Synthesis, in vitro antibacterial and antifungal evaluations of new α-hydroxyphosphonate and new α-acetoxyphosphonate derivatives of tetrazolo [1, 5-a] quinoline

Article abstract of DOI:10.1016/j.ejmech.2009.12.013

A series of new α-hydroxyphosphonate and α-acetoxyphosphonate derivatives have been synthesized for the first time of tetrazolo [1, 5-a] quinoline derivatives. Elemental analysis, IR, ¹H NMR, ¹³C NMR and mass spectral data elucidated the structures of the all newly synthesized compounds. In vitro antimicrobial activities of the synthesized compounds were investigated against Gram-positive Bacillus subtilis, Gram-negative Escherichia coli and fungi Candida albicans and Aspergillus niger. Some of the tested compounds showed significant antimicrobial activity.

Full text of DOI:10.1016/j.ejmech.2009.12.013

European Journal of Medicinal Chemistry 45 (2010) 1128–1132
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, in vitro antibacterial and antifungal evaluations of new
-hydroxyphosphonate and new -acetoxyphosphonate derivatives
of tetrazolo [1, 5-a] quinoline
a
a
Amol H. Kategaonkar a, Rajkumar U. Pokalwar a, Swapnil S. Sonar a, Vaibhav U. Gawali b,
,
Bapurao B. Shingate a, Murlidhar S. Shingare a
*
a Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, Maharashtra, India
b Pharmacology Laboratory, Maharashtra Institute of Pharmacy, Pune 411 038, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new a-hydroxyphosphonate and a-acetoxyphosphonate derivatives have been synthesized for
the first time of tetrazolo [1, 5-a] quinoline derivatives. Elemental analysis, IR, 1H NMR, 13C NMR and
mass spectral data elucidated the structures of the all newly synthesized compounds. In vitro antimi-
crobial activities of the synthesized compounds were investigated against Gram-positive Bacillus subtilis,
Gram-negative Escherichia coli and fungi Candida albicans and Aspergillus niger. Some of the tested
compounds showed significant antimicrobial activity.
Received 27 July 2009
Received in revised form
23 November 2009
Accepted 4 December 2009
Available online 24 December 2009
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
Tetrazolo [1, 5-a]quinoline
a
a
-Hydroxyphosphonate
-Acetoxyphosphonate
Antibacterial
Antifungal
1. Introduction
has been attributed to the relatively inert nature of the C–P bond
and to the physical and structural similarity of phosphonic and
Knowledge of phosphorous compounds has expanded so
rapidly that it constitutes now a major branch of chemistry, organic
molecules containing phosphorous offer fascinating possibilities
for structural, synthetic and mechanistic study [1,2]. A wide range
of natural phosphorus based biologically active compounds which
plays important roles as metabolic intermediates as common
regulatory switches for proteins and as a backbone for the genetic
information [3]. However, aside from prodrug applications, phos-
phate esters are normally considered impractical functional group
for drug design because they are subject to cleavage by digestive
phosphatases.
phosphinic acids to the biologically important phosphate ester and
carboxylic acid functionality [14]. In addition, -hydroxy phos-
phonates are useful precursors for the preparation of -function-
alized phosphonates, such as amino, keto, halo, and acetoxy
phosphonates [15–18].
Quinolines and their derivatives are important constituents of
pharmacologically active synthetic compounds. The quinoline
nucleus can also be frequently recognized in the structure of
numerous naturally occurring alkaloids. They have been associated
with broad spectrum of biological activities [19,20]. The fusion of
quinoline to the tetrazole ring is known to increase the biological
activity. The tetrazole group which is considered as analogues to
carboxylic group as a pharmacore possesses wide range of biolog-
ical activities. Several substituted tetrazoles have been shown to
possess anticonvulsant [21], anti-inflammatory [22], CNS disper-
sant [23], antimicrobial [24], anti-AIDS [25], and antifertility agents
[26,27].
a
a
The syntheses of
a-hydroxy phosphonates have received an
increasing amount of attention due to significant biological inter-
ests. They showed potential biological activities, such as antiviral,
antibacterial, anticancer, pesticides, renin inhibitors, HIV protease,
and enzyme inhibitor properties [4–13]. Much of these activities
By considering all above aspects, for the first time we have
synthesized the title compounds in regards to develop our on going
research work [28–31].
* Corresponding author. Tel.: þ91 240 2403313; fax: þ91 240 2403335.
E-mail address: prof_msshingare@rediffmail.com (M.S. Shingare).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.12.013

A.H. Kategaonkar et al. / European Journal of Medicinal Chemistry 45 (2010) 1128–1132
1129
2. Results and discussion
66.73–67.97 ppm regions for the compounds (3a–i) and (4a–i)
respectively.
2.1. Chemistry
2.2. Antimicrobial activity
Synthesis of these new compounds was carried out in
a straightforward manner. The key intermediates tetrazolo [1, 5-a]
quinoline-4 carbaldehyde derivatives (2a–i) were prepared by the
reaction of 2-chloroquinoline-3-carbaldehyde derivatives (1a–i)
with sodium azide in DMSO/AcOH mixture. [32] Furthermore, we
have synthesized new a-hydroxyphosphonate compounds (3a–i)
by reacting tetrazolo[1,5-a] quinoline derivatives (2a–i), triethyl-
phosphite and trimethylsilyl chloride (TMSCl) at room temperature
stirring. Additionally,
a-acetoxyphosphonate compounds (4a–i)
were synthesized by reacting compounds (3a–i) in acetic anhydride
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room tempera-
ture stirring. (Scheme 1). The time required for this protocol is less
than the previously reported methods [29] on other than this
nucleus.
Schrader-Clark [33] proposed that organophosphorus
compounds containing the general structure (A) may have signifi-
cant biological activity. All organophosphorus compounds are
inherently good phosphorylating agents of enzymes by virtue of
the group P-XYZ in the general structure (A). Slight variation in
structure can have very dramatic effects on the efficiency of
organophosphorus compounds in bio-activity. These chemically
and biologically variable parameters which are hard to estimate are
involved in deciding ‘‘structure–activity’’ relationship of these
compounds.
All the compounds synthesized in the present work were
screened for their potential biological activities such as antibacte-
rial activity against Bacillus subtilis (Gram positive) and Escherichia
coli (Gram negative) bacterial strains. Streptomycin was used as
a reference standard in antibacterial study. Compounds were also
screened for their potential antifungal activity against Candida
albicans and Aspergillus niger. Griseofluvin was used as reference
standard in antifungal study. The results of the antibacterial and
antifungal activity screening of the tested compounds are
summarized in Table 1 and Table 2, respectively.
Structures of compounds (3a–i) and (4a–i) were confirmed by
analytical and spectral data (see Section 5 for details). IR spectra of
compounds (3a–i) showed intense band in the region of 3205–
3253 cmꢀ1 of the
to
1022–1058 cmꢀ1 of
n
(O–H) stretch, 1592–1617 cmꢀ1 corresponding
n
(C]N) stretch, 1205–1249 cmꢀ1 of the
(P–O–C) stretch, which confirms the
n (P]O) stretch and
n
formation of desired compounds (3a–i). IR spectra compounds
(4a–i) showed intense band in the region of 1750–1757 cmꢀ1
corresponding to
(C]N) stretch, 1210–1231 cmꢀ1 of
1020–1042 cmꢀ1 due to
n n
(O–CO–CH3) stretch, 1593–1617 cmꢀ1 of the
n
(P]O) stretch and
n
(P–O–C) stretch. The absence of bands in
the region 3205–3253 cmꢀ1 and the presence of 1750–1757 cmꢀ1
are regarded as positive evidence for the formation of compounds
(3a–i) and (4a–i).
1H NMR spectra showed doublet due to (CH–P) proton in
compounds (3a–i) was observed in the range of 5.86–5.90 ppm and
also doublet due to (CH–P) proton in compounds (4a–i)
6.65–6.84 ppm, The variation in values of proton at (CH–P) position
confirms the formation of desired compounds. Carbon at (CH–P)
Most of the compounds tested were found to have good anti-
bacterial and antifungal activity, whereas compounds 3b, 3h, 3i, 4c
and 4i were acted as excellent antibacterial agents against B. sub-
tilis. Likewise compounds 3b, 3i and 4i showed better activity
against E. coli. The zone of inhibition of bacterial growth with these
position
showed
peak
around
67.04–67.58 ppm
and
Scheme 1. Synthesis of new a-hydroxyphosphonates and a-acetoxyphosphonates.

1130
A.H. Kategaonkar et al. / European Journal of Medicinal Chemistry 45 (2010) 1128–1132
Table 1
antifungal activity against A. niger of the corresponding
compounds.
Antibacterial activity of compounds (3a–i) and (4a–i).
Also the comparison of the biological activities among (4a–i)
shows as follows, against B. subtilis functional groups at R3 ¼ Et and
R2 ¼ Me exhibit potent antibacterial activity of the corresponding
compounds. R3 ¼ Et/OMe and R1 ¼ OEt functionalities might affect
the antibacterial activity of compounds against Escherichia coli. We
also found that functional groups at R1 ¼ OEt and R2 ¼ OMe inter-
feres in the antifungal activity of the corresponding compounds
against Candida albicans. At R1 ¼ OMe/Me and R2 ¼ Me positions
affect the potency regarding antifungal activity of the corre-
sponding compound.
Compound
Bacillus subtilis
Escherichia coli
ZIa(MIC)b
ZI(MIC)
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
12.0(10)
15.2(10)
13.6(10)
12.3(10)
12.4(10)
12.0(10)
12.5(10)
15.4(10)
14.5(10)
11.2(15)
12.0(10)
14.1(10)
13.1(20)
13.2(10)
12.5(10)
11.4(15)
12.1(10)
15.1(10)
16.4(05)
13.4(20)
15.0(10)
12.0(15)
13.7(25)
13.3(15)
13.6(15)
13.3(15)
13.5(15)
16.2(20)
12.5(10)
11.4(15)
13.2(15)
13.4(10)
12.4(10)
11.1(15)
13.9(25)
13.8(10)
14.2(10)
16.2(05)
3. Conclusion
We have synthesized new
a-hydroxyphosphonate and a-ace-
toxyphosphonate derivatives and their antimicrobial activities have
been evaluated. All compounds demonstrated potent inhibition
against all the strains tested. The importance of such work lies in
the possibility that the new compounds might be more efficacious
drugs against bacteria and fungi, which could be helpful in
designing more potent antibacterial and antifungal agents for
therapeutic use.
4h
4i
Streptomycin
a
Zone of inhibition in mm.
Minimum inhibitory concentration in mg/mL.
b
mentioned compounds was very close to the standard. Excellent
antifungal activities were also observed with compounds 3e, 4a
and 4h against C. albicans and compounds 3b, 3f, 3i, 4b, 4c, 4e and
4h were also acted as good antifungal agents against A. niger.
The data (Tables 1 and 2) indicate that a change in the substit-
uent might also affect the antimicrobial activity of synthesized
compounds (3a–i) and (4a–i). Comparison of biological activities
among (3a–i) shows functional groups at R1 ¼ Me/OEt and R3 ¼ Et
exhibit potent antibacterial activity against B. subtilis of corre-
sponding compounds. Against E. coli functional groups at R3 ¼ Me
and R2 ¼ OMe shows more activity. Higher activity of 3i (R3 ¼ Et)
than other compounds might be the indication of Et group
somehow playing a role in killing mechanism. Functional groups at
R1 ¼ OMe/OEt, R2 ¼ Me and R3 ¼ OMe has positional interference,
as results indicate the antifungal activity of the corresponding
compounds against Candida albicans. Positional changes of func-
tional groups at R1 ¼ Me, R2 ¼ OMe and R3 ¼ Et exhibit the potent
4. Experimental section
All chemicals and solvents were purchased from Merck, Spec-
trochem and S. D. Fine-chem. (India). Melting points were deter-
mined in open capillaries on Kumar’s melting point apparatus
(India) and are uncorrected. IR spectra were recorded on JASCO
FT-IR 4100, Japan using KBr discs. 1H NMR and 13C NMR spectra
were recorded on Bruker DRK-300 and NMR Spectrometer AC200.
Mass spectra were recorded on Single-Quadrupole Mass Detector
3100, Waters. Elemental analyses were performed on CHNS
analyzer Flash 1112, Thermo Finnigan. The progress of the reactions
was monitored by TLC on Merck silica plates. Results are presented
as, chemical shift
d in ppm, multiplicity, J values in Hertz (Hz),
number of protons, proton’s position. Multiplicities are shown as
the abbreviations: s (singlet), brs (broad singlet), d (doublet),
t (triplet), m (multiplet). Solvents were commercially available
materials of reagent grade.
Table 2
4.1. Diethyl hydroxy(tetrazolo[1,5-a]quinolin-4-
yl)methylphosphonate (3a)
Antifungal activity of compounds (3a–i) and (4a–i).
Compound
Candida albicans
Aspergillus niger
ZIa(MIC)b
ZI(MIC)
General procedure
A mixture of 2 (5 mmol), triethylphosphite (10 mmol) and
TMSCl (10 mmol) were stirred magnetically at room temperature.
The progress of reaction was monitored on TLC. After completion of
reaction (5 min), to the reaction mixture was poured on crushed
ice. The solid crude product was extracted with chloroform
(2 ꢁ 50 mL) and washed with water (2 ꢁ10 mL), brine (2 ꢁ 20 mL)
and dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure. The obtained crude product was purified by
column chromatography on silica gel by hexane: ethyl acetate (8:2)
as an eluent. Yield 94%, m.p. 178–180 ꢂC. IR (KBr, nmax/cmꢀ1): 3205
(O–H), 1614 (C]N), 1215 (P]O), 1058 (P–O–C). 1H NMR (200 MHz,
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
13.6(10)
13.2(10)
13.8(10)
13.0(10)
14.1(10)
13.4(10)
13.8(15)
13.8(10)
13.4(10)
14.2(10)
13.1(10)
13.4(10)
12.2(10)
13.4(10)
13.8(10)
12.1(15)
14.1(10)
12.1(10)
16.4(05)
12.1(15)
14.2(10)
13.2(15)
13.1(15)
12.2(15)
14.4(10)
11.5(15)
12.8(15)
14.2(10)
13.4(20)
14.1(10)
15.2(10)
12.2(15)
14.2(10)
12.5(25)
13.4(15)
14.5(10)
13.5(15)
16.5(05)
CDCl3, Me4Si,
d
ppm): 1.25 (t, 6H, J ¼ 6, 8 Hz, 2 ꢁ CH3), 2.13 (s, 1H,
OH), 4.12–4.33 (m, 4H, 2 ꢁ CH2), 5.87 (d, 1H, J ¼ 14 Hz, CH–P), 7.70
(t, 1H, J ¼ 6, 8 Hz, Ar–H), 7.87 (t, 1H, J ¼ 6, 8 Hz, Ar-H), 8.0 (d, 1H,
J ¼ 6 Hz, Ar-H), 8.27 (d, 1H, J ¼ 4 Hz, Ar–H), 8.65(d, 1H, J ¼ 8 Hz). 13C
4h
4i
Griseofluvin
NMR (75 MHz, CDCl3,
d ppm): 16.31 (CH3), 16.35 (CH3), 63.87 (O–
a
CH2), 65.42 (O–CH2), 67.04 (CH–P), 116.67, 123.41, 124.05, 128.09,
129.24, 130.09, 131.11, 139.15, 146.53 (Ar-C). MS: m/z 337.1 (m þ 1).
Zone of inhibition in mm.
Minimum inhibitory concentration in
b
mg/mL.

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1131
Elemental analysis: C14H17N4O4P Calcd.: C: 50.00%; H: 5.10%; N:
16.66%. Found: C: 49.96%; H: 5.05%; N: 16.60%.
J ¼ 7.5 Hz, Ar–H), 8.13 (d, 1H, J ¼ 3.3 Hz, Ar–H), 8.54 (d, 1H,
J ¼ 9.3 Hz, Ar–H). 13C NMR (75 MHz, CDCl3,
d ppm): 14.64 (CH3),
16.29 (CH3), 16.36 (CH3) 63.85 (O–CH2), 64.27 (O–CH2), 65.38
(O–CH2), 67.53 (CH–P), 110.32, 117.98, 120.99, 123.49,124.52, 125.41,
130.73, 145.81, 158.43 (Ar–C). MS: m/z 381.2(m þ 1). Elemental
analysis: C16H21N4O5P Calcd.: C: 50.53%; H: 5.57%; N: 14.73%.
Found: C: 50.49%, H: 5. 51%, N: 14.67%.
4.2. Diethyl hydroxy(7-methyltetrazolo[1,5-a]quinolin-4-
yl)methylphosphonate (3b)
Yield 95%, m.p. 216–218 ꢂC. IR (KBr, nmax/cmꢀ1): 3237 (O–H),
1610 (C]N), 1205 (P]O), 1022 (P–O–C). 1H NMR (200 MHz, CDCl3,
Me4Si,
d
ppm): 1.25 (t, 6H, J ¼ 6, 8 Hz, 2 ꢁ CH3), 1.81 (brs, 1H, OH),
4.7. Diethyl (9-ethyltetrazolo [1,5-a]quinolin-4-
yl)(hydroxy)methylphosphonate (3i)
3.17 (s, 3H, Ar–CH3), 4.12–4.37 (m, 4H, 2 ꢁ CH2), 5.89 (d, 1H,
J ¼ 14 Hz, CH–P), 7.55 (t, 1H, J ¼ 8 Hz, Ar–H), 7.66 (d, 1H, J ¼ 8 Hz,
Ar–H), 7.81 (d, 1H, J ¼ 8 Hz, Ar–H), 8.21 (d, 1H, J ¼ 4 Hz, Ar–H), 13C
Yield 88%, m.p. 140–142 ꢂC. IR (KBr, nmax/cmꢀ1): 3245 (O–H,
1592 (C]N), 1215 (P]O), 1052 (P–O–C). 1H NMR (75 MHz, CDCl3,
NMR (75 MHz, CDCl3,
d ppm): 16.31 (CH3), 16.37 (CH3), 21.40
(Ar–CH3), 63.84 (O–CH2), 65.75 (O–CH2), 67.35 (CH–P), 116.43,
123.03, 124.05, 128.24, 128.72, 130.98, 132.51, 138.43, 145.91 (Ar–C).
MS: m/z 351.2(m þ 1). Elemental analysis: C15H19N4O4P Calcd.: C:
51.43%; H: 5.47%; N: 15.99%. Found: C: 51.36%, H: 5.41%, N: 15.96%.
Me4Si,
d
ppm): 1.20 (t, 3H, J ¼ 7.2 Hz, CH3), 1.30–1.39 (m, 6H,
2 ꢁ CH3), 1.69 (brs, 1H, OH), 3.24 (q, 2H, J ¼ 7.2 Hz, CH2) 4.08–4.26
(m, 4H, 2 ꢁ CH2), 5.67 (d, 1H, J ¼ 11.4 Hz, CH–P), 7.46 (t, 1H,
J ¼ 7.2 Hz, Ar–H), 7.57 (d, 1H, J ¼ 6.9 Hz, Ar–H), 7.67 (d, 1H,
J ¼ 7.8 Hz, Ar–H), 8.52 (d, 1H, J ¼ 2.4 Hz, Ar–H), 13C NMR (75 MHz,
4.3. Diethyl hydroxy(8-methyltetrazolo[1,5-a]quinolin-4-
yl)methylphosphonate (3c)
CDCl3, d ppm): 14.73 (CH3), 16.28 (CH3), 16.35 (CH3), 24.11 (Ar–CH2)
63.54 (O–CH2), 65.93 (O–CH2), 67.55 (CH–P), 125.67, 126.97, 127.27,
128.88, 129.33, 138.47, 142.13, 145.71, 148.2 (Ar-C). MS: m/z
365.1(m þ 1). Elemental analysis: C16H21N4O4P Calcd.: C: 52.75%;
H: 5.81%; N: 15.38%. Found: C: 52.69%, H: 5. 75%, N: 15.34%.
Yield 90%, m.p. 176–178 ꢂC. IR (KBr, nmax/cmꢀ1): 3247 (O–H),
1615 (C]N), 1229 (P]O), 1038 (P–O–C). 1H NMR (200 MHz, CDCl3,
Me4Si,
2.66 (s, 3H, Ar–CH3), 4.10–4.31 (m, 4H, 2 ꢁ CH2), 5.86 (d, 1H,
J ¼ 12 Hz, CH–P), 7.51 (d, 1H, J ¼ 8 Hz, Ar–H), 7.87 (d, 1H, J ¼ 8 Hz,
Ar–H), 8.20 (d, 1H, J ¼ 4 Hz, Ar–H), 8.46 (s, 1H, Ar–H). MS: m/z
351.2(m þ 1). Elemental analysis: C15H19N4O4P Calcd.: C: 51.43%; H:
5.47%; N: 15.99%. Found: C: 51.37%, H: 5.41%, N: 15.95%.
d
ppm): 1.25 (t, 6H, J ¼ 6, 8 Hz, 2 ꢁ CH3), 1.78 (brs, 1H, OH),
4.8. (Diethoxyphosphoryl)(7-methyltetrazolo[1,5-a]quinolin-4-
yl)methyl acetate (4b)
General procedure
To the stirring solution of (3) (1.5 mmol) in acetic anhydride
(4.5 mmol) and DBU (1.5 mmol) was added at room temperature.
The reaction mixture was stirred at room temperature. Progress of
reaction was monitored on TLC. After completion of reaction
(5 min), the reaction mixture was poured on crushed ice and stirred
to get a solid product. The obtained solid was filtered and washed
with water, dried in oven at 60 ꢂC. This was purified by crystalli-
zation. Yield 85%, m.p. 120–122 ꢂC. IR (KBr, nmax/cmꢀ1): 1757 (O–
CO–CH3), 1615 (C]N), 1210 (P]O), 1020 (P–O–C). 1H NMR
4.4. Diethyl hydroxy(9-methyltetrazolo[1,5-a]quinolin-4-
yl)methylphosphonate (3d)
Yield 85%, m.p. 200–202 ꢂC. IR (KBr, nmax/cmꢀ1): 3239 (O–H),
1617 (C]N), 1249 (P]O), 1033 (P–O–C). 1H NMR (200 MHz, CDCl3,
Me4Si,
d
ppm): 1.26 (t, 6H, J ¼ 6, 8 Hz, 2 ꢁ CH3), 1.84 (brs, 1H, OH),
3.16 (s, 3H, Ar–CH3), 4.12–4.36 (m, 4H, 2 ꢁ CH2), 5.90 (d, 1H,
J ¼ 12 Hz, CH–P), 7.54 (t, 1H, J ¼ 6, 8 Hz, Ar–H), 7.65 (d, 1H, J ¼ 6 Hz,
Ar–H), 7.80 (d, 1H, J ¼ 8 Hz, Ar–H), 8.22 (d, 1H, J ¼ 4 Hz, Ar–H). MS:
m/z 351.2(m þ 1). Elemental analysis: C15H19N4O4P Calcd.: C:
51.43%; H: 5.47%; N: 15.99%. Found: C: 51.32%, H: 5.42%, N: 15.92%.
(200 MHz, CDCl3, Me4Si,
d
ppm): 1.16 (t, 3H, J ¼ 6, 8 Hz, CH3), 1.32 (t,
3H, J ¼ 6, 8 Hz, CH3), 2.23 (s, 3H, COCH3), 2.58 (s, 3H, Ar–CH3), 4.02–
4.40 (m, 4H, 2 ꢁ CH2), 6.84 (d, 1H, J ¼ 14 Hz, CH–P), 7.69 (d, 1H,
J ¼ 8 Hz, Ar–H), 7.76 (s,1H, Ar–H), 8.06 (d,1H, J ¼ 0.4 Hz, Ar–H), 8.55
(d, 1H, J ¼ 8 Hz, Ar–H). 13C NMR (75 MHz, CDCl3,
d ppm): 16.17
4.5. Diethyl hydroxy(7-methoxytetrazolo[1,5-a]quinolin-4-
yl)methylphosphonate (3e)
(CH3), 16.37 (CH3), 20.64 (O]C–CH3), 21.35 (Ar–CH3), 63.71 (O–
CH2), 64.08 (O–CH2), 66.73 (CH–P), 116.47, 120.45, 123.73, 128.46,
128.79, 131.58,132.88, 138.42, 146.12 (Ar–C), 168.85 (C]O). MS: m/z
393.2(m þ 1). Elemental analysis: C17H21N4O5P Calcd.: C: 52.04%;
H: 5.39%; N: 14.28%. Found: C: 52.00%, H: 5. 35%, N: 14.24%.
Yield 90%, m.p. 190–192 ꢂC. IR (KBr, nmax/cmꢀ1): 3251 (O–H),
1614 (C]N), 1211 (P]O), 1040 (P–O–C). 1H NMR (200 MHz, CDCl3,
Me4Si,
d
ppm): 1.26 (t, 6H, J ¼ 6, 8 Hz, 2 ꢁ CH3), 1.80 (brs, 1H, OH),
3.97 (s, 3H, O–CH3), 4.14–4.31 (m, 4H, 2 ꢁ CH2), 5.80 (d, 1H,
J ¼ 14 Hz, CH–P), 7.35 (d, 1H, J ¼ 2 Hz, Ar–H), 7.45 (d, 1H, J ¼ 4 Hz,
Ar–H), 7.48 (d, 1H, J ¼ 4 Hz, Ar–H), 8.14 (d, 1H, J ¼ 4 Hz, Ar–H). 13C
4.9. (Diethoxyphosphoryl)(7-methoxytetrazolo[1,5-a]quinolin-4-
yl)methyl acetate (4e)
NMR (75 MHz, CDCl3,
d
ppm): 16.33 (CH3), 16.38 (CH3), 55.88
(O–CH3), 63.85 (O–CH2), 65.98 (O–CH2), 67.58 (CH–P), 109.76,
118.11, 120.76, 123.41, 124.71, 129.6, 130.75, 145.54, 159.10 (Ar–C).
MS: m/z 367.1(m þ 1). Elemental analysis: C15H19N4O5P Calcd.: C:
49.18%; H: 5.23%; N: 15.29%; Found: C: 49.12%, H: 5. 18%, N: 15.22%.
Yield 90%, m.p. 156–158 ꢂC. IR (KBr, nmax/cmꢀ1): 1755 (O–CO–
CH3), 1616 (C]N), 1226 (P]O), 1032 (P–O–C). 1H NMR (200 MHz,
CDCl3, Me4Si,
d
ppm): 1.15 (t, 3H, J ¼ 6, 8 Hz, CH3), 1.32(t, 3H, J ¼ 6,
8 Hz, CH3), 2.23 (s, 3H, COCH3), 3.96 (s, 3H, OCH3), 4.05–4.41 (m, 4H,
2 ꢁ CH2), 6.84 (d, 1H, J ¼ 14 Hz, CH–P), 7.34 (d, 1H, J ¼ 0.4 Hz, Ar–H),
7.46 (d, 1H, J ¼ 10 Hz, Ar–H), 8.08 (d, 1H, J ¼ 0.4 Hz, Ar–H), 8.57 (d,
4.6. Diethyl (7-ethoxytetrazolo[1,5-a]quinolin-4-
yl)(hydroxy)methylphosphonate (3h)
1H, J ¼ 10 Hz, Ar–H). 13C NMR (75 MHz, CDCl3,
d ppm): 16.24 (CH3),
Yield 87%, m.p. 182–184 ꢂC. IR (KBr, nmax/cmꢀ1): 3253 (O–H),
1612 (C]N), 1207 (P]O), 1044 (P–O–C). 1H NMR (75 MHz, CDCl3,
16.26 (CH3), 20.69 (O]C–CH3), 55.58 (O–CH3), 63.84 (O–CH2),
64.31 (O–CH2), 66.76 (CH–P), 109.82, 118.21, 121.12, 129.92, 131.45.
138.42, 143.41, 146.13, 159.06, (Ar–C), 168.92 (C]O). MS: m/z
409.2(m þ 1). Elemental analysis: C17H21N4O6P Calcd.: C: 50.00%;
H: 5.18%; N: 13.72%. Found: C: 49.94%, H: 5. 11%, N: 13.65%.
Me4Si,
d
ppm): 1.20–1.37 (m, 6H, 2 ꢁ CH3), 1.51 (t, 3H, J ¼ 6.9, 7.2 Hz,
CH3), 1.84 (brs, 1H, OH), 4.08–4.32 (m, 6H, 3 ꢁ CH2), 5.83 (d, 1H,
J ¼ 12.9 Hz, CH–P), 7.28 (d, 1H, J ¼ 7.5 Hz, Ar–H), 7.43 (d, 1H,

1132
A.H. Kategaonkar et al. / European Journal of Medicinal Chemistry 45 (2010) 1128–1132
4.10. (Diethoxyphosphoryl)(7-ethoxytetrazolo[1,5-a]quinolin-4-
yl)methyl acetate (4h)
examined after 24 h and incubated further for 72 h, where
necessary. The lowest concentration of the drug in a plate that
failed to show any visible macroscopic growth was considered as
its MIC. The MIC determination was performed in triplicate for
each organism and the experiment was repeated where
necessary.
Yield 84%, m.p. 98–100 ꢂC. IR (KBr, nmax/cmꢀ1): 1755 (O–CO–
CH3), 1593 (C]N), 1231 (P]O), 1042 (P–O–C). 1H NMR (200 MHz,
CDCl3, Me4Si,
d
ppm): 1.18 (t, 3H, J ¼ 6, 8 Hz, CH3), 1.35(t, 3H, J ¼ 6,
8 Hz, CH3), 1.48 (t, 3H, J ¼ 6, 8 Hz, CH3), 2.19 (s, 3H, OCH3), 3.8–4.6
(m, 6H, 3 ꢁ CH2), 6.65 (d, 1H, J ¼ 14 Hz, CH–P), 7.08 (s, 1H, Ar–H),
7.40 (d, 1H, J ¼ 8 Hz, Ar–H), 7.89 (d, 1H, J ¼ 8 Hz, Ar–H), 8.33 (d, 1H,
Acknowledgements
J ¼ 0.4 Hz, Ar–H). 13C NMR (75 MHz, CDCl3,
d ppm): 14.67 (CH3),
The authors would like to thank the Head, Department of
Chemistry, Dr. B. A. M. University, Aurangabad for constant
encouragement and providing necessary facilities. AHK also wish to
express his gratitude to University Grant Commission, New Delhi
for providing the financial support as Rajiv Gandhi National
Fellowship to carry out the present work.
16.26 (CH3), 16.46 (CH3), 20.74 (O]C–CH3), 63.56 (O–CH2), 63.80
(O–CH2), 65.65 (O–CH2), 67.95 (CH–P), 105.90, 124.31, 126.70,
128.10, 129.66. 137.69, 143.38, 146.57, 157.71 (Ar–C), 168.80 (C]O).
MS: m/z 423.2(m þ 1). Elemental analysis: C18H23N4O6P Calcd.: C:
51.19%; H: 5.49%; N: 13.26%. Found: C: 51.14%, H: 5. 42%, N: 13.23%.
4.11. Diethoxyphosphoryl)(9-ethyltetrazolo[1,5-a]quinolin-4-
yl)methyl acetate (4i)
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