72; P, 5.29.
Diphenyl(4-carboxyphenylamino)(1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-
◦
4-yl)methylphosphonate (6). White solid; yield: 77%; mp 177–179 C; IR (KBr):
3420 (NH/OH), 1700 (C O), 1612 (C N), 1318 (P O), and 820 (P–O–C) cm−1. H
1
NMR (DMSO-d6): δ 9.29 (br s, exch., 1H, NH), 8.86–6.53 (m, 24H, Ar–H), and 5.90 (d,
J = 13 Hz, 1H, CH). EI–MS: m/z (%) 602 (M+, 2), 339 (26), 220 (73), and 93 (100). Anal.
calcd for C34H27N4O5P (602.57): C, 67.77; H, 4.52; N, 9.30; P, 5.14. Found: C, 67.60; H,
4.32; N, 9.41; P, 5.25.
Diphenyl(4-methoxyphenylamino)(1-phenyl-3-(pyridin-2-yl)◦-1H-pyrazol-
4-yl)methylphosphonate (7). White solid; yield: 80%; mp 166–168 C; IR (KBr):
1
3400 (NH), 1606 (C N), 1318 (P O), and 818 (P–O–C) cm−1. H NMR (DMSO-d6):
δ 9.14 (br s, exch., 1H, NH), 8.68–6.96 (m, 24H, Ar–H), 6.55 (d, J = 13 Hz, 1H, CH),
and 3.77 (s, 3H, OCH3). EI–MS: m/z (%) 588 (M+, 5), 511 (24), 325 (71), 221 (23), 93
(100). Anal. calcd for C34H29N4O4P (588.59): C, 69.38; H, 4.97; N, 9.52; P, 5.26. Found:
C, 69.43; H, 4.90; N, 9.39; P, 5.35.
Biological Assay
Gram-Negative Bacteria. The Gram-negative bacterium used in this study was
E. coli, which is known as the backbone example for Gram-negative bacteria and causes
urinary infection, wound infection, and gastroenteritis.
Gram-Positive Bacteria. The Gram-positive bacteria used in this study were
B. subtilis and S. aureus. B. subtilis are mostly involved in urinary infection, wound,
ulceration, and septicemia. S. aureus is the milestone of Gram-positive bacteria and it is a
causative agent of pneumonia, meningitis, and food poisoning.
Fungi. S. cerevisiae was obtained from the culture collection of the Bacteriology
Unit, Department of Botany, Faculty of Science, Tanta University, Egypt.
Media Used and Antimicrobial Assay
Nutrient and Sabouraud’s broths and Nutrient and Sabouraud’s agar were used for
growing and maintaining the tested bacteria and yeast, respectively. The plates were then

SYNTHESIS AND ANTIMICROBIAL ACTIVITIES
1467
◦
incubated at 30 C for 24–48 h, after which the diameters of the inhibition zones were
measured. Nutrient and Sabouraud’s broths were used for activation of organisms.55
Determination of MICs
The MIC was determined by agar diffusion assay using the filter paper disc method.
It was carried out by impregnation of different concentrations of synthesized compounds
(0–1000 µg/mL) in dimethyl sulfoxide (DMSO) and then placing them on filter paper
discs of the same diameter (5 mm). The antimicrobial activities of the tested samples were
determined by measuring the diameter of the zone of inhibition expressed in millimeters.
The inhibition zones were measured in triplicates and expressed as mean SD.56
The Lethal Dose
Brine shrimp lethality bioassay is a very simple bench-top assay used to measure
cytotoxicity of plant extracts as well as synthetic compounds. Three replicates were used
for each concentration and living larvae were counted after 72 h. All data were expressed
as mean SD.57
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