Synthesis, characterization, antimicrobial activity of novel n-substituted β-hydroxy amines and βhydroxy ethers contained chiral benzoxazine fluoroquinolones

Article abstract of DOI:10.2174/157018013804142492

Synthesis of novel N-substituted β-hydroxy amines 4(a-j) and β-hydroxyethers 5(a-c) with chiral benzoxazine fluoroquinolones has been described. Benzoxazinefluoroquinolone carboxylic acid 1, on reaction with piperizine in acetonitrile in presence of triethylamine under reflux gives 7- piperazinyl benzoxazine fluoroquinolone 2. The latter is reacted with epichlrohydrine in presence of NaOH in acetone to yield respective N-substituted epoxide 3 with retained chirality, the 3 on treatment with different amines gives respective β-hydroxy amines 4(a-j). On other hand, 3 on treatment with alcohols in presence of NaOH afforded the corresponding β-hydroxy ethers 5(a-c). The structures of the synthesized compounds have been established on the basis of its spectral and analytical data. The antimicrobial activity of newly synthesized compounds ware evaluated against different microorganisms comparing with levofloxacin and found all the compounds exhibited remarkable activity.

Full text of DOI:10.2174/157018013804142492

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86
Letters in Drug Design & Discovery, 2013, 10, 86-93
Synthesis, Characterization, Antimicrobial Activity of Novel N-Substituted
ꢀ-Hydroxy Amines and ꢀHydroxy Ethers Contained Chiral Benzoxazine
Fluoroquinolones
B. Guruswamy* and R. Arul
Neuland laboratories Research & Development centre, Bonthapally, Medak (Dist), Andhra Pradesh, India.
Abstract: Synthesis of novel N-substituted ꢀ-hydroxy amines 4(a-j) and ꢀ-hydroxyethers 5(a-c) with chiral benzoxazine
fluoroquinolones has been described. Benzoxazinefluoroquinolone carboxylic acid 1, on reaction with piperizine in
acetonitrile in presence of triethylamine under reflux gives 7- piperazinyl benzoxazine fluoroquinolone 2. The latter is
reacted with epichlrohydrine in presence of NaOH in acetone to yield respective N-substituted epoxide 3 with retained
chirality, the 3 on treatment with different amines gives respective ꢀ-hydroxy amines 4(a-j). On other hand, 3 on
treatment with alcohols in presence of NaOH afforded the corresponding ꢀ-hydroxy ethers 5(a-c). The structures of the
synthesized compounds have been established on the basis of its spectral and analytical data. The antimicrobial activity of
newly synthesized compounds ware evaluated against different microorganisms comparing with levofloxacin and found
all the compounds exhibited remarkable activity.
Keywords: Antimicrobial activity; Chiral benzoxazine fluoroquinolones; Epichlorohydrine; 7-Piperazinyl chiral benzoxazine
fluoroquinolones.
INTRODUCTION
synthesize modern fluoroquinolone antibacterials [12, 13]
with enhanced antimicrobial activity. The evolution as well
as the high potency in quinolones is mainly because of
modification at 7th position. Introduction of these new
quinolones has created an exciting era in antimicrobial
chemotherapy. Literature survey reveals that researchers hav
e attempted to make the various substituted
Fluoroquinolones are well established class of board
spectrum antibiotics, therapeutically useful in the treatment
of various pathogenic infections. When compared to previou
sly synthesized antibacterial drugs, the fluoroquinolones are
having extensive potent activity against various microorganis
ms [1]. These classes of antibiotics were also used in the
treatment of many sexually transmitted diseases (STDs),
complicated urinary tract and respiratory infections [2].
Fluoroquinolones (nalidixic acid) were discovered in 1962 as
a byproduct during the synthesis of anti-malarial drug
chloroquine [3]. In 1963 it was approved by Food and Drug
Administration (FDA) for the treatment of urinary tract
infection. After the discovery of norfloxacin, structure–
activity relationships (SAR) analysis of the fluoroquinolone
pharmacophore led to synthesize a new class of compounds
with good solubility and enhanced biological activity [4].
The bactericidal activity generated by fluoroquinolones is
caused by the inhibition of two bacterial enzymes: DNA
gyrase and topoisomerase IV [5]. These derivatives act
against Gram-positive and Gram-negative bacteria due to the
fluoroquinolones, which posses many desirable microbiologi
cal and pharmacokinetic properties [14-16].
In view of these reports, it was thought worthwhile to
synthesize and investigate the compounds containing N-
substituted piperazinyl fluoroquinolones. Present work is
concerned with the synthesis of N-substituted ꢀ-hydroxy
amines and ꢀ-hydroxy ethers contained fluoroquinolone
derivatives with the objective of discovering novel
antimicrobial agents.
EXPERIMENTAL
Materials and Methods
th
presence of fluorine atom at 6 position and piperazinyl
group at 7th position. In the past few years, research for new
quinolone antibacterial agents has focused on numerous
structural patterns at C-7 and C-8 position [6-9] of quinolone
carboxylic acid. Besides these studies, simple modifications
were done on 7-piperazinyl fluroquinolones, and
substitutions with bulky groups on N-4 of piperazine ring,
resulted in increase in biological activity by inhibiting DNA
gyrase [10, 11]. These kind of modifications leads to
All the reagents and solvents used analytical grade and
without further purification unless otherwise mentioned.
Thin layer chromatography (TLC) was carried out on
aluminium sheets coated with silica gel 60 F254 (Merck).
TLC plates were inspected under UV light. Elemental
analyses data were obtained by employing a Perkin-Elmer
240c analyzer. IR spectra (KBr pellets) were recorded with a
1
Perkin-Elmer-1700 spectro photometer. H NMR and 13C
NMR spectra were measured on avance BRUKER-300 MHz
spectrometer. Mass was recorded on Varian 300-MS
spectrometer and melting points were recorded on a Polmon
MP 96. Specific optical rotation performed on Rudolf model
number 420766APR/6W polarimeter.
*Addrss correspondence to this author at the Neuland laboratories Research
& Development centre, Bonthapally, Medak (Dist), Andhra Pradesh, India;
Tel: 08458392608; Fax: 08458392601;
E-mail: guruswamy2748@gmail.com
1875-628X/13 $58.00+.00
© 2013 Bentham Science Publishers

Synthesis, Characterization, Antimicrobial Activity of Novel N-Substituted
Letters in Drug Design & Discovery, 2013, Vol. 10, No. 1 87
(S)-9-fluoro-3,7-dihydro-3-methyl-7-oxo-10-(piperazin-1-
yl)-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid
(2).
confirmed by TLC and the excess amount of amine as well
as solvent was distilled off under vacuum, the residue was
dissolved in methanol (10 mL) followed by addition of ethyl
acetate (40 mL) with constant stirring at room temperature.
The separated solid was filtered, washed with ethyl acetate
(5 mL) to afford pure title compounds.
To a solution of 1 (100g, 356 mmol) in acetonitrile (500
mL) and piperazine (45.92 g, 534mmol) was stirred for 30
min at 25-30 °C, added triethylamine (108g, 1068 mmol)
and heated the reaction mass to reflux, maintained for 12h at
same temperature, progress of the reaction was monitored by
TLC. The reaction mass was cooled to 25-30 °C, stirred for
1h, filtered the isolated compound and washed with
acetonitrile. The crude solid was recrystallized from
methanol to obtain pure 2.
(S)-9-fluoro-3,7-dihydro-10-(4-(2-hydroxy-3-(methylami-
no)propyl)piperazin-1-yl)-3-methyl-7-oxo-2H-[1,4]oxazi-
no[2,3,4-ij]quinoline-6-carboxylic acid (4a)
Off-white solid, yield: 4.5g (83%), mp 229-233 °C; IR
1
(KBr, cm-1): 3430, 2985, 1707, 1625. H-NMR (DMSO d6):
Pale yellow solid, yield: 106g (86%), mp 263-265 °C; IR
(KBr) vmax (cm-1): 3412, 2814, 1728 and 1617. 1H-NMR
(DMSO d6): ꢀ 1.22-1.24 (d, 3H, J=6.0 Hz), 2.48-2.55 (m,
4H), 2.27 (s,1H, D2O exchangeable), 3.56-3.62 (m, 4H),
3.97-4.00 (m, 1H), 4.54-4.57 (m, 2H), 7.48-7.52 (d, 1H, J
=12.0 Hz ), 8.89 (s, 1H) and 15.17 (s, 1H, D2O
exchangeable, COOH). 13C-NMR (DMSO d6): ꢀ 18.39,
51.46, 54.32, 58.71, 60.31, 107.62, 120.34, 125.41, 131.08,
140.36, 146.54, 154.31, 157.29, 166.82, 177.09. Mass (ES):
m/z 348.07 [M+1]+; Anal. Calcd. for (C17H18FN3O4): C,
58.78; H, 5.22; N, 12.10. Found: C, 58.64; H, 5.09; N, 12.01
ꢀ
1.41-1.43(d, 3H, J=6.2 Hz) 2.26 (s, 1H, D2O
exchangeable), 2.40-2.49 (m, 4H), 2.57 (s, 3H), 2.91-2.95
(m, 2H), 3.09-3.12 (m, 2H), 3.26-3.36 (m, 4H), 3.66-3.71
(m,1H), 4.36-4.38 (d, 1H, J= 6.0 Hz),4.45-4.58 (d, 2H, J=6.0
Hz), 4.89 (s, 1H, D2O exchangeable), 7.52-7.56 (d, 1H, J
=12.0 Hz), 8.96 (s, 1H) and 15.10 (s, 1H, D2O exchangeable,
COOH). 13C-NMR (DMSO d6): ꢀ 18.31, 33.07, 51.43, 53.64,
55.34, 59.24, 61.38, 68.77, 107.07, 120.94, 125.12, 130.69,
140.89, 146.69, 154.95, 157.32, 166.40, 176.75. Mass (ES):
m/z 435.1 [M+1]+; Anal. Calcd. for (C21H27FN4O5): C, 58.05;
H, 6.26; N, 12.90. Found: C, 57.91; H, 6.13; N, 12.81 %.
Specific optical rotation: [ꢁ]D25 -37.84° (c=1.0 in Methanol:
DCM 1: 1).
25
%. Specific optical rotation: [ꢁ]D -69.4° (c=1.0 in
Methanol: DCM 1: 1)
(S)-9-fluoro-3,7-dihydro-3-methyl-10-(4-((oxiran-2-yl)m-
ethyl)piperazin-1-yl)-7-oxo-2H-[1,4]oxazino[2,3,4-
ij]quinoline-6-carboxylic acid (3)
(S)-10-(4-(3-(ethylamino)-2-hydroxypropyl)piperazin-1-
yl)-9-fluoro-3,7-dihydro-3-methyl-7-oxo-2H-[1,4]oxazino-
[2,3,4-ij]quinoline-6-carboxylic acid (4b)
To a solution of 2 (50g, 123 mmol) in acetone (250 mL),
add powdered NaOH (12g, 307 mmol) followed by
epichlorohydrine (23g, 0.246 mmol) and the reaction
mixture was maintained for 4h at 40-45 °C. At the end of
this period, the reaction mixture was cooled to 25-30 °C and
solvent was distilled off under vacuum. The residue was
dissolved in water (50 mL) and adjusted the pH 6.0-7.0 with
dil. HCl. The separated solid was filtered, washed with water
and dried. The crude solid was recrystallized from ethyl
acetate to obtain pure 3. Off-white solid, yield: 47g (82%),
mp 210-213°C; IR (KBr, cm-1): 3370, 3042, 2985, 1708 and
Off-white solid, Yield: 4.5g (82%); mp: 218-219 °C; IR
1
(KBr, cm-1): 3409, 2985,1707 and 1619. H-NMR (DMSO
d6): ꢀ 1.19-1.21 (t, 3H), 1.37-139 (d, 3H, J= 6.0 Hz), 2.29 (s,
1H, D2O exchangeable), 2.48-2.52 (m, 4H), 2.61 (m, 2H),
2.91-2.95 (m, 2H), 3.11-3.14 (m, 2H), 3.31-3.38 (m, 4H),
3.58-3.63 (m,1H), 4.34-4.36 (d, 1H, J= 6.0 Hz),4.52-4.54 (d,
2H, J=6.0 Hz), 5.18 (s, 1H, D2O exchangeable), 7.45-7.49
(d, 1H, J =12.0 Hz), 8.75 (s, 1H) and 15.12 (s, 1H, D2O
exchangeable, COOH). 13C-NMR (DMSO d6): ꢀ 18.31, 21.2,
46.81, 51.26, 54.13, 55.67, 59.42, 61.23, 68.85, 107.12,
120.75, 125.31, 130.43, 140.76, 146.27, 154.63, 157.11,
166.65, 176.62. Mass (ES): m/z 449.2 [M+1]+; Anal. Calcd.
1
1624. H-NMR (DMSO d6): ꢀ 1.42-1.44 (d, 3H, J=6.0 Hz),
2.34-2.41 (m, 4H), 2.49-2.51 (d, 2H, J=6.0Hz ), 3.23-3.32
(m, 4H), 3.51-3.53(d, 2H, J=6.2 Hz), 4.33-4.38 (m, 1H),
4.55-4.58 (m, 1H), 4.89-4.91 (d, 2H, J = 6.0 Hz ), 7.52-7.56
(d, 1H, J =12.0 Hz ), 8.94 (s, 1H) and 15.14 (s, 1H, D2O
exchangeable, COOH). 13C-NMR (DMSO d6): ꢀ 18.34,
45.29, 49.23, 50.72, 54.56, 55.25, 58.35, 61.61, 68.49,
107.32, 120.13, 125.19, 130.44, 132.56, 140.68, 146.79,
154.28, 166.45, 176.77. Mass (ES): m/z 404.02 [M+1]+;
Anal. Calcd. for (C20H22FN3O5): C, 59.55; H, 5.50; N, 10.42.
Found: C, 59.49; H, 5.40; N, 10.33 %. Specific optical
rotation: [ꢁ]D25 -73.06° (c=1.0 in Methanol: DCM 1: 1).
for (C22H29FN4O5): C, 58.92; H, 6.52, N, 12.49. Found: C,
20
58.76; H, 6.41; N, 12.32 %. Specific optical rotation: [ꢁ]D
-
44.84° (c=1.0 in Methanol: DCM 1: 1).
(S)-10-(4-(3-(dipropylamino)-2-hydroxypropyl) piperaz-
in-1-yl)-9-fluoro-3,7-dihydro-3-methyl-7-oxo-2H-[1,4]ox-
azino[2,3,4-ij]quinoline-6-carboxylic acid (4c)
Off-white solid, Yield: 5.2g (84%); mp: 247-250 °C; IR
(KBr, cm-1): 3425, 2928, 1707 and 1621cm-1. 1H-NMR
(DMSO d6): ꢀ 1.07-1.12 (m, 6H), 1.34-1.41 (m, 7H), 2.25-
2.32 (m, 4H), 2.48-2.52 (m, 4H), 2.77-2.79 (d, 1H, J=6.1
Hz), 3.06-3.13 (m, 2H), 3.51-3.54 (m, 4H), 3.66-3.72 (m,
1H), 4.28-4.33 (m, 1H),4.49- 4.51 (d, 2H, J=6.0 Hz), 5.06 (s,
1H, D2O exchangeable), 7.52-7.56 (d, 1H, J = 12.0 Hz ),
8.96 (s, 1H) and 15.14 (s, 1H, D2O exchangeable, COOH).
13C-NMR (DMSO d6): ꢀ 14.26, 18.42, 24.16, 51.26, 54.13,
55.67, 59.02, 59.70, 61.23, 68.92, 107.34, 120.49, 125.37,
130.58, 141.23, 146.41, 154.51, 157.34, 166.72,
General Procedure for the Synthesis of Compounds
4(a-j).
To a solution of 3 (5g, 12.3 mmol), in methanol (50 mL)
were added various amines in excess amount (aliphatic,
aromatic and cyclic). The reaction mass was heated to reflux
and maintained for 4h. The completion of the reaction was

88 Letters in Drug Design & Discovery, 2013, Vol. 10, No. 1
Guruswamy and Arul
176.81.Mass (ES): m/z 505.2 [M+1]+; Anal. Calcd. for
177.82. Mass (ES): m/z 497.2 [M+1]+; Anal. Calcd. for
(C26H37FN4O4): C, 61.89; H, 7.39; N, 11.10. Found: C,
(C26H29FN4O5): C, 62.89; H, 5.89; N, 11.28. Found: C,
25
25
61.74; H, 7.28; N, 10.96%. Specific optical rotation: [ꢀ]D
-
62.73; H, 5.81; N, 11.14%. Specific optical rotation: [ꢀ]D
-
14.60° (c=1.0 in Methanol : Water 1: 1).
32.04° (c=1.0 in Methanol: DCM 1: 1).
(S)-10-(4-(3-(tert-butylamino)-2-hydroxypropyl) pipera-
zin-1-yl)-9-fluoro-3,7-dihydro-3-methyl-7-oxo-2H-[1,4]-
oxazino[2,3,4-ij]quinoline-6-carboxylic acid (4d)
(S)-9-fluoro-2,3-dihydro-10-(4-(2-hydroxy-3-(piperidin-
1-yl) propyl)piperazin-1-yl)-6-(hydroxymethyl)-3- methyl
-[1,4]oxazino[2,3,4-ij]quinolin-7-one (4g)
Off-white solid, Yield: 5.0g (84%); mp: 221-224 °C; IR
Off-white solid Yield: 5.3g (87%); mp: 189-191 °C; IR
1
1
(KBr, cm-1): 3400, 2964, 1707 and 1620. H-NMR (DMSO
(KBr, cm-1): 3420, 2933, 1720 and 1619. H-NMR (DMSO
d6): ꢁ 1.13-1.21 (m, 9H) 1.36-1.38 (d, 3H, J=6.2 Hz), 2.27 (s,
1H, D2O exchangeable), 2.46-2.57 (m, 4H), 2.70-2.72 (d,
2H, J=6.3 Hz), 3.11-3.13 (d, 2H, J=6.1 Hz), 3.53-3.58 (m,
4H), 3.81-3.86 (m, 1H), 4.16-4.22 (m, 1H), 4.52-4.54 (d, 2H,
J=6.0), 4.71 (s, 1H, D2O exchangeable), 7.43-7.47 (d, 1H, J
= 12.0 Hz ), 8.62 (s, 1H) and 15.09 (s, 1H, D2O
exchangeable, COOH). 13C-NMR (DMSO d6): ꢁ 18.31,
34.07, 50.73, 54.14, 56.02, 59.38, 61.51, 69.27, 107.12,
121.14, 125.36, 130.71, 140.77, 146.58, 155.07, 157.41,
166.53, 176.67. Mass (ES): m/z 477.2 [M+1]+; Anal. Calcd.
d6): ꢁ 1.43-1.45 (d, 3H, J=6.0 Hz), 1.65-1.78 (m, 4H), 1.85-
1.89 (m, 2H), 2.51-2.56 (m, 4H), 2.71-2.73 (d, 2H, J=6.0
Hz), (m, 4H), 3.26-3.28 (d, 2H, J=6.2 Hz), 3.53-3.64 (m,
4H), 3.62-3.67 ( m, 1H), 4.38-4.40 (m, 1H), 4.58-4.60 (m,
2H), 4.95 (s, 1H, D2O exchangeable), 7.60-7.64 (d, 1H, J
=12.0 Hz), 8.98 (s, 1H) and 15.09 (s, 1H, D2O exchangeable,
COOH). 13C-NMR (DMSO d6): ꢁ 18.39, 24.56, 26.67, 50.72,
54.23, 55.28, 58.24, 58.93, 60.73, 65.41, 68.26, 107.07,
109.23, 120.56, 125.21, 130.51, 140.36, 146.27, 154.59,
157.23, 166.71, 177.05.Mass (ES): m/z 489.2 [M+1]+; Anal.
Calcd. for (C25H33FN4O5): C, 61.46; H, 6.81; N, 11.47.
Found: C, 61.33; H, 6.74; N, 11.39%. Specific optical
for (C24H33FN4O5): C, 60.49; H, 6.98; N, 11.76. Found: C,
25
60.34; H, 6.82; N, 11.66%. Specific optical rotation: [ꢀ]D
-
25
18.96° (c=1.0 in Methanol : Water 1: 1).
rotation: [ꢀ]D -28.32° (c=1.0 in Methanol : Water 1: 1)
2.98-3.00.
(S)-10-(4-(3-(benzylamino)-2-hydroxypropyl) piperazin-
1-yl)-9-fluoro-3,7-dihydro-3-methyl-7-oxo-2H-[1,4]oxaz-
ino[2,3,4-ij]quinoline-6-carboxylic acid (4e)
(S)-9-fluoro-2,3-dihydro-10-(4-(2-hydroxy-3-(piperazin-
1-yl) propyl)piperazin-1-yl)-6-(hydroxymethyl)-3-methyl-
[1,4]oxazino[2,3,4-ij]quinolin-7-one(4h)
Off-white solid, Yield: 5.0g (79%); mp: 234-236 °C; IR
Off-white solid, Yield: 5.1g (84%); mp: 229-230 °C; IR
1
(KBr, cm-1): 3391, 2935,1717 and 1619. H-NMR (DMSO
1
(KBr, cm-1): 3420, 2933, 1720 and 1619. H-NMR (DMSO
d6): ꢁ 1.36-1.38 (d, 3H, J=6.0 Hz), 2.29 (s, 1H, D2O
exchangeable), 2.38-2.43 (m, 4H), 2.72-2.74 (d, 2H, J=6.0
Hz), 3.14-3.16 (d, 2H, J=6.2 Hz), 3.69-3.72 (m, 4H), 3.75-
3.78 ( m, 1H), 3.92 (s, 2H), 4.29-4.35 (m, 1H), 4.42-4.44 (d,
2H, J=6.0 Hz), 4.96 (s, 1H, D2O exchangeable), 7.18-7.31
(m, 5H), 7.42-7.46 (d, 1H, J =12.0 Hz ), 8.96 (s, 1H) and
15.16 (s, 1H, D2O exchangeable, COOH). 13C-NMR (DMSO
d6): ꢁ 18.46, 50.64, 54.23, 55.61, 56.37, 57.12, 59.24, 61.38,
68.77, 107.07, 109.30, 120.94, 125.12, 127.36,
128.36,129.65, 130.69, 137.28, 140.89, 146.69, 154.95,
157.32, 166.40, 177.75. Mass (ES): m/z 511.5 [M+1]+; Anal.
Calcd. for (C27H31FN4O5): C, 63.52; H, 6.12; N, 10.97.
Found: C, 63.41; H, 6.02; N, 10.83%. Specific optical
rotation: [ꢀ]D25 -26.48° (c=1.0 in Methanol: DCM 1: 1)
d6): ꢁ 1.43-1.44 (d, 3H, J=6.0 Hz), 2.03 (s, 1H, D2O
exchangeable), 2.48-2.53 (m, 4H), 2.81-2.83 (d, 2H, J=6.0
Hz), 3.14-3.24 (m, 8H), 3.28-3.30 (d, 2H, J=6.0 Hz) 3.56-
3.61 (m, 4H), 3.71-3.75 (m, 1H), 4.38-4.41( m, 1H), 4.62-
4.64 (d, 2H, J=6.0 Hz), 4.95 (s, 1H, D2O exchangeable),
7.60-7.64 (d, 1H, J = 12.0 Hz ), 8.98 (s, 1H) and 15.12 (s,
1H, D2O exchangeable, COOH). 13C-NMR (DMSO d6): ꢁ
18.31, 44.24, 50.29, 54.23, 55.34, 56.58, 59.24, 61.38, 62.34,
68.77, 108.23, 109.09, 120.69, 125.26, 130.54, 140.68,
146.43, 154.74, 157.11, 166.63, 176.84. Mass (ES): m/z
490.5 [M+1]+; Anal. Calcd. for (C24H32FN5O5): C, 58.88; H,
6.51; N, 14.31. Found: C, 58.74; H, 6.38; N, 14.22%.
Specific optical rotation: [ꢀ]D25 -29.34° (c=1.0 in Methanol :
Water 1: 1).
(S)-9-fluoro-2,3-dihydro-10-(4-(2-hydroxy-3-(4-methylpi-
perazin-1-yl)propyl) piperazin-1-yl)-6-(hydroxymethyl)-
3-methyl-[1,4]oxazino[2,3,4-ij]quinolin-7-one (4i)
(S)-9-fluoro-3, 7-dihydro-10-(4-(2-hydroxy-3-(phenylami-
no)propyl) piperazin-1-yl)-3-methyl-7-oxo-2H-[1,4]oxaz-
ino[2,3,4-ij]quinoline-6-carboxylic acid (4f)
Off-white solid, Yield: 5.2g (83%); mp: 234-237 °C; IR
(KBr, cm-1): 3412, 2937, 1720 and 1620.1H-NMR (DMSO
d6): ꢁ 1.42-1.44 (d, 3H, J=6.0 Hz), 2.36 (s, 3H), 2.34-2.38
(m, 4H), 2.49-2.53 (m, 4H), 2.78-2.80 (d, 2H, J=6.1 Hz),
2.84-2.89 (m, 4H), 3.18-3.20 (d, 2H, J=6.0), 3.66-3.71 (m,
4H), 3.74-3.79 ( m, 1H), 3.93-3.98 (m, 1H), 4.56-4.58 (d,
2H, J= 6.0), 5.08 (s, 1H, D2O exchangeable), 7.56-7.60 (d,
1H, J =12.0 Hz ), 8.90 (s, 1H) and 15.10 (s, 1H, D2O
exchangeable, COOH). 13C-NMR (DMSO d6): ꢁ 18.35,
42.05,47.18,49.41, 53.04, 55.32, 58.71, 59.32, 60.68, 68.78,
107.10, 120.91, 125.12, 130.70, 140.96, 146.72, 154.04,
157.31, 166.35, 176.74. Mass (ES): m/z 504.2 [M+1]+; Anal.
Off-white solid Yield: 4.9g (81%); mp: 216-218 °C; IR
1
(KBr, cm-1): 3393, 2847,1718 and 1620. H-NMR (DMSO
d6): ꢁ 1.42-1.44 (d, 3H, J=6.0 Hz), 2.49-2.56 (m, 4H), 2.78-
2.79 (d, 2H, J=6.0 Hz), 3.29-3.31 (d, 2H, J=6.2 Hz), 3.57-
3.66 (m, 4H), 3.66-3.69
(
m, 1H), 3.84 (s,
1H, D2O exchangeable) 4.34-4.36 (m, 1H), 4.55-4.59 (m,
2H), 4.92 (s, 1H, D2O exchangeable), 6.51-6.61 (m, 3H),
7.03-7.08 (m, 2H), 7.56-7.60 (d, 1H, J =12.0 Hz ), 8.96 (s,
1H) and 15.16 (s, 1H, D2O exchangeable, COOH). 13C-NMR
(DMSO d6): ꢁ 18.46, 50.28, 53.96, 55.20, 57.34, 59.34,
61.07, 68.68, 108.32, 109.73, 118.61, 119.24, 130.51,
131.26, 134.01, 144.35, 150.33, 154.95, 157.61, 166.38,

Synthesis, Characterization, Antimicrobial Activity of Novel N-Substituted
Letters in Drug Design & Discovery, 2013, Vol. 10, No. 1 89
Calcd. for (C25H34 FN5O5): C, 59.63; H, 6.81; N,
13.91.Found: C, 59.52; H, 6.75 ; N, 13.83%. Specific optical
rotation: [ꢀ]D25 -21.37° (c=1.0 in Methanol : Water 1: 1).
d6): 1.08-1.13 (m, 2H), 1.43-1.45 (d, 3H, J=6.0 Hz), 2.48-
2.52 (m, 4H), 3.10-3.15 (m, 2H), 3.35 (s, 3H), 3.37-3.39 (d,
2H, J=6.0 Hz), 3.58-3.63 (m, 4H), 3.62-3.68 (m, 1H), 4.35-
4.37 (m, 1H), 4.55-4.57 (d, 2H, J=6.0 Hz), 5.21 (s, 1H, D2O
exchangeable), 7.59-7.63 (d, 1H, J =12.0 Hz ), 8.98 (s, 1H)
and 15.11 (s, 1H, D2O exchangeable, COOH). 13C-
NMR (DMSO d6): ꢁ 18.39, 20.24, 52.12, 53.41, 55.06, 58.75
(S)-9-fluoro-3,7-dihydro-10-(4-(2-hydroxy-3-morpholino-
propyl) piperazin-1-yl)-3-methyl-7-oxo-2H-[1,4]oxazino[-
2,3,4-ij]quinoline-6-carboxylic acid (4j)
,
59.57,
64.52,
74.66,
107.08,
Off-white solid, Yield: 5.2g (86%); mp: 235-237 °C; IR
(KBr, cm-1): 3420, 2933, 1720 and 1619 cm-1. 1H-NMR
(DMSO d6) ꢁ: 1.36-1.38 (d, 3H, J=6.0 Hz), 2.52-2.56 (m,
4H), 2.72-2.74 (d, 2H, J=6.1 Hz), 3.01-3.08 (m, 4H), 3.12-
3.17 (d, 2H, J=6.0), 3.54-3.59 (m, 4H), 3.64-3.69 (m, 4H),
3.82-3.86 (m, 1H), 4.08-4.18 (m, 1H), 4.43-4.45 (d, 2H, J=
6.0), 4.98 (s, 1H, D2O exchangeable), 7.43-7.47 (d, 1H, J
=12.0 Hz ), 8.62 (s, 1H) and 15.08 (s, 1H, D2O
exchangeable, COOH). 13C-NMR (DMSO d6): ꢁ 18.38,
50.23, 54.18, 55.56, 58.21, 58.71, 59.32, 60.68, 66.14, 68.68,
108.23, 109.46, 119.87, 126.31, 131.28, 141.08, 146.62,
154.31, 156.65, 166.82, 177.34. Mass (ES): m/z 491.2
[M+1]+; Anal. Calcd. for (C24H31FN4O6): C, 58.77; H, 6.37;
N, 11.42. Found: C, 58.63; H, 6.28; N, 11.31%. Specific
optical rotation: [ꢀ]D25 -33.80° (c=1.0 in Methanol : Water 1:
1).
120.23, 125.27, 130.71, 141.13, 146.55, 154.34, 157.06,
166.42, 176.58. Mass (ES): m/z 450.2 [M+1]+; Anal. Calcd.
for (C22H28FN3O6): C, 58.79; H, 6.28; N, 9.35. Found: C,
58.63; H, 6.14; N, 9.22%. Specific optical rotation: [ꢀ]D
58.44° (c=1.0 in Methanol : DCM 1: 1).
25
-
9-fluoro-3,7-dihydro-10-(4-(2-hydroxy-3-isopropoxypro-
pyl)piperazin-1-yl)-3-methyl-7-oxo-2H-[1,4]oxazino[2,3,
4-ij]quinoline-6-carboxylic acid (5c)
Off-white solid, Yield: 4.4g (74%); mp 218-221 °C; IR
(KBr, cm-1): 3412, 2937, 1720 and 1620 cm-1. 1H-NMR
(DMSO d6): ꢁ 1.07-1.09 (m, 6H), 1.42-1.44 (d, 3H, J=6.0
Hz), 2.52-2.56 (m, 4H), 3.14-3.18 (m, 2H), 3.21-3.25 (m,
1H), 3.41-3.46 (m, 4H), 3.60-3.64 (m, 1H), 3.68-3.73 (m,
2H), 4.33-4.35 (m, 1H), 4.57-4.59 (d, 2H, J=6.0 Hz), 5.21 (s,
1H, D2O exchangeable), 7.56-7.60 (d, 1H, J =12.0 Hz ), 8.99
(s, 1H) and 15.13 (s, 1H, D2O exchangeable, COOH). 13C-
NMR (DMSO d6): ꢁ 18.34, 26.52, 51.73, 54.12, 55.61, 59.21
, 60.27, 65.02,
74.51, 76.39, 107.33, 120.61, 125.31, 130.46, 141.37, 146.74
, 154.69, 156.79, 166.51, 176.67. Mass (ES): m/z 464.4
[M+1]+; Anal. Calcd. for(C23H30FN3O6) : C, 59.60; H, 6.52;
N, 9.07. Found: C, 59.51; H, 6.44; N, 8.96%. Specific optical
rotation: [ꢀ]D25 -47.64° (c=1.0 in Methanol: DCM 1: 1).
General Procedure for the Synthesis of Compounds 5(a-
c).
To a solution of 3 (5g , 12.39 mmol) in corresponding
alcoholic NaOH (1g, 23.9 mmol in 50 mL) was refluxed for
4h. On completion of the reaction as shown by TLC, solvent
was distilled off under vacuum. The residue was dissolved in
water (50 mL) and adjusted pH 6.0-7.0 with dil. HCl. The
separated solid was filtered, washed with water (5 mL) to
give corresponding crude compounds. Latter on
recrystallization from methanol afforded pure title
compounds.
BIOLOGICAL EVALUATION
Antibacterial Activity
9-fluoro-3,7-dihydro-10-(4-(2-hydroxy-3-methoxypropyl-
)piperazin-1-yl)-3-methyl-7-oxo-2H-[1,4]oxazino[2,3,4-ij]-
quinoline-6-carboxylic acid (5a).
The compounds 2, 3, 4(a-j) and 5(a-c) were assayed for
antibacterial activity against three representative Gram-
positive organisms viz. Bacillus subtilis (MTCC 441),
Staphylococcus aureus (MTCC 96), Staphylococcus
epidermidis and Gram-negative organisms viz Escherichia
coli (MTCC 443), Pseudomonas aeruginosa (MTCC 741)
and Klebsiella pneumoniae (MTCC 618) by broth dilution
method recommended by National Committee for Clinical
Laboratory (NCCL) standards [17]. Levofloxacin was used
as reference standard. The minimum inhibitory concentration
(MIC) values are presented in Table 1.
Off-white solid Yield: 4.0 g (73%); mp 237-240 °C; IR
1
(KBr, cm-1): 3415, 2939, 1715 and 1620. H-NMR (DMSO
d6): ꢁ 1.43-1.45 (d, 3H, J=6.0 Hz), 2.49-2.53 (m, 4H), 3.12-
3.16 (m, 2H), 3.25 (s, 3H), 3.26-3.30 (m, 4H), 3.54-3.61 (m,
1H), 3.65-3.71(m, 2H), 4.37-4.39 (d, 1H, J=6.0 Hz), 4.58-
4.60 (d, 1H, J=6.0 Hz), 4.92-4.94 (d, 1H, J=6.0 Hz), 5.74 (s,
1H, D2O exchangeable, OH), 7.59-7.63 (d, 1H, J =12.0 Hz ),
8.99 (s, 1H) and 15.12 (s, 1H, D2O exchangeable, COOH).
13C-NMR (DMSO d6): ꢁ 18.39, 52.38, 53.58, 55.30, 58.99,
59.68, 64.34, 74.89, 107.25, 120.78, 125.18, 130.80,
140.91, 146.75, 154.01, 157.31, 166.36, 176.79. Mass (ES):
m/z 436.6 [M+1]+; Anal. Calcd. for (C21H26FN3O6): C, 57.92;
H, 6.02; N, 9.65. Found: C, 57.84; H, 5.91; N, 9.53%.
Anti-fungal Activity
In vitro antifungal activity of the newly synthesized
compounds was studied against the fungal strains viz
Candida albicans (MTCC 227), Candida rugosa (NCIM
3467), Aspergillus flavus (MTCC 277), and Saccharomyces
cervisiae (MTCC 36) of yeasts by Agar Well Diffusion
Method [18] in 100 and 150 ug/ml concentrations. The
Potato Dextrose Agar (PDA) medium was suspended in
distilled water (39g in 1000ml) and heated to boiling until it
dissolved completely, the medium and Petri dishes were
25
Specific optical rotation: [ꢀ]D -68.0° (c=1.0 in Methanol :
DCM 1: 1).
10-(4-(3-ethoxy-2-hydroxypropyl)piperazin-1-yl)-9-fluo-
ro-3,7-dihydro-3-methyl-7-oxo-2H-[1,4]oxazino[2,3,4-ij]-
quinoline-6-carboxylic acid 5(b)
Off-white solid, Yield: 4.0 g (73%); mp 227-229 °C; IR
1
(KBr, cm-1): 3429, 2939, 1715 and 1620. H-NMR (DMSO

90 Letters in Drug Design & Discovery, 2013, Vol. 10, No. 1
Guruswamy and Arul
Table 1. Minimum inhibitory concentration (MIC) values of compounds 2, 3, 4(a-j) and 5(a-c).
Test
compounds
S. No
Micro organisms and minimum inhibitory concentration (MIC) ꢀg /mL
B.subtilis
S.aureus
S.epidermidis
E.coli
P.aeruginosa
K.pneumoniae
1
2
2
6.9
0.75
6.17
0.79
0.93
0.46
0.38
1.17
1.17
1.34
1.20
7.37
1.51
0.93
0.93
0.24
0.68
0.46
0.68
0.75
7.37
1.80
0.93
0.46
0.24
2.34
1.17
0.68
2.20
6.68
2.25
0.46
0.46
0.34
2.34
1.17
0.68
2.20
3.75
1.23
7.53
3.75
0.91
0.37
8.75
0.37
3
7.5
3
4a
4b
4c
4d
4e
4f
4g
0.75
1.52
0.98
0.61
0.46
0.37
0.68
4
5
6
7
8
9
10
4h
4i
0.92
0.56
0.41
0.32
0.75
0.98
0.78
1.64
0.21
0.41
0.32
1.17
1.12
0.19
1.34
0.21
0.36
0.93
1.68
1.39
0.19
1.37
0.68
0.22
0.46
1.34
0.76
0.19
1.37
0.22
0.46
0.51
2.34
0.54
0.19
0.75
0.78
1.34
0.55
0.79
1.34
1.56
11
12
13
14
15
16
4j
5a
5b
5c
Levofloxacin
Ref std.
autoclaved at pressure of 15 lb/inc2 for 20 min. Agar well
bioassay was employed for testing antifungal activity. The
medium was poured into sterile Petri dishes under aseptic
conditions in a laminar air flow chamber. When the medium
in the plates solidified, 0.5 ml of (week old) culture of test
organism was inoculated and uniformly spread over the agar
surface with a sterile L-shaped rod. Solutions were prepared
by dissolving the compound in DMSO at different
concentrations. After inoculation, wells were scooped out
with 6 mm sterile cork borer and the lids of the dishes were
replaced. To each well different concentrations of test
solutions were added. Controls were maintained. The treated
and the controls were kept at 27 °C for 48 h. Inhibition zones
were measured, the diameter calculated in millimetre.
results of the activity against Candida albicans are tabulated
in Table 2.
RESULTS AND DISCUSSION
(3S)-9,10-Difluoro-3-methyl-7-oxo-3,7-dihydro-2H-
[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid 1 reacted
with piperizine in presence of triethylamine in acetonitrile
under reflux given the previously reported [19], (S)-9-fluoro-
3,7-dihydro-3-methyl-7-oxo-10-(piperazin-1-yl)-2H-
[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid
treatment with epichlrohydrine in presence
2
on
of
NaOH in acetone at 40-45 °C yielded the corresponding 9-
fluoro-3,7-dihydro-3-methyl-10-(4-((oxiran-2-
yl)methyl)piperazin-1-yl)-7-oxo-2H-[1,4]oxazino[2,3,4-
ij]quinoline-6-carboxylic acid 3 as shown in Scheme 1.
Some of newly synthesized compounds shown excellent
to good activity against Candida albicans (MTCC 227) only
at 150ꢀg/mL concentrations and inactive against100ꢀg/mL
concentration, these compounds didn’t shown any
appreciable activity against the other fungal strains. The
The structure 3 was determined on the basis of its
spectral data. The IR (KBr) spectrum of compound 3 has
shown absorptions at 1708 & 1624 cm-1 assignable to two
carbonyl groups as diagnostic absorptions. Typical aliphatic

Synthesis, Characterization, Antimicrobial Activity of Novel N-Substituted
Letters in Drug Design & Discovery, 2013, Vol. 10, No. 1 91
O
N
O
O
N
O
F
NH
HN
F
OH
OH
N
Acetonitrile
F
HN
O
Triethylamine
Reflux
O
2
1
Acetone
Cl
O
Sodium hydroxide
40 - 45 °C
O
N
O
F
OH
N
O
N
O
3
Scheme 1. Synthesis of Compound 3 from 1.
O
N
O
O
O
F
OH
F
Aliphatic / Aromatic /
Cyclic anines
OH
OH
N
N
N
O
R
N
O
Methanol
Reflux, 4h
N
O
4 (a - j)
3
CH3
H3C
R =
H3C
N
N
H3C
H3C
H3C
N
H
H
H
N
N
H
a
b
c
H3C
d
e
H
N
O
HN
N
N
N
N
N
j
g
i
h
f
Scheme 2. Synthesis of Compounds 4 (a-j) from 3.
1
shift alignment in H NMR spectrum at 3.51-3.53 (d, 2H),
4.33-4.38 (m, 1H) confirms the epoxide ring protons.
However the chemical shift at 7.52-7.56 (d, 1H) with
coupling constant 12.0 Hz indicates proton coupled with
adjacent fluorine and broad singlet at 15.17 ppm
exchangeable with D2O confirmed the presence of
carboxylic acid. In 13C NMR chemical shift at 18.34
indicated the methyl group and signal at 146.51 shown the
carbon attached to fluorine. Enone carbon resonated
downfield than all other carbons at 176.77 ppm, where as
carboxylic acid carbon resonated at 166.45.
Further, the nucleophilic opening of epoxide 3 was
carried out with various amines like aliphatic amines (20%
methyl amine in methanol, ethyl amine, isopropyl amine and
t-butyl amine), aromatic amines (benzyl amine, aniline) and
cyclic amine (piperidine, piperzine, n-methyl piperizine and
morphiline) in excess amount in methanol under reflux for

92 Letters in Drug Design & Discovery, 2013, Vol. 10, No. 1
Guruswamy and Arul
O
N
O
O
N
O
F
F
OH
OH
R - OH
OH
N
N
O
NaOH
R
N
O
N
O
CH3
CH3
Reflux, 4h
5 (a - c)
3
O
O
O
R =
a
b
c
Scheme 3. Synthesis of Compounds 5 (a-c) from 3.
Table 2. Inhibition activity of compounds 2, 3, 4(a-j) and 5(a-c) in mm at 100 & 150 ꢀg/mL concentrations.
S. No
Test compounds
C. albicans
100 ꢀg
150 ꢀg
1
2
2
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
6
7
3
3
4a
3
4
4b
5
5
4c
5
6
4d
9
7
4e
6
8
4f
7
9
4g
9
10
11
12
13
14
15
16
4h
10
8
4i
4j
10
5
5a
5b
6
5c
6
Levofloxacin Ref std.
4
4h by classical approach [20-23] given the corresponding ꢀ-
hydroxy amines 4(a-j), the reaction shown in Scheme 2.
The structure of 5(a-c) have confirmed based on its
spectral and analytical data.
The structure 4a was confirmed by its spectral analysis.
IR (KBr) spectrum of compound 4a shown an absorption at
3430 cm-1 indicated the presence of hydroxy group and
absorption at 1707 and 1625 cm-1 shown the presence of
carbonyl groups. Chemical shift in 1H NMR spectrum at 4.89
as broad singlet, exchangeable to D2O proven the presence
of –OH group. The chemical shift at 33.07 in 13C NMR
shown the methyl carbon and chemical shift at 68.24 is due
to presence of CH2 group adjacent to asymmetric carbon of
oxazin ring. On the other hand, 3 on treatment with various
alcohols in the presence of NaOH under reflux for 4h
afforded the corresponding ꢀ- hydroxy ethers 5(a-c)
reactions were shown in Scheme 3.
All newly synthesized compounds 3, 4(a-j) and 5(a-c)
shown in table 1 were tested invitro against Gram-positive
organisms
viz.
Bacillus
subtilis
(MTCC
441),
Staphylococcus aureus (MTCC 96), Staphylococcus
epidermidis and Gram-negative organisms viz Escherichia
coli (MTCC 443), Pseudomonas aeruginosa (MTCC 741),
and Klebsiella pneumoniae (MTCC 618) and also
synthesized compounds were screened invitro for antifungal
activity aganist Candida albicans (MTCC 227), Candida
rugosa (NCIM 3467), Aspergillus flavus (MTCC 277), and
Aspergillus niger (MTCC 282). Saccharomyces cervisiae
(MTCC 36) of yeasts. Most of the evaluated compounds
exhibited remarkable antimicrobial activity.

Synthesis, Characterization, Antimicrobial Activity of Novel N-Substituted
Letters in Drug Design & Discovery, 2013, Vol. 10, No. 1 93
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[6]
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In conclusion, we have synthesized novel N-substituted
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and fungi strains. Compounds 4d, 4i and 4j are exhibited
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negative organisms. Compounds 4g and 5a shown good
activity and remaining compounds shown good to moderate
activity compared with levofloxacin used as reference
standard. In the same way compounds 4d, 4g, 4h and 4j
were shown good anti fungal activity in 150 ꢁg/mL
concentration.
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The authors confirm that this article content has no
conflicts of interest.
ACKNOWLEDGEMENTS
The authors express their gratitude towards Neuland
Laboratories Limited, Hyderabad (A.P.), India for supporting
this research work and Indian Institute of Chemical
Technology (IICT) Hyderabad for studying antimicrobial
activity. Authors would also like to thank authorities of
Jawaharlal Nehru Technological University, Kukatpally,
Hyderabad (A.P.), India for their kind support.
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463.
Received: August 10, 2012
Revised: September 30, 2012
Accepted: October 03, 2012