Synthesis and antimicrobial activity of N-(substituted)-N'-(2,3-dihydro-2-oxido-5-benzoyl-1H-1,3,2-benzodiazaphosphol-2-yl) ureas.

Article abstract of DOI:10.1248/cpb.51.860

N-(substituted)-N'-(2,3-dihydro-5-benzoyl-2-oxido-1H-1,3,2-benzodiazaphosphol-2-yl) ureas were synthesized by reacting 3,4-diaminobenzophenone (4) with different chlorides of carbamidophosphoric acids (3) in the presence of triethylamine at 40-45 degrees C. Their 1H-, 13C- and 31P-NMR spectral data are discussed. The title compounds were screened for antifungal and antibacterial activity against the fungi Aspergillus niger and Fusarium solani and bacteria Escherichia coli and Staphylococcus aureus. These compounds showed higher antibacterial activity when compared with antifungal activity.

Full text of DOI:10.1248/cpb.51.860

860
Notes
Chem. Pharm. Bull. 51(7) 860—863 (2003)
Vol. 51, No. 7
Synthesis and Antimicrobial Activity of N-(Substituted)-N؅-(2,3-dihydro-
2-oxido-5-benzoyl-1H-1,3,2-benzodiazaphosphol-2-yl) Ureas
*
Peddaiahgari VASU GOVARDHANA REDDY, Cirandur SURESH REDDY, and Chamarthi NAGA RAJU
Department of Chemistry, Sri Venkateswara University College of Engineering; Tirupati-517 502, India.
Received January 20, 2003; accepted April 1, 2003
N-(Substituted)-N؅-(2,3-dihydro-5-benzoyl-2-oxido-1H-1,3,2-benzodiazaphosphol-2-yl) ureas were synthe-
sized by reacting 3,4-diaminobenzophenone (4) with different chlorides of carbamidophosphoric acids (3) in the
presence of triethylamine at 40—45 °C. Their 1H-, 13C- and 31P-NMR spectral data are discussed. The title com-
pounds were screened for antifungal and antibacterial activity against the fungi Aspergillus niger and Fusarium
solani and bacteria Escherichia coli and Staphylococcus aureus. These compounds showed higher antibacterial
activity when compared with antifungal activity.
Key words 3,4-diamino benzophenone; isocyanatophosphonic dichloride; carbamidophosphoric acid dichloride
Extensive investigation of compounds containing P–N toluene led to the corresponding carbamido phosphoric
linkages by numerous research groups have led to many in- acid dichloride (3). When equimolar quantities of 3,4-di-
teresting and far reaching developments.1) Organophospho- aminobenzophenone (4) reacted with carbamido phosphoric
rus heterocycles bearing P–N functionality have shown pesti- acid dichloride (3a—i) in dry toluene–tetrahydrofuran mix-
cidal and medicinal activity.2—6) Benzimidazol-2-yl-carba- ture (1 : 1) in the presence of triethylamine at 40—45 °C
mates have proven anthelmintic activity.7,8) In continuation of (Chart 1), the title compounds were formed. Purifications of
our research interests, several new classes of substituted 5a—i were achieved by filtering off triethylamine hydrochlo-
ureas of the type RRЈP(O)NHC(O)NHRЉ were synthesized ride, evaporation of the filtrate, washing the residue with
and characterized by spectral data and they were also water and recrystallization of the residue from methanol.
screened for their antifungal and antibacterial activity.
Their structures were established by elemental analyses, IR,
1H-, 13C- and 31P-NMR spectral data (Tables 1—3).
Results and Discussion
Reaction yields, elemental analyses, IR and 31P-NMR data
1
Addition of equivalent amounts of isocyanatophosphonic of 5a—i are given in Table 1. Tables 2 and 3 contain H-
dichloride9,10) (1) to various amines (2) at Ϫ15 °C in dry and 13C-NMR spectral data. The IR spectra of 5a—i11)
Chart 1
To whom correspondence should be addressed. e-mail: csureshsvu@yahoo.com
© 2003 Pharmaceutical Society of Japan

July 2003
861
Table 1. Physicochemical, IR and 31P-NMR Spectral Data of 5a—i
Elemental analyses
Calcd/Found
b)
IR (cmϪ1
)
31P-NMR datac,d)
Compound
mp (°C)
Yielda)
Molecular formula
(ppm)
C
H
N
ArCOAr PϭO
P–NH
3369
3340
3329
3317
3361
3361
3348
3371
3372
NH–CO
1659
1655
1636
1656
1660
1662
1672
1654
1664
5a
5b
5c
5d
5e
5f
145—147 (dec)
142—144 (dec)
151—153 (dec)
69—71
54
59
56
60
52
51
58
46
47
C20H17N4PO3
C20H16N4PO3Cl
C20H16N4PO3Br
C21H19N4PO3
C22H21N4PO3
C21H18N4PO3Cl
C22H17N4PO5
C20H23N4PO3
C18H19N4PO3
61.22
61.54
56.28
55.69
50.97
50.48
62.06
—
62.85
62.43
57.21
57.68
58.40
—
4.36
4.10
3.77
3.45
3.42
3.06
4.71
—
5.03
5.28
4.11
4.56
4.67
—
14.27
14.69
13.12
13.56
11.89
11.25
13.78
—
13.32
13.84
12.70
12.36
12.38
—
1618
1626
1603
1601
1630
1624
1613
1625
1617
1278
1260
1303
1307
1283
1283
1229
1284
1260
Ϫ11.20, 1.36
—
Ϫ8.32
Ϫ11.53
Ϫ11.88, 1.28
Ϫ11.45, 1.19
Ϫ11.48
—
158—160 (dec)
136—138 (dec)
165—167 (dec)
194—196 (dec)
164—166 (dec)
5g
5h
5i
60.29
59.78
55.96
—
5.81
5.46
4.96
—
14.06
13.52
14.50
—
—
a) Recrystallized from methanol. b) Recorded as KBr pellets. c) Recorded in dimethyl sulfoxide-d6. d) Chemical shifts in ppm from 85% phosphoric acid.
Table 2. 1H-NMR Dataa,b) of 5a—i
Compound
H (4, 6 & 7)
Ar–H
Ar–CH3/Ar–OCH3
—
P–NH
–NHC(O)
C(O)NH–
5a
7.16 (s, 1H, 4-H)
7.39—7.86
(m, 10H)
6.04
(s, 2H)
9.42
(br s, 1H)
8.68
(br s, 1H)
6.92 (d, 8.1 Hz, 6-H)
7.28 (d, 8.0 Hz, 7-H)
7.14 (s, 1H, 4-H)
7.07 (d, 8.8 Hz, 6-H)
7.29 (d, 8.6 Hz, 7-H)
7.25 (s, 1H, 4-H)
6.77 (d, 8.5 Hz, 6-H)
7.55 (d, 7.2 Hz, 7-H)
7.01 (s, 1H, 4-H)
6.75 (d, 7.3 Hz, 6-H)
7.26 (d, 6.9 Hz, 7-H)
7.23 (s, 1H, 4-H)
6.64 (d, 8.2 Hz, 6-H)
7.07 (d, 8.1 Hz, 7-H)
7.06 (s, 1H, 4-H)
6.50 (d, 8.1 Hz, 6-H)
6.96 (d, 8.1 Hz, 6-H)
5b
5c
5d
5e
5f
7.46—7.91
(m, 9H)
—
—
5.94
(s, 2H)
9.58
(br s, 1H)
8.72
(br s, 1H)
7.68—7.95
(m, 9H)
5.93
(s, 2H)
—
8.24
(br s, 1H)
7.35—7.75
(m, 9H)
2.21 (s, 3H)
6.39
(s, 2H)
9.64
(br s, 1H)
8.42
(br s, 1H)
7.48—7.64
(m, 8H)
2.20 (s, 3H)
2.51 (s, 3H)
5.73
(s, 2H)
—
—
7.16—7.59
(m, 9H)
4.16
—
4.78
(s, 2H)
9.43
(br s, 1H)
9.24
(br s, 1H)
(s, 2H, NH–CH2)
7.29—7.74
(m, 8H)
5g
5h
6.84 (s, 1H, 4-H)
3.76 (s, 3H)
3.74 (s, 3H)
5.51
(s, 2H)
9.60
(br s, 1H)
8.34
(br s, 1H)
6.68 (d, 8.0 Hz, 6-H)
7.13 (d, 8.0 Hz, 7-H)
7.10 (s, 1H, 4-H)
6.92 (d, 8.4 Hz, 6-H)
7.31 (d, 8.3 Hz, 7-H)
7.42—7.73
(m, 5H)
1.26—1.89
(m, 11H)
7.52—7.68
(m, 5H)
3.22—3.56
(m, 8H, CH2)
—
6.12
(2, 2H)
—
—
—
5i
7.17 (d, 1.9 Hz, 4-H)
6.60 (d, 8.1 Hz, 6-H)
6.93 (d, 8.0 Hz, 7-H)
—
5.54
(2,2H)
8.10
(br s, 1H)
a) Chemical shifts in d and J (Hz) given in parentheses. b) Recorded in dimethyl sulfoxide-d6.
(Table 1) showed bands at 3317—3372 (P–NH), 1601— 7.55 ppm (Jϭ6.9—8.6 Hz) were attributed to H-7. The
1630 (Ar–CO–Ar), 1229—1303 (PϭO) and 1636—1672 arylcarbamido and benzoyl moieties in 5a—i exhibited mul-
(–NH–CO) cmϪ1.
tiplets in the range of 7.16—7.95 ppm. The proton in the
The 1H-NMR spectra of 5a—i12) (Table 2) showed singlets P–NHCϭO appeared at extreme downfield, at 9.42—
for H-4 at 6.84—7.25 ppm, the doublets at 6.60—7.07 ppm 9.64 ppm as a singlet when compared to the other three NH
(Jϭ7.3—8.0 Hz) for H-6; the other doublets found at 6.93— protons. It is of interest to note that phosphorus coupling is

862
Vol. 51, No. 7
limited to P–NH protons only and not extended to other pro- 129.8, 131.1—131.6 and 128.7—129.3, respectively. The ni-
tons of carbamido moiety. The NH proton signals were con- trogen bearing C-8 and C-9 exhibited signals in the down
firmed by D2O exchange experiments.
field at 143.1—144.8 and 137.9—138.9. The signal for the
The 13C-NMR chemical shifts (Table 3) were recorded for carbonyl of the carbamido function C-(1Љ) is observed at
some members of the title compounds (5b, d—g). The chem- 148.4—154.7 ppm, while the signals for the benzoyl car-
ical shifts for C-4, C-5, C-6 and C-7 appeared at 113.5— bonyl group C(10) occurred at 193.6—194.6 ppm. The
115.8, 135.9—138.1, 125.2—125.9 and 116.7—119.9 re- chemical shifts could not be identified in the 13C-NMR spec-
spectively. In the case of C-1Ј, C-(2Ј, 6Ј), C-4Ј and C-(3Ј, 5Ј) tra of 5a, c, h and i because of the poor quality of the spec-
the range of chemical shifts was 138.0—139.3, 129.3— trum due to their meagre solubility in DMSO.
The 31P-NMR chemical shifts13) of these compounds (5)
appeared in the range of Ϫ11.88 to 1.36 ppm. Compounds
5a, e and f showed two signals.
Table 3. 13C-NMR Dataa—c) of 5a—i
Antimicrobial Activity The compounds 5a—i (Table 4)
were screened at two different concentrations (25, 75 mg/
disc) for their antifungal activity on Fusarium solani and As-
pergillus niger, Nystatin (25 mg/disc) is used as standard
according to disc-diffusion method.14) The fungal cultures
were grown on potato dextrose broth at 25 °C for 3 d and fi-
nally spore suspension was adjusted to 106 spores/ml. Their
antibacterial activity was evaluated against Staphylococcus
aureus and Escherichia coli (105 cell/ml) on nutrient agar
plates at 37 °C for 24 h.15) Vancomycin (25 mg/disc) and gen-
tamycin (25 mg/disc) were used as standard antibiotics. The
title compounds were potent against tested fungi and bacte-
ria. The compounds showed higher antibacterial activity
when compared with antifungal activity.
Carbon atoms
5b
5d
5e
5f
5g
C(1Ј)
C(2Ј, 6Ј)
C(4Ј)
C(3Ј, 5Ј)
C(10)
C(4)
C(5)
C(6)
C(7)
C(8)
139.2
129.8
131.5
128.7
193.8
115.2
135.9
125.6
117.4
144.8
137.9
154.6
144.1
116.2
129.3
124.4
129.3
116.2
—
138.0
129.5
131.3
129.0
194.1
115.7
136.1
125.2
118.6
144.2
138.0
153.4
144.2
114.7
130.1
126.4
130.1
114.7
20.1
139.3
129.7
131.1
129.3
194.6
115.8
136.2
125.8
118.5
144.1
138.2
154.7
144.1
124.6
130.8
127.3
125.4
114.9
21.1
138.9
129.3
131.1
128.8
193.6
113.5
137.0
125.9
119.9
143.1
138.9
153.4
137.0
135.3
128.3
127.1
125.9
130.2
—
138.1
129.5
131.6
129.2
194.4
114.3
138.1
125.2
116.7
143.6
138.1
148.4
132.3
131.6
143.6
104.2
121.9
112.0
—
C(9)
C(1Љ)
C(2Љ)
C(3Љ)
C(4Љ)
C(5Љ)
C(6Љ)
C(7Љ)
CЉ(CH3)
Experimental
The melting points were determined on a Mel-Temp apparatus and were
uncorrected. Elemental analyses were performed by the Central Drug Re-
search Institute, Lucknow, India. All IR spectra were recorded as KBr pellets
on a Perkin-Elmer 1430 unit. 1H- and 13C-NMR spectra were recorded on
18.5
—
CЉ(OCH3)
—
—
—
—
—
55.6
55.2
—
AMX 400 MHz spectrometer operating at 400 MHz for 1H, 100 MHz for 13
C
and 161.9 MHz for 31P. The compounds were dissolved in DMSO-d6. The
chemical shifts were referenced to TMS (1H and 13C) and 85% H3PO4 (31P).
3,4-Diamino benzophenone (4) was procured from Aldrich Chemical
Company, Inc., U.S.A. and was used without further recrystallization.
Methylene carbon
—
79.6
a) Chemical shifts in ppm. b) Recorded in dimethyl sulfoxide-d6. c) 5a, c, h
and i gave unresolved spectra due to poor solubility.
Table 4. Antimicrobial Activity of 5a—i
Zone of inhibition (mm)b)
Concentration
(mg/disc)
Compound
Fungi
Bacteria
Staphylococcus aureus
Aspergillus niger
Fusarium solani
Escherichia coli
5a
25
75
25
75
25
75
25
75
25
75
25
75
25
75
25
75
25
75
25
2
4
1
—
—
—
—
—
—
2
3
6
5
8
4
10
3
7
3
8
2
5
4
9
5
3
3
6
2
3
2
5
3
8
2
6
9
12
3
6
5
9
4
9
5
9
5b
3
5c
—
—
1
3
2
5d
4
5e
—
—
—
—
—
—
1
2
2
8
8
6
5f
—
—
1
5g
2
5h
5i
—
—
1
3
4
Standardsa)
10
8
a) Nystatin (25 mg/disc) for Aspergillus niger and Fusarium solani, vancomycin (25 mg/disc) for Staphylococcus aureus and gentamycin (25 mg/disc) for Escherichia coli.
b) Diameter of filter paper is 16 mm, compounds 5a—i tested in 20% N,N-dimethylformamide. “—” indicates no activity.

July 2003
Preparation of N-Phenyl-N؅-(2,3-dihydro-2-oxido-5-benzoyl-1H-1,3,2-
863
2) Venugopal M., Sankar Reddy B., Devendranath Reddy C., Berlin K.
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0.002 mol) in dry toluene (20 ml) was added dropwise over a period of
20 min to a cold solution (Ϫ15 °C) of isocyanatophosphonic dichloride (1,
0.320 g, 0.002 mol) in dry toluene (20 ml). After the addition, the tempera-
ture of the reaction mixture was allowed to rise slowly to room temperature
and was maintained further for 2 h. Phenyl carbamidophosphoric acid
dichloride (3a) being insoluble in toluene separated out. To this mixture was
added a cold solution (0 °C) of 3,4-diaminobenzophenone (4, 0.424 g,
0.002 mol) and triethylamine (0.404 g, 0.004 mol) in 30 ml of tetrahydrofu-
ran–toluene mixture (1 : 1). The temperature of the reaction mixture was
raised slowly 40—45 °C and kept under stirring for 4—5 h. The precipitated
triethylamine hydrochloride was filtered off and the solvent from the filtrate
was evaporated under reduced pressure. The residue after washing with
water was recrystallized from methanol to afford a pure material of (5a) as
an amorphous powder, yield 0.42 g (54%) mp 145—147 °C (dec.). The other
compounds (5b—i) were prepared by adopting the same procedure.
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Acknowledgements The authors express their thanks to Professor C.
Devendranath Reddy for his helpful guidance and discussions, the Director
of SIF, IISC, Bangalore for the spectral data, Dr. K. Vijaya Lakshmi, Associ-
ate Professor, Dr. P. Umamaheswari Devi, Assistant Professor, Department
of Microbiology, Sri Padmavathi Mahila University, Tirupati for their help in
antimicrobial studies, Dr. M. R. Ashok, Head of the Dept. of English, S. V.
University, Tirupati for carrying out English Editorial Corrections and P. V.
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