Quinolones: Novel probes in antifilarial chemotherapy

Article abstract of DOI:10.1021/jm990438d

Quinolones have been discovered in our laboratory was a new class of antifilarial agents. This has led to the design, synthesis, and antifilarial evaluation of a number of N-substituted quinol-4(1H)-one-3-carboxamide derivatives 4-6. The macrofilaricidal activity of the target compounds was initially evaluated in vivo against Acanthoeilonema viteae by oral administration of 200 mg/kg x 5 days. Among all the synthesized compounds, 13 displayed activity, with the most potent compound (4a) exhibiting 100% macrofilaricidal and 90% microfilaricidal activities. Compound 4e elicited significant macrofilaricidal (80%) response while compound 5c showed 100% sterilization of female worms. Finally, the two most potent macrofilaricidal compounds, namely 4a and 4e, have been screened for their potency against DNA topoisomerase II, and it has been observed that both have the capability to interfere with this enzyme at 10 μmol/mL concentration. The structure- activity relationship (SAR) associated with position-3 and aryl ring substituents is discussed.

Full text of DOI:10.1021/jm990438d

J . Med. Chem. 2000, 43, 2275-2279
2275
Brief Articles
Qu in olon es: Novel P r obes in An tifila r ia l Ch em oth er a p h y+,
Sanjay K. Srivastava,†,§ Prem M. S. Chauhan,*,† Amiya P. Bhaduri,† Nigar Fatima,‡ and Ranjit K. Chatterjee‡
Divisions of Medicinal Chemistry and Parasitology, Central Drug Research Institute, Lucknow 226001, India
Received August 25, 1999
Quinolones have been discovered in our laboratory as a new class of antifilarial agents. This
has led to the design, synthesis, and antifilarial evaluation of a number of N-substituted quinol-
4(1H)-one-3-carboxamide derivatives 4-6. The macrofilaricidal activity of the target compounds
was initially evaluated in vivo against Acanthoeilonema viteae by oral administration of 200
mg/kg × 5 days. Among all the synthesized compounds, 13 displayed activity, with the most
potent compound (4a ) exhibiting 100% macrofilaricidal and 90% microfilaricidal activities.
Compound 4e elicited significant macrofilaricidal (80%) response while compound 5c showed
100% sterilization of female worms. Finally, the two most potent macrofilaricidal compounds,
namely 4a and 4e, have been screened for their potency against DNA topoisomerase II, and it
has been observed that both have the capability to interfere with this enzyme at 10 µmol/mL
concentration. The structure-activity relationship (SAR) associated with position-3 and aryl
ring substituents is discussed.
In tr od u ction
The chemotherapy of filariasis is not possible due to
the nonavailability of macrofilaricidal agents.1-6 The
age-old drug diethyl carbamazine (DEC) removes almost
F igu r e 1.
all the microfilariae from the blood stream and has a
lethal effect on the adult worms.6 Ivermectin is highly
effective in reducing microfilariae, but it does not
irreversibly damage the adult filarial worms.6 As a
result, in 1995 the World Health Organization (WHO)
adopted a goal to develop a nontoxic macrofilaricidal
agent, or at least an agent which could sterilize filariae
permanently.7 Such an agent would block further
transmission of infection, and to this end a screening
program based on Acanthoeilonema viteae infection was
initiated.7 In a continuation of our earlier studies toward
the search for a potential macrofilaricidal agent,1,3,5 we
have developed a range of quinolones as a new class of
antifilarial agents. The details of the design, synthesis,
and antifilarial evaluation of this study are presented
here.
Recently, the presence of ATP-dependent DNA topo-
isomerase II activity in the filarial parasites has been
demonstrated in our laboratory.8,9 As yet the effect of
chemotherapeutic agents on this newly discovered
biochemical target site has not been extensively ex-
plored, although bacterial DNA topoisomerase II inhibi-
tors, and particular quinolone antibacterials, have
shown an ability to inhibit this enzyme in filarial
F igu r e 2. Proposed DNA gyrase-N-substituted quinol-4(1H)-
one-3-carboxamide interaction model.
parasites.10 To ascertain the actual utility of quinolone
in the filarial chemotherapy, potent compounds are
required. However, the optimal structural requirements
for potent macrofilaricidal activity have not yet been
determined, and therefore, in order to define the struc-
tural modification important for activity, it was consid-
ered essential to evaluate N-substituted quinol-4(1H)-
one-3-carboxamides (Figure 1).
The prototype N-substituted quinol-4(1H)-one-3-car-
boxamides (Figure 1) have been envisaged to interact
in biophase, mimicking the model proposed for bacterial
DNA gyrase (DNA topoisomerase II)-quinolone inter-
actions published previously.11 The hypothetical picture
of this interaction is presented in Figure 2. The main
concern of this model is to view the quinolone derivative
in a three-dimensional structure after its binding with
magnesium. It is apparent that a large number of
factors contribute to this picture; however, the key
+ CDRI Communication No. 5955.
A part of this work has been presented in the Third National
Conference on Trends in Drugs and Pharmaceutical Research: Global
Scenario, 1998, at College of Pharmaceutical Sciences, Manipal, India.
* Corresponding author. Phone: 91-522-212411-18 ext. 4332. Fax:
91-0522-223405/223938. E-mail: root@cscdri.ren.nic.in.
† Division of Medicinal Chemistry.
‡ Division of Parasitology.
§ Present address: Organic & Biological Section, School of Chem-
istry, Cantock’s Close, University of Bristol, Bristol, BS8 1TS, England.
Email: S.K.Srivastava@bristol.ac.uk
10.1021/jm990438d CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/11/2000

2276 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Brief Articles
Ta ble 1. Antifilarial in Vivo Activity of N-Substituted
Sch em e 1a
Quinol-4(1H)-one-3-carboxamides 4-6 against A. vteae at 200
mg/kg × 5 days (po)
antifilarial activityb
(% reduction in parasites load)
compounda
4a
4c
4d
4e
4f
5a
5b
mif.
maf.
sterl. of ?
90
54
50
24
54
25
30
40
48
17
37
54
60
90
100
0
31
80
0
NA
0
36
0
0
0
0
100
0
0
25
0
0
50
38
0
0
47
0
5c
5d
5f
5g
6c
6h
0
0
0
0
DECc citrate
a
Inactive compounds are not listed here. bmif. ) microfilariae;
a
Reagents and conditions: (i) neat; (ii) Dowtherm in a ratio
maf. ) macrofilariae; sterl. ) sterilization; ? ) female worms; NA
1:10 with the solvent, reflux, 250 °C; (iii) amine (RNH2), pyridine,
125 °C, under pressure.
c
) not applicable; 0 ) inactive. DEC ) diethylcarbamazine
(standard antifilarial drug).
points of concern for the present study are π-stacking
interactions of the heterocyclic nucleus and the interac-
tion of the amide nitrogen with the receptor.
activities. This compound was also the most potent
compound among all the N-substituted quinol-4(1H)-
one-3-carboxamides in the present study. Introduction
of a nitro group at position-6 in this compound resulted
compound 4c, which showed only 54% microfilaricidal
response. However, the introduction of a nitro group at
position-7 (4e) resulted in 80% macrofilaricidal activity
and 24% microfilaricidal effect. It was interesting to note
that N-cyclohexyl 6-fluoroquinol-4(1H)-one-3-carboxa-
mide (4d ) showed 50% micro- and 31% macrofilaricidal
activities along with 36% sterilization of female worms.
The methyl group at position-8 in cyclohexyl quinol-
4(1H)-one-3-carboxamide (4f) was less effective since it
showed only 54% microfilaricidal activity. The other
compounds of this series such as N-cyclohexyl 6-chloro
(4b), 8-fluoro (4g), and 7-chloro 6-fluoro (4h ) quinol-
4(1H)-one-3-carboxamides did not elicit any antifilarial
activity.
Ch em istr y
The synthetic strategy for constructing the molecular
framework of quinolone ring 3a-h is outlined in Scheme
1. First diethyl ethoxymethylenemalonate was reacted
with the anilines 1a -h to yield the corresponding
enamine diesters12 2a -h . This was followed by thermal
cyclization in Dowtherm in a ratio of 1:10 with the
solvent at 250 °C to afford ethyl quinol-4(1H)-one-3-
carboxylates13 3a -h . Compounds 3a -h were treated
separately with primary amines (RNH2) in pyridine in
a steel bomb at 125 °C to furnish their respective
N-substituted quinol-4(1H)-one-3-carboxamides 4a -h ,
5a -d , 5f-h , 6c, 6d , and 6h (Scheme 1).
An tifila r ia l Eva lu a tion
Unlike the N-cyclohexyl quinol-4(1H)-one-3-carboxa-
mide series (4a -h ), among N-octyl quinol-4(1H)-one-3-
carboxamides (5a -d , 5f-h ), the most active derivative
was N-octyl 6-nitroquinol-4(1H)-one-3-carboxamide (5c).
Compound 5c exhibited 100% sterilization of female
worms along with 40% micro- and 38% macrofilaricidal
activities. The compound with no substituent in its
aromatic ring (5a ) produced insignificant microfilari-
cidal (25%) activity. Substituents such as chloro (5b) or
fluoro (5d ) at position-6 did not produce any significant
antifilarial response, with 5b exhibiting 50% macro- and
30% microfilaricidal activities while compound 5d showed
48% microfilaricidal activity only. The compound with
a fluoro group at position-8 (5g) showed 47% macro- and
37% microfilaricidal activities along with 25% steriliza-
tion of female worms while the corresponding methyl
derivative 5f caused insignificant microfilaricidal (17%)
response. Compound 5h failed to elicit any antifilarial
response.
All the synthesized componds 4-6 were evaluated for
their antifilarial activity in vivo against A. viteae at 200
mg/kg × 5 days by oral administration (po). The model
used in this experiment was Mastomys coucha since this
model has been recommended by WHO for the experi-
mental chemotherapy of filariasis.7,14 The antifilarial
activities of N-substituted quinol-4(1H)-one-3-carboxa-
mides 4-6 against A. viteae are summarized in Table
1. The effect of compounds 4a and 4e on DNA topo-
isomerase II of filarial parasite was assessed at 10 µmol/
mL concentration.
Resu lts a n d Discu ssion
The micro- and macrofilaricidal activities in quinol-
4(1H)-ones with various substituents at position-3 and
in the aromatic ring were monitored as follows. With a
particular substituent at position-3, the effect of various
substituent in the aromatic ring of quinol-4(1H)-ones
was monitored.
Among the N-cyclohexylquinol-4(1H)-one-3-carboxa-
mide derivatives 4a -h , the most potent compound was
the one with no substituent on the aromatic ring (4a ).
It exhibited 100% macro- and 90% microfilaricidal
None of the N-(N′,N′-diethylamino-1′-methyl)butyl
quinol-4(1H)-one-3-carboxamide series (6c, 6d , 6h )
showed any interesting antifilarial activity. For ex-
ample, compounds 6c and 6h exhibited only 54% and
60% microfilaricidal activity, respectively.

Brief Articles
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11 2277
1H, H-2), 8.89 (s, 1H, ArH), 8.46 (d, 1H, J ) 4 Hz, ArH), 7.76
(d, 1H, J ) 6.0 Hz, ArH), 4.08 (bs, 1H, N-CH), 2.10-1.92 (m,
2H, CH2), 1.86-1.74 (m, 2H, CH2), 1.48-1.28 (m, 6H, CH2).
Anal. (C16H17N3O4) C, H, N.
The most potent macrofilaricidal compounds, namely
4a and 4e, were screened for their DNA topoisomerase
II activity at 10 µmol/mL concentration. Compound 4a
displayed >80% enzyme inhibition while compound 4e
exhibited >70% inhibitory activity. These data clearly
indicate that both compounds have the capability to
interact with filarial DNA topoisomerase II and could
provide an important tool for future drug design.
However, the highlight of the present study was the
discovery of quinol-4(1H)-one-3-carboxamides as a new
class of antifilarial agents. For the macrofilaricidal
efficacy in particular, the optimum pharmacophoric
requirement of the substituent on the amide nitrogen
was the cyclohexyl moiety. Studies are now underway
to further explain the SAR of this series and generate
compounds with improved potency.
N-Cycloh exyl
6-F lu or oq u in ol-4(1H )-on e-3-ca r b ox-
a m id e (4d ). Compound 4d was prepared from ethyl 6-flouo-
roquinol-4(1H)-one-3-carboxylate (3d ) (0.58 g, 2.47 mmol) and
cyclohexylamine (0.3 mL, 2.62 mmol) in pyridine (1.5 mL) by
following the method as described for 4a : 0.43 g (61.5%). Rf
0.79; mp 41 °C; IR (KBr) 3018, 2935, 1647, 1215, 758 cm-1
;
1
MS m/z 289 (M + 1), 288 (M); H NMR (300 MHz, CDCl3) δ
10.41 (d, 1H, J ) 6.0 Hz, NH), 8.80 (s, 1H, H-2), 8.09 (m, 1H,
ArH), 7.66-7.36 (m, 2H, ArH), 4.05 (bs, 1H, N-CH), 1.98-1.90
(m, 2H, CH2), 1.79-1.42 (m, 4H, CH2), 1.35-1.11 (m, 4H, CH2).
Anal. (C16H17FN2O2) C, H, N.
N-Cycloh exyl 7-Nitr oqu in ol-4(1H)-on e-3-ca r boxa m id e
(4e). Ethyl 7-nitroquinol-4(1H)-one-3-carboxylate (3e) (0.50 g,
1.90 mmol) was treated with cyclohexylamine (0.24 mL, 2.20
mmol) in pyridine (1.5 mL) as for 4a to provide 4e: 0.33 g
(54.8%); Rf 0.68; mp 63 °C; IR (KBr) 3020, 2934, 1636, 1350,
Exp er im en ta l Section
788 cm-1; MS m/z 315 (M); 1H NMR (200 MHz, CDCl3
+
Ch em istr y. The compounds were routinely checked for
their purity by thin-layer chromatography (TLC) on silica gel
G. Rf values were determined using 4% MeOH-CHCl3.
Visualization was achieved by I2 vapor. Column chromatog-
raphy separations were carried out on Merck silica gel (230-
400 mesh), and the eluent was 0.5-1% MeOH-CHCl3. Melting
points (mp) were determined in capillary tubes on an electro-
thermal melting point Toshiniwal CL-03001 apparatus and are
uncorrected. Infrared (IR) spectra were run on a Beckman-
Acculab-10 spectrophotometer (νmax in cm-1). Nuclear magnetic
resonance (NMR) spectra were recorded on either Bruker-400-
FT or 300-FT or 200-FT instruments, and chemical shifts (δ
in ppm) were reported relative to the solvent peak (CHCl3 in
CDCl3 at 7.23 ppm, and DMSO in DMSO-d6 at 2.49 ppm) or
TMS. Signals were designated as follows: s, singlet; bs, broad
signal; d, doublet; t, triplet; m, multiplet. EI mass spectra were
recorded on a JEOL-JMS-D-300 spectrometer. Chemical analy-
ses were carried out on a Carlo-Erba EA 1108 elemental
analyzer. Reagents and solvents were purchased from com-
mercial suppliers and used as received. Organic solutions were
dried over anhydrous Na2SO4 and concentrated with a Buchi
rotary evaporator at low pressure. Yields were of purified
product and were not optimized.
DMSO-d6) δ 9.89 (d, 1H, J ) 7.8 Hz, NH), 8.88 (d, 1H, J ) 6.5
Hz, H-2), 8.55-8.45 (m, 2H, ArH), 8.26-8.11 (m, 1H, ArH),
3.99 (bs, 1H, N-CH), 2.25-1.04 (m, 10H, CH2). Anal.
(C16H17N3O4) C, H, N.
N-Cycloh exyl
8-Met h ylq u in ol-4(1H )-on e-3-ca r b ox-
a m id e (4f). By a procedure similar to that for 4a , compound
4f was obtained from ethyl 8-methylquinol-4(1H)-one-3-car-
boxylate (3f) (0.50 g, 2.17 mmol) and cyclohexylamine (0.30
mL, 2.60 mmol) in pyridine (1.0 mL): 0.38 g (61.6%); Rf 0.89;
mp 56 °C; IR (KBr) 3010, 2928, 1632, 1200, 760 cm-1; MS m/z
281 (M - 3); 1H NMR (200 MHz, CDCl3) δ 11.11 (bs, 1H, NH),
10.35 (d, 1H, J ) 8.0 Hz, NH), 8.91 (d, 1H, J ) 6.6 Hz, H-2),
8.26 (d, 1H, J ) 8.0 Hz, ArH), 7.48 (d, 1H, J ) 7.0 Hz, ArH),
7.31 (t, 1H, J ) 8.8 Hz, ArH), 3.99 (bs, 1H, N-CH), 2.59 (s,
3H, CH3), 2.22-1.38 (m, 10H, CH2). Anal. (C17H20N2O2) C, H,
N.
N-Cycloh exyl
8-F lu or oq u in ol-4(1H )-on e-3-ca r b ox-
a m id e (4g). Ethyl 8-flouoroquinol-4(1H)-one-3-carboxylate
(3g) (0.50 g, 2.13 mmol) and cyclohexylamine (0.3 mL, 2.62
mmol) in pyridine (1.5 mL) were reacted in a manner similar
to that described under 4a to afford 4g: 0.35 g (57.6%); Rf 0.74;
mp 55 °C; IR (KBr) 3012, 2928, 1652, 1360, 774 cm-1; MS m/z
1
286 (M - 2); H NMR (200 MHz, CDCl3) δ 10.25 (d, 1H, J )
N-Cycloh exyl Qu in ol-4(1H)-on e-3-ca r boxa m id e (4a ). A
solution of ethyl quinol-4(1H)-one-3-carboxylate (3a ) (0.55 g,
2.5 mmol) and cyclohexylamine (0.3 mL, 2.62 mmol) in
pyridine (1.5 mL) was heated at 125 °C in a steel bomb for 30
h. The reaction mixture was then poured in water and
extracted with chloroform (3 × 100 mL). The chloroform
extract was washed by water, dried over Na2SO4, and concen-
trated to furnish an oil which was washed by hexane and after
purification afforded 4a : 0.37 g (53.1%); Rf 0.84; mp 46 °C; IR
7.8 Hz, NH), 9.90 (s, 1H, H-2), 8.17-8.02 (m, 1H, ArH), 7.49-
7.35 (m, 2H, ArH), 4.20 (bs, 1H, N-CH), 1.95-1.73 (m, 2H,
CH2), 1.60-1.25 (m, 8H, CH2). Anal. (C16H17FN2O2) C, H, N.
N-Cycloh exyl 7-Ch lor o-6-flu or oq u in ol-4(1H )-on e-3-
ca r boxa m id e (4h ). Ethyl 7-chloro-6-flouoroquinol-4(1H)-one-
3-carboxylate (3h ) (0.58 g, 2.15 mmol) and cyclohexylamine
(0.25 mL, 2.20 mmol) in pyridine (1.5 mL) were reacted as for
4a to afford 4h : 0.39 g (56.6%); Rf 0.65; mp 49 °C; IR (KBr)
1
3066, 2929, 1647, 1253, 798 cm-1; MS m/z 322 (M); H NMR
1
(KBr) 2930, 1642, 1202, 706 cm-1; MS m/z 270 (M); H NMR
(300 MHz, CDCl3) δ 8.83 (s, 1H, H-2), 8.16 (d, 1H, J ) 9.0 Hz,
ArH), 7.77 (d, 1H, J ) 6.0 Hz, ArH), 4.08 (bs, 1H, N-CH), 2.04-
2.01 (m, 2H, CH2), 1.81-1.78 (m, 2H, CH2), 1.63-1.47 (m, 2H,
CH2), 1.39-1.26 (m, 2H, CH2). Anal. (C16H16FClN2O2) C, H,
N.
(200 MHz, CDCl3) δ 10.55 (d, 1H, J ) 7.7 Hz, NH), 8.95 (s,
1H, H-2), 8.43 (d, 1H, J ) 7.9 Hz, ArH), 7.71-7.41 (m, 3H,
ArH), 4.08 (bs, 1H, N-CH), 2.14-1.36 (m, 10H, CH2). Anal.
(C16H18N2O2) C, H, N.
N-Cycloh exyl
6-Ch lor oq u in ol-4(1H )-on e-3-ca r b ox-
N-Octyl Qu in ol-4(1H)-on e-3-ca r boxa m id e (5a ). Com-
pound 3a (0.55 g, 2.5 mmol) and n-octylamine (0.50 mL, 3.2
mmol) in pyridine (1.5 mL) were treated as for 4a to provide
5a : 0.47 g (61.4%); Rf 0.82; mp 59 °C; IR (KBr) 3008, 2926,
a m id e (4b). Reaction of ethyl 6-chloroquinol-4(1H)-one-3-
carboxylate (3b) (0.76 g, 3 mmol) and cyclohexylamine (0.4 mL,
3.5 mmol) in pyridine (2.5 mL) using a procedure identical to
that described for 4a furnished 4b: 0.45 g (48.8%); Rf 0.76;
mp 52 °C; IR (KBr) 2916, 1652, 1252, 730 cm-1; MS m/z 304
1
1640, 1210, 702 cm-1; MS m/z 300 (M); H NMR (200 MHz,
1
CDCl3) δ 10.56 (t, 1H, J ) 5.4 Hz, NH), 8.89 (d, 1H, J ) 6.6
Hz, H-2), 8.43 (d, 1H, J ) 8.0 Hz, ArH), 7.63-7.40 (m, 3H,
ArH), 3.53 (m, 2H, N-CH2), 1.73-1.22 (m, 12H, CH2), 0.8 (t,
3H, J ) 6.2 Hz, CH3). Anal. (C18H24N2O2) C, H, N.
(M); H NMR (200 MHz, CDCl3) δ 10.48 (d, 1H, J ) 6.6 Hz,
NH), 8.94 (d, 1H, J ) 7.2 Hz, H-2), 8.40 (s, 1H, ArH), 7.69-
7.53 (m, 2H, ArH), 4.15 (bs, 1H, N-CH), 2.28-1.45 (m, 10H,
CH2). Anal. (C16H17ClN2O2) C, H, N.
N-Cycloh exyl 6-Nitr oqu in ol-4(1H)-on e-3-ca r boxa m id e
(4c). A solution of ethyl 6-nitroquinol-4(1H)-one-3-carboxylate
(3c) (0.48 g, 1.83 mmol) in pyridine (1 mL) and cyclohexyl-
amine (0.2 mL, 1.9 mmol) was reacted as for 4a to afford 4c:
0.35 g (60.8%); Rf 0.78; mp 48 °C; IR (KBr) 3030, 2931, 1645,
N-Octyl 6-Ch lor oqu in ol-4(1H)-on e-3-ca r boxa m id e (5b).
In a manner similar to the preparation of 4a , compound 5b
was obtained from compound 3b (0.8 g, 3.19 mmol) and
n-octylamine (0.58 mL, 3.0 mmol) in pyridine (2.0 mL): 0.47
g (43.9%); Rf 0.69; mp 57 °C; IR (KBr) 3018, 2958, 1680, 1210,
830 cm-1; MS m/z 300 (M - Cl + 1); 1H NMR (200 MHz,
CDCl3) δ 10.39 (bs, 1H, NH), 8.82 (s, 1H, H-2), 8.51 (s, 1H,
1
1215, 759 cm-1; MS m/z 315 (M); H NMR (200 MHz, CDCl3)
δ 11.18 (bs, 1H, NH), 10.16 (d, 1H, J ) 6.0 Hz, NH), 9.30 (s,

2278 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Brief Articles
ArH), 7.62-7.52 (m, 2H, ArH), 3.51 (m, 2H, N-CH2), 1.66-
1.25 (m, 12H, CH2), 0.86 (m, 3H, CH3). Anal. (C18H23ClN2O2)
C, H, N.
1H, ArH), 7.80-7.50 (m, 2H, ArH), 6.25 (bs, 1H, NH), 4.40-
4.41 (m, 1H, N-CH), 3.30-2.70 (m, 6H, CH2), 2.65-2.10 (m,
4H, CH2), 1.75-1.50 (m, 3H, CH3), 1.40-1.20 (m, 3H, CH3),
1.10-0.90 (m, 3H, CH3). Anal. (C19H26FN3O2) C, H, N.
N-Octyl 6-Nitr oqu in ol-4(1H)-on e-3-ca r boxa m id e (5c).
Compound 3c (0.48 g, 1.83 mmol) was reacted with n-
octylamine (0.3 mL, 1.9 mmol) in pyridine (1.0 mL) as
described for 4a to afford 5c: 0.42 g (66.7%); Rf 0.70; mp 51
°C; IR (KBr) 3118, 2925, 1651, 1494, 758 cm-1; MS m/z 345
N-(N′,N′-Dieth yla m in o-1′-m eth yl)bu tyl 7-Ch lor o-6-flu -
or oqu in ol-4(1H)-on e-3-ca r boxa m id e (6h ). By a procedure
similar to that described for 4a , compound 6h was obtained
from the compound 3h (0.65 g, 2.41 mmol) and 2-amino-5-
diethylaminopentane (0.50 mL, 2.55 mmol) in pyridine (1.5
mL): 0.59 g (64%); Rf 0.69; mp 45 °C; IR (KBr) 3018, 2929,
1
(M); H NMR (400 MHz, CDCl3) δ 12.06 (bs, 1H, NH), 10.56
(t, 1H, J ) 3.0 Hz, NH), 8.72 (s, 1H, H-2), 7.59 (s, 1H, ArH),
7.44 (d, 1H, J ) 6.0 Hz, ArH), 7.02 (m, 1H, ArH), 3.49 (m, 2H,
N-CH2), 1.64-1.23 (m, 12H, CH2), 0.85 (t, 3H, J ) 4.0 Hz,
CH3). Anal. (C18H23N3O4) C, H, N.
1
1647, 1215, 759 cm-1; MS m/z 381 (M); H NMR (400 MHz,
CDCl3) δ 10.18 (bs, 1H, NH), 8.75 (s, 1H, H-2), 8.16-7.88 (m,
2H, ArH), 6.20 (bs, 1H, NH), 3.50 (m, 1H, N-CH), 3.00-2.70
(m, 4H, CH2), 1.84-1.50 (m, 6H, CH2), 1.49-0.9 (m, 9H, CH3).
Anal. (C19H25ClFN3O2) C, H, N.
N-Octyl 6-F lu or oqu in ol-4(1H)-on e-3-ca r boxa m id e (5d ).
By an analogous procedure as described for 4a , compound 5d
was obtained from compound 3d (0.68 g, 2.89 mmol) and
n-octylamine (0.50 mL, 3.2 mmol) in pyridine (1.5 mL): 0.64
g (69.3%); Rf 0.72; mp 43 °C; IR (KBr) 3080, 2929, 1647, 1533,
752 cm-1; MS m/z 318 (M); 1H NMR (400 MHz, CDCl3) δ 12.30
(bs, 1H, NH), 10.18 (bs, 1H, NH), 9.28 (s, 1H, H-2), 8.91 (s,
1H, ArH), 8.46 (d, 1H, J ) 10.0 Hz, ArH), 7.76 (d, 1H, J )
10.0 Hz, ArH), 3.50 (m, 2H, N-CH2), 1.90-1.58 (m, 4H, CH2),
1.50-1.08 (m, 8H, CH2), 0.88 (t, 3H, J ) 5.0 Hz, CH3). Anal.
(C18H23FN2O2) C, H, N.
N-Octyl 8-Meth ylqu in ol-4(1H)-on e-3-ca r boxa m id e (5f).
In an analogous procedure as described for 4a , compound 5f
was obtained from compound 3f (1.0 g, 4.34 mmol) and
n-octylamine (0.80 mL, 5.0 mmol) in pyridine (3.0 mL): 0.81
g (59.5%); Rf 0.82; mp 48 °C; IR (KBr) 3020, 2934, 1686, 1644,
774 cm-1; MS m/z 314 (M); 1H NMR (200 MHz, CDCl3) δ 10.27
(t, 1H, J ) 5.4 Hz, NH), 8.79 (d, 1H, J ) 6.9 Hz, H-2), 8.11 (d,
1H, J ) 7.7 Hz, ArH), 7.36 (d, 1H, J ) 6.8 Hz, ArH), 7.19 (t,
1H, J ) 7.8 Hz, ArH), 3.32 (m, 2H, N-CH2), 2.37 (s, 3H, CH3),
1.51-1.15 (m, 12H, CH2), 0.77 (t, 3H, J ) 6.3 Hz, CH3). Anal.
(C19H26N2O2) C, H, N.
N-Octyl 8-F lu or oqu in ol-4(1H)-on e-3-ca r boxa m id e (5g).
In a manner similar to the preparation of 4a , compound 5g
was prepared from compound 3g (0.65 g, 2.77 mmol) and
n-octylamine (0.56 mL, 3.4 mmol) in pyridine (1.5 mL): 0.48
g (53.8%); Rf 0.66; mp 54 °C; IR (KBr) 3040, 2982, 1680, 1416,
764 cm-1; MS m/z 318 (M); 1H NMR (200 MHz, CDCl3) δ 10.20
(t, 1H, J ) 4.9 Hz, NH), 8.98 (d, 1H, J ) 6.4 Hz, H-2), 8.19-
8.15 (m, 1H, ArH), 7.46-7.33 (m, 2H, ArH), 3.48 (m, 2H,
N-CH2), 2.23-2.17 (m, 2H, CH2), 1.67-1.60 (m, 2H, CH2),
1.56-1.24 (m, 8H, CH2), 0.85 (t, 3H, J ) 6.2 Hz, CH3). Anal.
(C18H23FN2O2) C, H, N.
Ma ter ia ls a n d Meth od for An tifila r ia l Eva lu a tion . A.
viteae infection was transmitted to 6 weeks old male M. coucha
through the vector Ornithodorus moubata by the method as
reported in the literature.15 The micro- and macrofilaricidal
activities of the compounds 4-6 were assessed at 200 mg/kg
(po) for five consecutive days according to literature meth-
ods.16,17 The effect of compounds, namely 4a and 4e, on DNA
topoisomerase II of filarial parasite has been assessed at
10µmol/mL concentration, and the procedure for topoisomerase
II assay was as reported in the literature.8-10
Ack n ow led gm en t. S.K.S. is grateful to CSIR for the
award of Senior Research Fellowship and N.F. is thank-
ful to ICMR for the award of Research Associate. We
are thankful to Dr. J . K. Saxena, Division of Biochem-
istry, CDRI, Lucknow, for providing the data of DNA
topoisomerase II activity. We are also indebted to RSIC,
Lucknow, for providing spectroscopic and analytical
data. Thanks to Dr. Stephen M. Husbands, University
of Bristol, England, for valuable suggestions.
Refer en ces
(1) Srivastava, S. K.; Agarwal, A.; Chauhan, P. M. S.; Agarwal, S.
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20.
N-Octyl 7-Chloro-6-fluoroquinol-4(1H)-on e-3-ca r boxa m id e
(5h ). Compound 3h (0.58 g, 2.15 mmol) and n-octylamine (0.36
mL, 2.2 mmol) in pyridine (1.5 mL) were reacted as for 4a to
provide 5h : 0.47 g (61.8%); Rf 0.64; mp 53 °C; IR (KBr) 3060,
2925, 1645, 1356, 798 cm-1; MS m/z 344 (M - F - 1); 1H NMR
(200 MHz, CDCl3) δ 10.15 (bs, 1H, NH), 8.90 (s, 1H, H-2), 8.10
(m, 1H, ArH), 7.85 (m, 1H, ArH), 4.02 (m, 2H, N-CH2), 1.70-
1.52 (m, 12H, CH2), 0.88 (t, 3H, J ) 6.0 Hz, CH3). Anal. (C18H22
ClFN2O2) C, H, N.
-
(5) Singh, S. N.; Bhatnagar, S.; Fatma, N.; Chauhan, P. M. S.;
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N-(N′,N′-Dieth yla m in o-1′-m eth yl)bu tyl 6-Nitr oqu in ol-
4(1H)-on e-3-ca r boxa m id e (6c). By an analogous procedure
as described for 4a , compound 6c was prepared from the
compound 3c (0.53 g, 2.02 mmol) and 2-amino-5-diethylami-
nopentane (0.50 mL, 2.6 mmol) in pyridine (1.0 mL): 0.44 g
(58.9%); Rf 0.62; mp 42 °C; IR (KBr) 3108, 2920, 1635, 1028,
758 cm-1; MS m/z 374 (M); 1H NMR (200 MHz, CDCl3) δ 10.28
(bs, 1H, NH), 8.90 (s, 1H, H-2), 8.20-7.70 (m, 3H, ArH), 4.50
(m, 1H, N-CH), 3.20-2.50 (m, 6H, CH2), 2.40-2.10 (m, 4H,
CH2), 1.80 (m, 3H, CH3), 1.50-0.85 (m, 6H, CH3). Anal.
(C19H26N4O4) C, H, N.
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N-(N′,N′-Dieth ylam in o-1′-m eth yl)bu tyl 6-Flu or oqu in ol-
4(1H)-on e-3-ca r boxa m id e (6d ). In a manner similar to the
preparation of 4a , compound 6d was synthesized from the
compound 3d (0.65 g, 2.76 mmol) and 2-amino-5-diethylami-
nopentane (0.55 mL, 2.85 mmol) in pyridine (1.5 mL): 0.57 g
(59.8%); Rf 0.66; mp 40 °C; IR (KBr) 3142, 2925, 1636, 1035,
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1
798 cm-1; MS m/z 348 (M + 1), 347 (M); H NMR (90 MHz,
CDCl3) δ 10.25 (bs, 1H, NH), 8.80 (s, 1H, H-2), 8.10-7.90 (m,

Brief Articles
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J M990438D