Design synthesis and antibacterial activity studies of new thiadiazoloquinolone compounds

Article abstract of DOI:10.3109/14756366.2013.855925

New 9-(alkyl/aryl)-4-fluoro-6-oxo[1,2,5]thiadiazolo[3,4-h]quinoline-5-carboxylic acids and their esters were designed and synthesized. A detailed discussion of the reactions utilized in the preparation of the intermediate and target compounds is reported.

Full text of DOI:10.3109/14756366.2013.855925

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ISSN: 1475-6366 (print), 1475-6374 (electronic)
J Enzyme Inhib Med Chem, 2014; 29(6): 777–785
2014 Informa UK Ltd. DOI: 10.3109/14756366.2013.855925
!
ORIGINAL ARTICLE
Design synthesis and antibacterial activity studies of new
thiadiazoloquinolone compounds
Raed A. Al-Qawasmeh1, Mohammed M. Abadleh2, Jalal A. Zahra1, Mustafa M. El-Abadelah1, Rabab Albashiti1,
Franca Zani3, Matteo Incerti3, and Paola Vicini3
2
1Chemistry Department, Faculty of Science, The University of Jordan, Amman, Jordan, College of Pharmacy, Taibah University, Al Madinah,
3
Saudia Arabia, and Dipartimento di Farmacia, Universita degli Studi di Parma, Parma, Italy
`
Abstract
Keywords
New 9-(alkyl/aryl)-4-fluoro-6-oxo[1,2,5]thiadiazolo[3,4-h]quinoline-5-carboxylic acids and their
esters were designed and synthesized. A detailed discussion of the reactions utilized in the
preparation of the intermediate and target compounds is reported. All the newly synthesized
compounds were fully characterized using all the physico-chemical means needed. All the
intermediates and the final esters and acids were tested against bacterial and fungal strains.
The acids 25a and 25c proved to be very active against Gram positive and Gram negative
bacteria with MIC 0.15–3 mg/mL. The structure–activity relationship of antibacterial thiadiazo-
loquinolones shows that compounds 25a and 25c are twice less potent than the correspond-
ing cyclopropyl derivative 16. Therefore, the cyclopropyl moiety on N-9 seems to be the most
suitable substituent.
6-Fluoroquinolone, antibacterial activity,
synthesis, thiadiazoloquinolone
History
Received 28 June 2013
Revised 3 October 2013
Accepted 7 October 2013
Published online 5 February 2014
Introduction
introduction of the fluorine atom, for its crucial advantage, and
also on the replacement of the ethyl with the cyclopropyl moiety,
with respect to thiadiazoloquinolones 14 and 15.
The result of that study was very interesting, the strategy
proved its success via enhancement of the activity compared to
the previous thiadiazoloquinolones 14 and 15, and also the
potency of compound 16 was comparable to the drug
ciprofloxacin.19
Herein, we report on the synthesis and the antibacterial
activities of new compounds based on the same strategy by fixing
the fluorine atom and replacing the cyclopropyl with different
moieties, namely ethyl, phenyl, p-fluorophenyl and p-methox-
yphenyl, which are based on the structure of important fluoro-
quinolone agents.
Norfloxacin (1) and ciprofloxacin (2) were among the first
quinolones marketed as chemotherapeutic agents for the treatment
of systemic bacterial infections1–3. Several new members of the
quinolone family have emerged with enhanced activities such as
grepafloxacin (3), levofloxacin (4), rufloxacin (5), and com-
pounds 6–9 (Figure 1). Much has been learned about how
molecular modifications of the core quinolone structure affect the
antibacterial profile. The structure–activity relationship of the
quinolones has been the subject of extensive reviews4–16
In our continuous effort to develop new chemotherapeutics
with enhanced activities against resistant bacterial strains17,18
we introduced a new class of tricyclic compounds, namely
thiadiazoloquinolones19. In our methodology, we took advan-
tage of many known benzothiadiazoles (Figure 2) with diverse
biopharmaceutical activities20–26 and we hybridized the thia-
diazole moiety with the fluoroquinolone structure to introduce
the new compound 9-cyclopropyl-4-fluoro-6-oxo-6,9-dihydro
[1,2,5]thiadiazolo[3,4-h]quinoline carboxylic acid (16). The
latter compound was tested against several clinical isolate
bacterial strains and did prove to be quite active compared to
the drugs used in the market19.
.
,
Materials and methods
All the chemicals and solvents used in this study were
purchased from Acros. Melting points were measured by
Fischer-Johns Melting Point Apparatus and were uncorrected.
1H NMR and 13C NMR spectra were measured on a Bruker
DPX-300 instrument. Chemical shifts (ꢀ) are expressed in
ppm with reference to TMS as internal standard. High
resolution mass spectra (HRMS) were measured in positive
Several drugs used in the market show a variation at N-1, e.g.
cyclopropyl, ethyl, 2,4-difluorophenyl and many others. Our
strategy for the synthesis of compound 16, banked on the
ion mode by electrospray ionization (ESI) on
a Bruker
instrument APEX IV 2008. The samples were dissolved
in acetonitrile, diluted in spray solution (methanol/water 1:1
v/v þ 0.1% formic acid) and injected using a syringe pump with
a flow rate of 2 mL/min. External calibration was conducted
using Arginine cluster in a mass range m/z 175–871. For all
HRMS data, mass error: 0.00–0.50.
Address for correspondence: Raed A. Al-Qawasmeh, Chemistry
Department, Faculty of Science, The University of Jordan, Amman
11942, Jordan. Tel: +962 65355000, extn 22169. E-mail:
r.alqawasmeh@ju.edu.jo

778 R. A. Al-Qawasmeh et al.
J Enzyme Inhib Med Chem, 2014; 29(6): 777–785
CH
3
O
N
O
O
O
O
O
F
F
F
OH
OH
OH
N
N
N
N
N
R
HN
N
O
HN
CH
H C
3
3
CH
3
1 Norfloxacin (R = Et)
3 Grepafloxacin
4 Levofloxacin
c
2 Ciprofloxacin (R = Pr)
O
O
F
O
O
OH
F
OH
N
N
N
N
N
R
X
N
S
R'
CH
3
6 R = H, R' = CH , X = 2', 4' di-F (Temafloxacin)
3
7 R = R' = H, X = 4'-F (Sarafloxacin)
5 Rufloxacin
8 R = CH3, R' H, X = 4'-OH
9
R = R' = X = H
Figure 1. Some fluoroquinolones of which 1–6 are in clinical use.
N
N
Figure 2. Some compounds containing thia-
diazolo moiety known in the literature.
S
N
N
N
N
S
S
Cl
N
NH
N
N
N
R
N
S
NH
13
10
12
11
O
O
O
O
S
O
O
N
F
N
OH
OH
OH
N
N
N
N
N
N
Et
N
S
S
Et
16
14
15
Chemistry
Ethyl 3-(N-ethylamino)-2-(2,4-dichloro-5-fluoro-3-nitroben-
zoyl)acrylate (19a). Yield 95%; m.p. 154 ꢁC; 1H NMR ꢀ ppm
(CDCl3): 1.01 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.35 (t, J ¼ 7.1 Hz,
General procedure for the preparation of compounds
Ethyl
3-(N,N-dimethylamino)-2-(2,4-dichloro-5-fluoro-3-nitro- 3H, NCH2CH3), 3.52 (q, J ¼ 7.1 Hz, 2H, NCH2CH3), 3.98 (q,
3
benzoyl)acrylate (18). It was prepared using reported J ¼ 7.1 Hz, 2H, OCH2CH3), 7.11 (d, JH–F ¼ 8.0 Hz, 1H, H-6),
methods starting from 2,4-dichloro-5-fluoro-3-nitrobenzoic acid 8.19 (d, J ¼ 14.4 Hz, 1H, N–C(300)-H), 10.99 (br d, J ¼ 14.4 Hz,
17 (Scheme 1).19
1H, exchangeable N–H); 13C NMR ꢀ ppm (CDCl3): 13.9
Preparation of ethyl 3-N-(aryl/alkyl)-2-(2,4-dichloro-5-fluoro- (OCH2CH3), 15.6 (NCH2CH3), 40.5 (NCH2CH3), 60.1
2
3-nitrobenzoyl)acrylates (19a–d). A stirred solution of (18) (OCH2CH3), 99.8 (C-200), 114.1 (d, JC–F ¼ 23.3 Hz, C-4), 115.8
(ꢀ38 mmol) in chloroform (50 mL) and methanol (10 mL), (d, 2JC–F ¼ 23.3 Hz, C-6), 117.7 (d, 3JC–F ¼ 4.4 Hz, C-1), 144.0 (d,
cooled to 8–10 ꢁC, was treated dropwise with the appropriate 3JC–F ¼ 6.2 Hz, C-3), 148.6 (C-2), 156.7 (d, JC–F ¼ 253.4 Hz, C-
1
aryl or alkylamine (1.5 eq) dissolved in MeOH (3 mL). The 5), 161.2 (N–C-300), 165.9 (CO2Et), 188.3 (C¼O ketone); HRMS
resulting mixture was further stirred for additional 10–15 min at (ESI): calcd. for C14H13Cl2FN2O5Na [M þ Na]þ: 401.00832,
5–10 ꢁC. Methanol (90 mL) was then added and the reaction found: 401.00778.
mixture was stirred at rt for 1–2 h. The precipitated white
Ethyl 3-(N-phenylamino)-2-(2,4-dichloro-5-fluoro-3-nitroben-
solid product was filtered, washed with cold ethanol (10–20 mL) zoyl)acrylate (19b). Yield 95%; m.p. 150 ꢁC; 1H NMR ꢀ ppm
and air dried. The resultant product was used for the next step (CDCl3): 1.07 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 4.07 (q, J ¼ 7.1 Hz,
3
without further purification. For identification purpose, a small 2H, OCH2CH3), 7.19 (d, JH–F ¼ 8.0 Hz, 1H, H-6), 7.24 (d,
amount was purified on TLC plates eluting with 2% MeOH/ J ¼ 7.6 Hz, 1H, H-40), 7.28 (dd, J ¼ 7.8, 7.6, Hz, 2H, H-30/H-50),
CHCl3 (50:1, v/v).
7.44 (d, J ¼ 7.8 Hz, 2H, H-20/H-60), 8.67 (d, J ¼ 13.8 Hz, 1H,

DOI: 10.3109/14756366.2013.855925
Thiadiazoloquinolone compounds 779
O
O
Scheme 1. synthesis of ethyl 7-chloro-1-
(ethyl/aryl)-6-fluoro-8-nitro-4-oxo-1,4-dihy-
droquinoline-3-carboxylates (20a–d).
F
CO Et
F
2
OH
(i)
(iii)
(ii)
Cl
Cl
Cl
Cl
N(Me)
2
NO
NO
2
2
(17)
(18)
O
O
6
5
CO Et
2''
F
2
CO Et
F
4a
8a
2
5
1
2
(iv)
4
6
3
2
3''
1
N
4
Cl
Cl
3
7
Cl
NH
8
NO
2
R
NO
R
2
(19a-d)
(20a-d)
c
b
d
a
entry
4'
1'
1'
4'
1'
4'
R
-
CH CH
2
3
F
OMe
Reagents and conditions:
(i) SOCl , benzene / reflux;
2
(ii) (EtO C)HC = CHN(Me) , benzene, NEt ;
2
2
3
(iii) RNH , methanol, chloroform;
2
(iv) DMF, K CO / 60 °C, 1h.
2
3
N–C(300)-H), 12.65 (br d, J ¼ 13.8 Hz, 1H, exchangeable N–H); N–C(300)-H), 12.7 (br d, J ¼ 13.9 Hz, 1H, exchangeable N–H); 13C
13C NMR ꢀ ppm (CDCl3): 13.9 (OCH2CH3), 60.7 (OCH2CH3), NMR ꢀ ppm (CDCl3): 13.9 (OCH2CH3), 55.7 (OCH3), 60.5
2
2
102.2 (C-200), 114.3 (d, JC–F ¼ 23.3 Hz, C-4), 115.9 (d, JC– (OCH2CH3), 101.5 (C-200), 114.3 (d, 2JC–F ¼ 23.3 Hz, C-4), 115.2
2
¼ 22.7 Hz, C-6), 118.0 (C-1), 118.5 (C-30/C-50), 127.0 (C-40), (C-30/C-50), 115.9 (d, JC–F ¼ 23.4 Hz, C-6), 117.8 (C-1), 120.0
F
130.1 (C-20/C-60), 138.1 (C-10), 143.5 (C-3), 148.6 (C-2), 154.2 (C-20/C-60), 131.4 (C-10), 143.6 (d, 3JC–F ¼ 6.3 Hz, C-3), 148.6 (C-
1
1
(N–C-300), 156.7 (d, JC–F ¼ 254 Hz, C-5), 165.6 (CO2Et), 189.3 2), 154.3 (C-300), 156.7 (d, JC–F ¼ 253.7 Hz, C-5), 158.6 (C-40),
(C¼O ketone); HRMS (ESI): Calcd for C18H13Cl2FN2O5Na 165.6 (CO2Et), 188.8 (C¼O Ketone); HRMS (ESI): Calcd for
[M þ Na]þ: 449.00832, found: 449.00778.
C19H15Cl2FN2Oþ6 [M þ H]þ: 457.03694, found: 457.03694.
Ethyl 3-(N-4-fluorophenylamino)-2-(2,4-dichloro-5-fluoro-3-
1
Preparation of ethyl 7-chloro-1-(aryl/alkyl)-6 fluoro-8-nitro-4-
A solution
nitrobenzoyl)acrylate (19c). Yield 91%; m.p. 130 ꢁC; H NMR oxo-1,4-dihydroquinoline-3-carboxylates (20a–d).
ꢀ ppm (CDCl3): 1.05 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 4.05 (q, of the particular precursor 19a–d (30 mmol) in DMF (50 mL)
3
J ¼ 7.1 Hz, 2H, OCH2CH3), 7.09 (d, JH–F ¼ 8.0 Hz, 1H, H-6), and potassium carbonate (90 mmol) was heated at 60 ꢁC. The
3
7.15 (d, J ¼ 8 Hz, 2H, H-20/C-60), 7.25 (dd, J
¼ 8 Hz, J
progress of the cyclization reaction was monitored by TLC
H–H
H–
¼ 8 Hz, 2H, H-30/H-50), 8.57 (d, J ¼ 11.9 Hz, 1H, N–C(300)-H), (eluent: EtOAc: N–Hexane, 1:1/v:v). The reaction was complete
F
12.66 (br d, J ¼ 11.9 Hz, 1H, exchangeable N–H); 13C NMR ꢀ within 80 to 90 min. The reaction mixture was then poured slowly
ppm (CDCl3): 13.8 (OCH2CH3), 60.6 (OCH2CH3), 102.2 (C-200), onto crushed ice (100 g) under vigorous stirring, the precipitated
2
2
114.3 (d, JC–F ¼ 23.3 Hz, C-4), 115.9 (d, JC–F ¼ 23.6 Hz, C-6), pale yellow solid product was collected, washed with water,
2
3
117.0 (d, JC–F ¼ 23.3 Hz, C-30/C-50), 117.8 (C-1), 120.3 (d, JC– triturated with cold ethanol, and air dried to produce the pure
¼ 8.3 Hz, C-20/C-60), 134.5 (C-10), 143.4 (C-3), 148.6 (C-2), product.
F
1
1
154.6 (N–C-300), 156.7 (d, JC–F ¼ 254.1 Hz, C-5), 161.2 (d, JC–
Ethyl 7-chloro-1-ethyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroqui-
1
¼ 245.8 Hz, C-40), 165.5 (CO2Et), 189.3 (C¼O ketone); HRMS noline-3-carboxylate (20a).Yield 97%; m.p. 150 ꢁC; H NMR ꢀ
F
(ESI): Calcd for C18H12Cl2F2N2O5Na [M þ Na]þ: 466.99890, ppm (CDCl3): 1.39 (t, J ¼ 7.2 Hz, 3H, OCH2CH3), 1.43 (t,
found: 466.99835.
J ¼ 7.2 Hz, 3H, NCH2CH3), 4.04 (q, J ¼ 7.2 Hz, 2H, NCH2CH3),
Ethyl 3-(N-4-methoxyphenylamino)-2-(2,4-dichloro-5-fluoro- 4.40 (q, J ¼ 7.2 Hz, 2H, OCH2CH3), 8.43 (s, 1H, H-2), 8.47 (d,
3-nitrobenzoyl)acrylate (19d). Yield 97%; m.p. 162 ꢁC; 1H 3JH–F ¼ 8.34 Hz, 1H, H-5); 13C NMR ꢀ ppm (CDCl3): 14.7
NMR ꢀ ppm (CDCl3): 1.05 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 3.81 (OCH2CH3), 16.1 (NCH2CH3), 50.3 (NCH2Me), 60.9 (OCH2Me),
2
2
(s, 3H, OCH3), 4.04 (q, J ¼ 7.1 Hz, 2H, OCH2CH3), 6.93 (d, 112.1 (C-3), 115.8 (d, JC–F ¼ 22.8 Hz, C-5), 120.7 (d, JC–
3
4
J ¼ 8.9 Hz, 2H, H-30/H-50), 7.15 (d, JH–F ¼ 8.0 Hz, 1H, H-6),
¼ 23.9 Hz, C-7), 128.8 (C-4a), 130.9 (d, JC–F ¼ 5.7 Hz, C-8a),
F
1
7.21 (d, J ¼ 8.9 Hz, 2H, H-20/H-60), 8.56 (d, J ¼ 13.9 Hz, 1H, 140.5 (C-8), 152.6 (C-2), 154.0 (d, JC–F ¼ 249 Hz, C-6), 164.0

780 R. A. Al-Qawasmeh et al.
J Enzyme Inhib Med Chem, 2014; 29(6): 777–785
(CO2Et), 170.4 (C-4) (C¼O ketone); HRMS (ESI): calcd. for HRMS (ESI): Calcd for C14H12FN5O5Na [M þ Na]þ: 372.07202,
C14H12ClFN2O5 [M þ H]þ: 343.04970, found: 343.04915.
found: 372.07147.
Ethyl 7-chloro-6-fluoro-8-nitro-4-oxo-1-phenyl-1,4-dihydro-
Ethyl 7-azido-6-fluoro-8-nitro-4-oxo-1-phenyl-1,4-dihydroqui-
quinoline-3-carboxylate (20b). Yield 97%; m.p. 194 ꢁC; 1H noline-3-carboxylate (21b). Yield 92%; m.p. 160 ꢁC; H NMR ꢀ
NMR ꢀ ppm (CDCl3): 1.36 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), ppm (CDCl3): 1.35 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 4.35 (q,
4.36 (q, J ¼ 7.1 Hz, 2H, OCH2CH3), 7.33 (d, J ¼ 7.7 Hz, 2H, H-20/ J ¼ 7.1 Hz, 2H, OCH2CH3), 7.30 (d, J ¼ 7.6 Hz, 2H, H-20/H-60),
H-60), 7.48 (dd, J ¼ 7.7, 7.3 Hz, 2H, H-30/H-50), 7.56 (d, 7.45 (dd, J ¼ 7.6, 7.3 Hz, 2H, H-30/H-50),7.55 (d, J ¼ 7.3 Hz, 1H,
1
3
3
J ¼ 7.3 Hz, 1H, H-40), 8.37 (s, 1H, H-2), 8.44 (d, JH–F ¼ 8.3 Hz, H-40), 8.31 (d, JH–F ¼ 9.4 Hz, 1H, H-5), 8.37 (s, 1H, H-2). 13C
1H, H-5); 13C NMR ꢀ ppm (CDCl3): ꢀ 14.4 (OCH2CH3), 61.6 NMR ꢀ ppm (CDCl3): 14.4 (OCH2CH3), 61.5 (OCH2CH3), 112.2
2
2
(OCH2Me), 112.0 (C-3), 115.4 (d, JC–F ¼ 22.9 Hz, C-5), 121.8 (C-3), 115.4 (d, JC–F ¼ 21.2 Hz, C-5), 118.1 (C-4a), 127.5 ¼ (C-
2
3
(d, JC–F ¼ 23.9 Hz, C-7), 127.6 (C-30/C-50), 128.8 (d, JC– 30/C-50), 128.9 (C-8a), 129.8 (C-20/C-60), 130.5 (C-40), 132.4 (d,
¼ 3 Hz, C-4a), 129.8 (C-8a), 129.9 (C-20/C-60), 131.0 (C-40), 2JC–F ¼ 23.9 Hz, C-7), 141.5 (C-8), 139.6 (C-10), 151.7 (C-2),
F
1
1
139.5 (C-10), 141.5 (C-8), 152.0 (C-2), 154.8 (d, JC–F ¼ 253 Hz, 153.1 (d, JC–F ¼ 251 Hz, C-6), 164.2 (CO2Et), 171.0 (C-
C-6), 164.1 (CO2Et), 171.0 (C-4) (C¼O ketone); HRMS (ESI): 4)(C¼O). HRMS (ESI): calcd. for C18H12FN5O5Na [M þ Na]þ:
Calcd for C18H12ClFN2O5Na [M þ Na]þ: 413.03165, found: 420.07202, found: 420.07147.
413.03110.
Ethyl 7-azido-6-fluoro-1-(4-fluorophenyl)-8-nitro-4-oxo-1,4-
Ethyl 7-chloro-6-fluoro-1-(4-fluorophenyl)-8-nitro-4-oxo-1,4- dihydroquinoline-3-carboxylate (21c). Yield 91%; m.p. 172 ꢁC;
dihydroquinoline-3-carboxylate (20c). Yield 97%; m.p. 226 ꢁC; 1H NMR ꢀ ppm (CDCl3): 1.36(t, J ¼ 7.1 Hz, 3H, OCH2CH3), 4.36
1H NMR ꢀ ppm (CDCl3): 1.36 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), (q, J ¼ 7.1 Hz, 2H, OCH2CH3), 7.14 (dd, J ¼ 8.9 Hz, JH–
4
3
4.36 (q, J ¼ 7.1 Hz, 2H, OCH2CH3), 7.18 (dd, J ¼ 8.9 Hz,
¼ 2.2 Hz, 2H, H-20/H-60), 7.31 (dd, J ¼ 8.9 Hz, JH–F ¼ 4.5 Hz,
F
2JH–F ¼ 7.9 Hz, 2H, H-30/H-50), 7.35(dd, JH–H ¼ 8.9 Hz, JH– 2H, H-30/H-50), 8.34 (d, 3JH–F ¼ 11.2 Hz, 1H, H-5), 8.38 (s, 1H, H-
3
3
¼ 4.5 Hz, 2H, H-20/H-60), 8.31 (s, 1H, H-2), 8.43 (d, JH– 2); 13C NMR
ꢀ ppm (CDCl3): 14.3 (OCH2CH3), 61.6
F
¼ 8.2 Hz, 1H, H-5); 13C NMR
ꢀ
ppm (CDCl3): 14.4 (OCH2CH3), 112.2 (C-3), 116.8 (d, JC–F ¼ 22.8 Hz, C-5),
2
F
2
2
(OCH2CH3), 61.7 (OCH2Me), 112.2 (C-3), 115.4 (d, JC– 117.1 ¼ (d, JC–F ¼ 22.5 Hz, C-30/C-50), 126.5 (C-4a), 129.7 (d,
¼ 22.8 Hz, C-5), 117.1 ¼ (d, JC–F ¼ 23.2 Hz, C-30/C-50), 122.0 3JC–F ¼ 7.2 Hz, C-20/C-60), 129.9 (d, JC–F ¼ 23.7 Hz, C-7), 132.6
2
2
F
2
3
(d, JC–F ¼ 23.7 Hz, C-7), 128.7 (C-4a), 129.7 (C-8a), 129.8 (d, (C-8a), 135.2 (d, JC–F ¼ 3.2 Hz, C-8), 135.5 (C-10), 151.7 (C-2),
3JC–F ¼ 9.2 Hz, C-20/C-60), 135.2 (d, JC–F ¼ 3.4 Hz, C-8), 135.5 154.7 (d, 1JC–F ¼ 247 Hz, C-6), 163.5 (d, 1JC–F ¼ 252.2 Hz, C-40),
3
(C-10), 151.9 (C-2), 154.8 (d, 1JC–F ¼ 253 Hz, C-6), 163.5 (d, 1JC– 164 (CO2Et), 171.0 (C-4)(C¼O). HRMS (ESI): Calcd for
¼ 253 Hz, C-40), 164 (CO2Et), 170.9 (C-4)(C¼O); HRMS (ESI): C18H11F2N5O5Na [M þ Na]þ: 438.06259, found: 438.06205.
F
Calcd for C18H11Cl2F2N2O5Na [M þ Na]þ: 431.02223, found:
Ethyl 7-azido-6-fluoro-1-(4-methoxyphenyl)-8-nitro-4-oxo-1,4-
431.02168.
dihydroquinoline-3-carboxylate (21d). Yield 94 %; m.p. 170 ꢁC;
Ethyl 7-chloro-6-fluoro-1-(4-methoxyphenyl)-8-nitro-4-oxo- 1H NMR ꢀ ppm (CDCl3): 1.35 (t, J ¼ 7.1 Hz, 3H, OCH2CH3),
1,4-dihydroquinoline-3- carboxylate (20d). Yield 96%; m.p. 3.86 (s, 3H, OCH3), 4.34 (q, J ¼ 7.1 Hz, 2H, OCH2CH3), 6.90 (d,
176 ꢁC; 1H NMR ꢀ ppm (CDCl3): 1.33 (t, J ¼ 7.1 Hz, 3H, J ¼ 8.9 Hz, 2H, H-20/H-60), 7.21 (d, J ¼ 8.9 Hz, 2H, H-30/H-50),
OCH2CH3), 3.86 (s, 3H, OCH3), 4.32 (q, J ¼ 7.1 Hz, 2H, 8.28 (d, JH–F ¼ 6.5 Hz, 1H, H-5) 8.38 (s, 1H, H-2); 13C NMR ꢀ
3
OCH2CH3), 6.91 (d, J ¼ 8.8 Hz, 2H, H-20/H-60), 7.24 (d, ppm (CDCl3): 14.3 (OCH2CH3), 55.7 (OCH3), 61.4 (OCH2CH3),
3
2
J ¼ 8.8 Hz, 2H, H-30/H-50), 8.31 (s, 1H, H-2), 8.38 (d, JH– 112.0 (C-3), 114.6 (d, JC–F ¼ 21.5 Hz, C-5), 117.9 (C-30/C-50),
¼ 8.1 Hz, 1H, H-5).13C NMR ꢀ ppm (CDCl3): 14.4 (OCH2CH3), 126.6 (d, JC–F ¼ 23.5 Hz, C-7),128.6 (C-4a), 129.0 (C-20/C-60),
2
F
3
55.8 (OCH3), 61.5 (OCH2CH3), 111.7 (C-3), 114.7 (C-30/C-50), 129.3 (C-8a), 132.1 (d, JC–F ¼ 3.4 Hz, C-8), 132.3 (C-10), 152.2
2
2
1
115.2 (d, JC–F ¼ 23 Hz, C-5), 121.7 (d, JC–F ¼ 23.5 Hz, (C-2), 154.6 (d, JC–F ¼ 252.8 Hz, C-6), 161.0 (C-40), 164.4
C-7),128.6 (C-4a), 129.1 (C-20/C-60), 129.7 (C-8a), 132.0 (d, (CO2Et), 171.1 (C-4)(C¼O). HRMS (ESI): Calcd for
3JC–F ¼ 3.4 Hz, C-8), 141.2 (C-10), 152.4 (C-2), 154.6 (d, JC– C19H14FN5O6 [M þ H]þ: 428.10064, found: 428.10009.
1
¼ 252.8 Hz, C-6), 161.1 (C-40), 164.1 (CO2Et), 171.0 (C-
Preparation of ethyl 7,8-diamino-1-(aryl/alkyl)-6-fluoro-4-
4)(C¼O). HRMS (ESI): Calcd for C19H14ClFN2O6Na oxo-1,4-dihydroquinoline-3-carboxylates (22a–d). Anhydrous
F
[M þ Na]þ: 421.06027, found: 421.05972.
stannous chloride (5 g, 26 mmol) was added portionwise to a
Preparation of ethyl 7-azido-1-(aryl/alkyl)-6-fluoro-8-nitro-4- stirred ice-cooled (4–8 ꢁC) solution of the appropriate ethyl 7-
oxo-1,4-dihydroquinoline-3-carboxylates (21a–d). A warm (ꢀ35 azido-1-alkyl or 1-aryl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquino-
to 40 ꢁC) solution of soduim azide (7.8 g, 120 mmol) in line-3-carboxylate (21a–d) (Scheme 2) (6.3 mmol) in concen-
dimethylsulfoxide (DMSO, 50 mL) was added to a solution of trated hydrochloric acid (36%, 50 mL). The reaction mixture was
the appropriate ethyl 7-chloro-1-aryl(or alkyl)-6-fluoro-8-nitro-4- further stirred at room temperature (24 h), and the reaction
oxo-1,4-dihydroquinoxaline-3-carboxylate (20 mmol) (20a–d) in progress was monitored by TLC. Upon completion of the
DMSO (50 mL). The resulting mixture acquired yellow turbidity reaction, the reaction mixture was diluted with ice-cold water
within few minutes, and was further stirred at (ꢀ35 to 40 ꢁC) for (50 mL), basified with 40% cold aqueous sodium hydroxide
16–20 h. Thereafter, the reaction mixture was diluted with cold solution to pH ꢀ 13 and set aside for a few minutes. The
water (250 mL), and the precipitated solid product was collected precipitated solid product was collected by suction filtration and
under suction, washed with cold water and air dried.
recrystallized from 90% ethanol.
Ethyl 7-azido-1-ethyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroqui-
Ethyl 7,8-diamino-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquino-
noline-3-carboxylate (21a). Yield 90%; m.p. 150 ꢁC; H NMR ꢀ line-3-carboxylate (22a). Yield 85%; m.p. (dec) 347 ꢁC; 1H
ppm (CDCl3): 1.39 (m, 6H, NCH2CH3, OCH2CH3), 3.98 (q, NMR ꢀ ppm (CDCl3): 1.08 (t, J ¼ 7.0 Hz, 3H, OCH2CH3), 1.23 (t,
J ¼ 7.2 Hz, 2H, NCH2CH3), 4.38 (q, J ¼ 7.2 Hz, 2H, OCH2CH3), J ¼ 7.0 Hz, 3H, NCH2CH3), 4.16 (q, J ¼ 7.0 Hz, 2H, NCH2CH3),
1
3
8.37 (s, 1H, H-2), 8.39 (d, JH–F ¼ 11.2 Hz, 1H, H-5);13C NMR ꢀ 4.63 (q, J ¼ 7.0 Hz, 2H, OCH2CH3), 4.73 (br s, 2H, C(8)–NH2),
3
ppm (CDCl3): 14.4 (OCH2CH3), 16.2 (NCH2CH3), 50.5 5.53 (br s, 2H, C(7)–NH2),7.32 (d, JH–F ¼ 11.3 Hz, 1H, H-5),
2
(NCH2CH3), 61.5 (OCH2CH3), 112.3 (C-3), 115.9 (d, JC– 8.38 (s, 1H, H-2).13C NMR ꢀ ppm (CDCl3):14.8 (OCH2CH3),
2
¼ 20.9 Hz, C-5), 128.2 (C-4a), 128.8 (d, JC–F ¼ 11.1 Hz, C-7), 16.0 (NCH2CH3), 50.8 (NCH2CH3), 60.0 (OCH2CH3), 101.9 (d,
F
4
3
127.7 (d, JC–F ¼ 5.7 Hz, C-8a), 135.2 (C-8), 151.3 (C-2), 154.9 2JC–F ¼ 20.6 Hz, C-5), 108.7 (C-3), 120.7 (C-4a), 124.7 (d, JC–
1
3
(d, JC–F ¼ 250.2 Hz, C-6), 164.5 (CO2Et), 171.0 (C-4)(C¼O);
¼ 5.1 Hz, C-8), 127.7 (C-8a), 131.2 (d, JC–F ¼ 15.1 Hz, C-7),
F

DOI: 10.3109/14756366.2013.855925
Thiadiazoloquinolone compounds 781
1
2
3
150.0 (d, JC–F ¼ 236.6 Hz, C-6), 151.8 (C-2), 165.4 (CO2Et), (d, JC–F ¼ 23.0 Hz, C-30/C-50), 120.9 (d, JC–F ¼ 8.3 Hz, C-4a),
3
3
173.1 (C-4)(C¼O); IR (KBr) v: br 3472.33, 3387.38, 1710.58, 124.4 (d, JC–F ¼ 6.1 Hz, C-8), 125.8 (C-8a), 128.6 (d, JC–
1682.94, 1611.55, 1555.40, 1460.96, 1202.94 cmꢂ1; HRMS
¼ 8.9 Hz, C-20/C-60), 129.7 (d, JC–F ¼ 16.1 Hz, C-7), 140.2 (d,
162 (d, 1JC–F ¼ 244 Hz, C-40), 164.9 (CO2Et), 172.7 (C-4)(C¼O);
2
F
(ESI): calcd. for C14H16FN3O3 [M þ H]þ: 294.12539, found: 4JC–F ¼ 2.9 Hz, C-10), 150.0 (d, 1JC–F ¼ 236 Hz, C-6), 151.2 (C-2),
294.12485.
Ethyl 7,8-diamino-6-fluoro-1-phenyl-4-oxo-1,4-dihydroquino- HRMS (ESI): calcd. for C18H15F2N3O3Na [M þ Na]þ: 382.09792,
1
line-3-carboxylate (22b). Yield 80%; m.p. 240 ꢁC; H NMR, ꢀ found: 382.09737.
ppm (DMSO-d6): 1.19 (t, J ¼ 7.0 Hz, 3H, OCH2CH3), 4.14 (q,
Ethyl 7,8-diamino-6-fluoro-1-(4-methoxyphenyl)-4-oxo-1,4-
J ¼ 7.0 Hz, 2H, OCH2CH3), 3.87 (br s, 2H, C(8)-NH2), 5.39 (br s, dihydroquinoline-3-carboxylate (22d). Yield 89%; m.p. 274 ꢁC;
2H, C(7)-NH2),7.32 (dd, JH–H ¼ 8.6 Hz, JH–F ¼ 2.3 Hz, 2H, H-20/ 1H NMR, ꢀ ppm (DMSO-d6): 1.20 (t, J ¼ 7.1 Hz, 3H, OCH2CH3),
3
H-60), 7.38 (dd, JH–H ¼ 8.6 Hz, JH–F ¼ 4.3 Hz, 2H, H-30/H-50), 3.75 (br s, 2H, C(8)-NH2), 3.81 (s, 3H, OCH3), 4.14 (q,
7.56 (d, 3JH–F ¼ 8.3 Hz, 1H, H-5), 8.15 (s, 1H, H-2); 13C NMR, ꢀ J ¼ 7.1 Hz, 2H, OCH2CH3), 5.29 (br s, 2H, C(7)-NH2), 7.09 (d,
3
ppm (DMSO-d6): 14.7 (OCH2CH3), 60.3 (OCH2Me), 112.2 (C-3), J ¼ 8.9 Hz, 2H, H-20/H-60), 7.32 (d, JH–F ¼ 11.3 Hz, 1H, H-5),
115.4 (d, 3JC–F ¼ 22.8 Hz, C-5), 117.1 ¼ (d, 2JC–F ¼ 23.2 Hz, C-30/ 7.48 (d, J ¼ 8.9 Hz, 2H, H-30/H-50), 8.11 (s, 1H, H-2). 13C NMR, ꢀ
2
C-50), 122.0 (d, JC–F ¼ 23.7 Hz, C-7),128.6 (C-4a), 129.8 (d, ppm (DMSO-d6): 14.8 (OCH2CH3), 56.1 (OCH3), 60.1
2
3JC–F ¼ 7.2 Hz, C-20/C-60), 129.9 (C-8a), 135.2 (d, 3JC–F ¼ 3.4 Hz, (OCH2CH3), 100.9 (d, JC–F ¼ 20.9 Hz, C-5), 108.5 (C-3), 115.4
3
3
C-8), 135.5 (C-10), 151.9 (C-2), 154.8 (d, 1JC–F ¼ 253 Hz, C-6), (C-30/C-50), 120.1 (d, JC–F ¼ 7.2 Hz, C-4a), 124.5 (d, JC–
1
2
163.5 (d, JC–F ¼ 253 Hz, C-40), 164 (CO2Et), 170.9 (C-4);
¼ 6.1 Hz, C-8), 125.7 (C-8a), 127.8 (C-20/C-60), 129.3 (d, JC–
F
HRMS (ESI): Calcd for C15H17FN3Oþ3 [M þ H]þ: 306.12540,
¼ 16.2 Hz, C-7), 136.6 (C-10), 150.0 (d, JC–F ¼ 235.5 Hz, C-6),
1
F
found: 306.12475.
151.2 (C-2), 159.8 (C-40), 164.9 (CO2Et), 172.7 (C-4). IR (cmꢂ1
,
Ethyl 7,8-diamino-6-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihy- KBr): br 3294.77, 2980.30, 1716.58, 1674.64, 1616.90, 1508.57,
droquinoline-3-carboxylate (22c). Yield 83%; m.p. 274 ꢁC; 1H 1461.32 cmꢂ1; HRMS (ESI): Calcd for C19H18FN3O4 [M þ H]þ:
NMR, ꢀ ppm (DMSO-d6): 1.19 (t, J ¼ 7.0 Hz, 3H, OCH2CH3), 372.13596, found: 372.13541.
4.14 (q, J ¼ 7.0 Hz, 2H, OCH2CH3), 3.87 (br s, 2H, C(8)-NH2),
Preparation of ethyl(methyl) 9-(aryl/alkyl)-4 fluoro-6-oxo-6,9-
5.39 (br s, 2H, C(7)-NH2),7.32 (dd, J ¼ 8.6 Hz, JH–F ¼ 2.3 Hz, dihydro-[1,2,5]thiadiazolo[3,4-h]quinoline-7-carboxylates
4
3
2H, H-20/H-60), 7.38 (dd, J ¼ 8.6 Hz, JH–F ¼ 4.3 Hz, 2H, H-30/H- (23a,b,d/24b–d). To a stirred suspension of the particular diamine
3
50), 7.56 (d, JH–F ¼ 8.3 Hz, 1H, H-5), 8.15 (s, 1H, H-2); compound (22a–d) (Scheme 3) (3 mmol) in dry benzene (25 mL),
13C NMR,
ꢀ ppm (DMSO-d6): 14.7 (OCH2CH3), 60.3 was added purified thionylchloride (6 mL) and the resulting
2
(OCH2CH3), 101.1 (d, JC–F ¼ 21 Hz, C-5), 109.0 (C-3), 116.8 mixture was heated at 80–85 ꢁC for 8 h. Benzene and excess
O
O
F
CO Et
CO Et
F
2
2
NaN /DMSO
SnCl /HCl
3
2
(20a-d)
r t
rt, 24h
N
R
H N
N
R
N
2
3
NH
NO
2
2
(21a-d)
(22a-d)
b
c
a
d
entry
R
1'
4'
1'
4'
1'
-CH CH
4'
2
3
F
OMe
Scheme 2. Synthesis of ethyl 7,8-diamino-1-(aryl/alkyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylates (22a–d).
O
O
F
CO R'
F
CO H
2
2
SOCl /benzene
2
3N HCl
reflux
(22a-d)
reflux
N
R
N
R
N
N
N
N
S
S
23a R = Et,
23b R = Ph,
R' = Me
R' = Me
(25a-d)
23d R = 4-OMe-ph, R' = Me
24b R = Ph
R' = Et
R' = Et
24c R = 4-F-ph,
24d R = 4-OMe-ph, R' = Et
Scheme 3. Synthesis of 9-(aryl/alkyl)-4-fluoro-6-oxo-6,9-dihydro[1,2,5]thiadiazolo[3,4-h]quinoline-7-carboxylic acids 25a–d.

782 R. A. Al-Qawasmeh et al.
J Enzyme Inhib Med Chem, 2014; 29(6): 777–785
3
4
thionyl chloride were distilled off in vacuum and the residue was 129.2 (d, JC–F ¼ 9.0 Hz, C-20/C-60), 130.1 (d, JC–F ¼ 3 Hz,
2
cooled, dissolved in CHCl3 and washed with water (2 ꢃ 30 mL). C-9a), 139.0 (C-10), 148.4 (d, JC–F ¼ 10.5 Hz, C-3a), 148.7 (d,
The organic layer was separated, dried (anhydrous MgSO4) 3JC–F ¼ 1.6 Hz, C-9b), 148.9 (C-8), 150.5 (d, JC–F ¼ 261 Hz,
1
and the solvent CHCl3 was then evaporated to dryness under C-4), 163.3 (d, 1JC–F ¼ 249 Hz, C-40), 164.7 (CO2Et), 172.3 (C-6);
reduced pressure. The residual product was recrystallized from HRMS (ESI): Calcd for C18H11F2N3O3SNa [M þ Na]þ:
dichloromethane/methanol. In some cases, methanol was used to 410.03869, found: 410.04116.
destroy the excess thionyl chloride within the reaction. Upon
using this workup process transesterfication occurs and the thiadiazolo[3,4-h]quinoline-7-carboxylate (24d). Yield 40%;
Ethyl 4-fluoro-9-(4-methoxyphenyl)-6-oxo-6,9-dihydro[1,2,5]
1
resultant product was either methyl ester instead of ethyl ester or m.p. 237 ꢁC; H NMR, ꢀ ppm (DMSO-d6): 1.24 (t, J ¼ 7.1 Hz,
a mixture of both esters.
3H, OCH2CH3), 3.85 (s, 3H, OCH3), 4.20 (q, J ¼ 7.1 Hz, 2H,
Methyl 9-ethyl-4-fluoro-6-oxo-6,9-dihydro[1,2,5]thiadiazolo OCH2CH3), 7.09 (d, J ¼ 8.8 Hz, 2H, H-20/H-60), 7.54 (d,
3
[3,4-h]quinoline-7-carboxylate (23a). Yield 80%, m.p. 325 ꢁC. J ¼ 8.8 Hz, 2H, H-30/H-50), 8.04 (d, JH–F ¼ 10.8 Hz, 1H, H-5),
1H NMR, ꢀ ppm (D2O): 1.42 (t, J ¼ 6.9 Hz, 3H, NCH2CH3), 3.76 8.37 (s, 1H, H-2); 13C NMR, ꢀ ppm (DMSO-d6): 14.7
2
(s, 3H, CO2CH3), 5.05 (q, J ¼ 6.9 Hz, 2H, NCH2CH3), 8.49 (d, (OCH2CH3), 56.1 (OCH3), 61.5 (OCH2CH3), 108.9 (d, JC–
3JH–F ¼ 10.2 Hz, 1H, H-5), 8.86 (s, 1H, H-2); 13C NMR, ꢀ ppm
¼ 19.1 Hz, C-5), 114.1 (C-7), 115.1 (C-30/C-50),127.5 (d, JC–
3
F
(D2O): 16.5 (NCH2CH3), 52.1 (OCH3), 52.1 (NCH2CH3), 109.1
¼ 5.4 Hz, C-5a), 129.0 (C-20/C-60), 131.3 (C-9a), 136.6 (C-10),
F
2
3
(d, JC–F ¼ 19.7 Hz, C-5), 114.1 (C-7), 127.5 (d, JC–F ¼ 5.8 Hz, 148.3 (C-3a), 148.9 (C-9b), 149.4 (C-8), 150.1 (d, 1JC–F ¼ 249 Hz,
2
C-5a), 130.4 (Hz, C-9a), 148.4 (d, JC–F ¼ 10.5 Hz, C-3a), 148.8 C-4), 160.4 (C-40), 164.2 (CO2Et), 171.7 (C-6); HRMS (ESI):
3
1
(d, JC–F ¼ 1.6 Hz, C-9b), 149.5 (C-8), 150.0 (d, JC–F ¼ 256 Hz, Calcd for C19H14FN3O4SNa [M þ Na]þ: 422.05867, found:
C-4), 165.1 (CO2Me), 171.3 (C-6)(C¼O); HRMS (ESI): Calcd for 422.05809.
C14H12FN3O3S [M þ H]þ: 308.05052, found: 308.04982.
Preparation
4-fluoro-6-oxo-9-phenyl-6,9-dihydro[1,2,5]thiadia- dro[1,2,5]thiadiazolo[3,4-h]quinoline-7-carboxylic acids (25a–
of
9-(aryl/alkyl)-4-fluoro-6-oxo-6,9-dihy-
Methyl
zolo[3,4-h]quinol-ine-7-carboxylate (23b). Yield 40% m.p. d). A vigorously stirred suspension of the ester (23a,b,d/24b–d).
300 ꢁC; 1H NMR, ꢀ ppm (DMSO-d6): 3.74 (s, 3H, CO2CH3), (1.5 mmol) in 6 N HCl (15 mL) and ethanol (6 mL) was heated
3
7.61 (m, 5H, H-20/H-30/H-40/H-50/H-60), 8.09 (d, JH–F ¼ 10.8 Hz, at 80–85 ꢁC under reflux conditions. Progress of the ester
H-5), 8.43 (s, 1H, H-8); 13C NMR, ꢀ ppm (DMSO-d6): 52.2 hydrolysis was monitored by TLC and was completed within
(CO2CH3), 108.9 (d, 2JC–F ¼ 18.7 Hz, C-5), 113.9 (C-7), 127.6 (C- 20–24 h. Thereafter, the reaction mixture was cooled, poured onto
5a), 127.7 (C-30/C-50), 130.1 (C-20/C-60), 130.2 (C-40), 130.9 (C- crushed ice (30 g) and the resulting heavy pale yellow precipitate
9a), 143.6 (C-10), 148.5 (C-3a), 148.9 (C-9b), 149.3 (C-8), 150.0 was collected, washed with cold water, dried and recrystallized
1
(d, JC–F ¼ 214 Hz, C-4), 164.7 (CO2Et), 171.7 (C-6); HRMS from N,N-dimethylformamide (DMF) to produce
a
pure
(ESI): Calcd for C17H10FN3O3SNa [M þ Na]þ: 378.03246, found: compound.
378.03209.
Methyl
9-Ethyl-4-fluoro-6-oxo-6,9-dihydro[1,2,5]thiadiazolo[3,4-
4-fluoro-9-(4-methoxyphenyl)-6-oxo-6,9-dihydro h]quinoline-7-carboxylic acid (25a). Yield 95%; m.p. 315 ꢁC; H
1
[1,2,5]thiadiazolo [3, 4-h]quinoline-7-carboxylate (23d). Yield NMR ꢀ ppm (D2O): 1.48 (t, J ¼ 7.0 Hz, 3H, NCH2CH3), 5.26 (q,
3
40%; m.p. 281 ꢁC; 1H NMR, ꢀ ppm (CDCl3):ꢀ 3.93 (s, 6H, OCH3, J ¼ 7.0 Hz, 2H, NCH2CH3), 8.23 (d, JH–F ¼ 10.4 Hz, 1H, H-5),
CO2CH3), 7.04 (d, J ¼ 8.9 Hz, 2H, H-20/H-60), 7.29 (d, J ¼ 8.9 Hz, 8.68 (s, 1H, H-8), 15.14 (br s, 1H, CO2H); 13C NMR ꢀ ppm
2
2H, H-30/H-50), 8.32 (d, 3JH–F ¼ 10.3 Hz, 1H, H-5), 8.52 (s, 1H, H- (D2O): 16.4 (NCH2CH3), 53.5 (NCH2CH3), 108.1 (d, JC–
3
8); 13C NMR, ꢀ ppm (CDCl3): 52.5 (CO2CH3), 55.8 (OCH3),
¼ 19.6 Hz, C-5), 111.9 (C-7), 125.7 (d, JC–F ¼ 6.5 Hz, C-5a),
F
2
2
3
109.7 (d, JC–F ¼ 19.6 Hz, C-5), 113.8 (C-7), 114.9 (C-30/C-50), 132.2 (C-9a), 148.7 (d, JC–F ¼ 10.5 Hz, C-3a), 149.1 (d, JC–
3
1
128.2 (C-20/C-60), 128.7 (d, JC–F ¼ 5.7 Hz, C-5a), 130.5 (C-9a),
¼ 3 Hz, C-9b), 149.7 (C-8), 154.4 (d, JC–F ¼ 259 Hz, C-4),
F
135.9 (C-10), 148.5 (C-3a), 148.8 (C-9b), 149.6 (C-8), 150.5 (d, 165.7 (CO2H), 176.3 (C-6); HRMS (ESI): Calcd for
1JC–F ¼ 261 Hz, C-4), 160.5 (C-40), 165.5 (CO2Et), 172.3 (C-6); C12H8FN3O3S [M ꢂ H]ꢂ: 292.01921, found: 292.01976.
HRMS (ESI): Calcd for C18H12FN3O4SNa [M þ Na]þ:
4-Fluoro-6-oxo-9-phenyl-6,9-dihydro[1,2,5]thiadiazolo[3,4-
408.04302, found: 408.04225.
Ethyl
h]quinoline-7-carboxylic acid (25b). Yield 90%; m.p. 301 ꢁC; 1H
4-fluoro-6-oxo-9-phenyl-6,9-dihydro[1,2,5]thiadia- NMR ꢀ ppm (D2O): 7.64 (m, 5H, H-10/H-20/H-30/H-40/H-50),
3
zolo[3,4-h]quinoline-7-carboxylate (24b). Yield 40%, m.p. 285 8.23 (d, JH–F ¼ 10.7 Hz, 1H, H-5), 8.68 (s, 1H, H-8), 14.91
ꢁC; 1H NMR, ꢀ ppm (DMSO-d6): 1.25 (t, J ¼ 7.1 Hz, 3H, (br s,1H, CO2H); 13C NMR ꢀ ppm (D2O): 107.9 (d, JC–
2
OCH2CH3), 4.22 (q, J ¼ 7.1 Hz, 2H, OCH2CH3), 7.60 (m, 5H, H-
¼ 19.0 Hz, C-5), 111.4 (C-7), 125.7 (Hz, C-5a), 127.5 (C-30/C-
F
3
20/H-30/H-40/H-50/H-60), 8.11 (d, JH–F ¼ 10.8 Hz, H-5), 8.41 (s, 50), 130.2 (C-20/C-60), 130.7 (C-40), 131.2 (C-9a), 143.4 (C-10),
1H, H-2); 13C NMR, ꢀ ppm (DMSO-d6): 14.7 (OCH2CH3), 60.9 148.6 (d, 2JC–F ¼ 10.5 Hz, C-3a), 149.0 (C-9b), 149.7 (C-8), 154.3
2
1
(OCH2CH3), 108.9 (d, JC–F ¼ 19.2 Hz, C-5), 114.4 (C-7), 127.8 (d, JC–F ¼ 259 Hz, C-4), 165.5 (CO2H), 176.8 (C-6); HRMS
(C-30/C-50),128.7 (d, JC–F ¼ 5.8 Hz, C-5a), 130.1 (C-20/C-60), (ESI): Calcd for C16H8FN3O3S [M ꢂ H]ꢂ: 340.01921, found:
3
130.2 (C-40), 130.9 (d, 4JC–F ¼ 3 Hz, C-9a), 139.0 (C-10), 148.4 (d, 340.01976.
2JC–F ¼ 10.5 Hz, C-3a), 148.7 (d, 3JC–F ¼ 1.6 Hz, C-9b), 148.9 (C-
4-Fluoro-9-(4-fluorophenyl)-6-oxo-6,9-dihydro[1,2,5]thiadia-
1
8), 150.5 (d, JC–F ¼ 214 Hz, C-4), 164.2 (CO2Et), 171.7 (C- zolo[3,4-h]quinoline-7-carboxylic acid (25c). Yield 93%; m.p.
6)(C¼O); HRMS (ESI): Calcd for C18H12FN3O3SNa [M þ Na]þ: 278 ꢁC; H NMR ꢀ ppm (DMSO-d6); 7.44 (d, J ¼ 8.4 Hz, 2H, H-
1
392.04811, found: 392.04934.
Ethyl
20/H-60), 7.72 (dd, J ¼ 8.4 Hz, 3JH–F ¼ 4.4 Hz, 2H, H-30/H-50), 8.19
3
4-fluoro-9-(4-fluorophenyl)-6-oxo-6,9-dihydro[1,2,5] (d, JH–F ¼ 10.4 Hz, 1H, H-5), 8.71 (s, 1H, H-8), 14.9 (br s,1H,
thiadiazolo[3,4-h]quinoline-7-carboxylate (24c). Yield 79%, CO2H); 13C NMR ꢀ ppm (DMSO-d6); 107.9 (d, JC–F ¼ 19.3 Hz,
2
1
2
m.p. 274 ꢁC; H NMR, ꢀ ppm (DMSO-d6): 1.38 (t, J ¼ 7.1 Hz, C-5), 114.3 (C-7), 117.0 (d, JC–F ¼ 23.0 Hz, C-30/C-50),125.7 (d,
3H, OCH2CH3), 4.38 (q, J ¼ 7.1 Hz, 2H, OCH2CH3), 7.26 (d, 3JC–F ¼ 6.5 Hz, C-5a), 130.1 (d, JC–F ¼ 9.0 Hz, C-20/C-60), 132.2
3
4
2
J ¼ 8.3 Hz, 2H, H-20/H-60), 7.41 (dd, J ¼ 8.3 Hz, JH–F ¼ 4.6 Hz, (C-9a), 139.6 (C-10), 148.6 (d, JC–F ¼ 10.5 Hz, C-3a), 149.0 (d,
1
2H, H-30/H-50), 8.28 (d, 3JH–F ¼ 10.2 Hz, 1H, H-5), 8.46 (s, 1H, H- 3JC–F ¼ 3 Hz, C-9b), 149.7 (C-8), 151.3 (d, JC–F ¼ 259 Hz, C-4),
2); 13C NMR, ꢀ ppm (DMSO-d6): 14.4 (OCH2CH3), 61.5 163.1 (d, JC–F ¼ 245 Hz, C-40), 165.6 (CO2H), 176.6 (C-6);
1
(OCH2Me), 109.6 (d, JC–F ¼ 19.6 Hz, C-5), 114.3 (C-7), 117.0 HRMS (ESI): Calcd for C16H7F2N3O3SNa [M þ Na]þ:
2
2
3
(d, JC–F ¼ 23.0 Hz, C-30/C-50),128.7 (d, JC–F ¼ 5.8; Hz, C-5a), 382.00739, found: 382.00684.

DOI: 10.3109/14756366.2013.855925
Thiadiazoloquinolone compounds 783
2
4-Fluoro-9-(4-methoxyphenyl)-6-oxo-6,9-dihydro[1,2,5]thia-
1J ¼ 253–254 Hz), (C-6, J ¼ 22.5–22.7 Hz). The 13C NMR spec-
diazolo[3,4-h]quinoline-7-carboxylic acid (25d). Yield 92%; m.p. tra also indicate the presence of the keto group at 189.3–
300 ꢁC; 1H NMR ꢀ ppm (DMSO-d6); 3.86 (OCH3), 7.12 (d, 189.8 ppm, while the carbonyl carbon of the ester group resonates
J ¼ 8.9 Hz, 2H, H-20/H-60), 7.57 (d, J ¼ 8.9 Hz, H-30/H-50), 8.20 in the range 164.1–165.9 ppm. The C-300 carbon resonates in the
3
(d, JH–F ¼ 10.4 Hz, 1H, H-5), 8.64 (s, 1H, H-8), 14.86 (br s,1H, range 154.2–161.2 ppm, while C-200 in the range 99.8–102.2 ppm.
CO2H); 13C NMR ꢀ ppm (DMSO-d6); 56.1 (OCH3), 107.9 (d,
The quinolone ring in 20a–d was constructed through
2JC–F ¼ 19.5 Hz, C-5), 111.4 (C-7), 115.2 (C-30/C-50), 125.7 (d, intramolecular cyclization of (19a–d) in which the chlorine
3JC–F ¼ 6.5 Hz, C-5a), 128.8 (C-20/C-60), 132.2 (C-9a), 136.4 (C- atom at position 2 was replaced by the amino group via
2
3
10), 148.6 (d, JC–F ¼ 10.5 Hz, C-3a), 149.0 (d, JC–F ¼ 3 Hz, C- nucleophilic aromatic substitution (SNAr) assisted by the neigh-
9b), 150.0 (C-8), 150.9 (d, JC–F ¼ 259 Hz, C-4), 160.7 (C-40), boring nitro group and fluorine atom28,29
.
In this group of compounds, H NMR showed the disappear-
1
1
165.5 (CO2H), 176.8 (C-6).; IR (KBr) v: 3061.36, 1732.53,
1611.62, 1504.53, 1474.49, 1253.78 cmꢂ1; HRMS (ESI): Calcd ance of N–H broad peak at 11–12.7 ppm present in their acyclic
for C17H10FN3O4S [M ꢂ H]ꢂ: 370.02978, found: 370.03033.
precursors 19a–d; the spectrum showed a change in the doublet
peak of CH to a singlet one. Both H-5 and H-2 in 20a–d are more
deshielded than the corresponding protons in the 19a–d precur-
sors. These changes constitute diagnostic criteria for ring closure
(19a–d ! 20a–d).
Antimicrobial activity
The biological screening of compounds 19–22a–d, 23a, 24b–d
and 25a–d was performed in vitro by the two fold broth dilution
method27. The antibacterial activity was tested against Bacillus
subtilis ATCC 6633 and Staphylococcus aureus ATCC 6538
Gram positive strains, Escherichia coli ATCC 8739 and
Haemophilus influenzae ATCC 19418 Gram negative ones
using Mueller Hinton medium. The antifungal properties were
evaluated against Candida tropicalis ATCC 1369 and
Saccharomyces cerevisiae ATCC 9763 yeasts and Aspergillus
niger ATCC 6275 mould in Sabouraud dextrose broth. The
compounds at the concentration range of 0.0015–400 mg/mL in
1% DMSO were used in this study, with ciprofloxacin as reference
antibacterial substance and miconazole as reference antifungal
drug. DMSO was loaded as negative control. Suspensions of the
microorganisms were prepared to inoculate 5 ꢃ 105 bacteria/mL
and 1ꢃ 103 fungi/mL. The minimum inhibitory concentration
(MIC, mg/mL) value was taken as the lowest concentration of
compound that showed inhibition of microbial growth after 24 h
of incubation at 37 ꢁC for bacteria and after 48 h of incubation at
30 ꢁC for fungi. Each experiment has been done in triplicate and
repeated at least three times.
The 13C NMR spectra of compounds 20a–d reveal that most of
the carbons are deshielded except for C-2, C-4 and C-8a.
In the 13C NMR spectrum, the carbon of the keto group [¼O
on C-4] for 20a–d resonates in the range 170.4–170.9 ppm, which
is more shielded than the corresponding C-4 in compounds 19a–d
(188–189 ppm); similarly, C-2 resonates around 152 ppm and
C-8a resonates around 130 ppm and are more shielded than the
corresponding carbons in 19a–d (154 ppm) and (148 ppm),
respectively.
Having the essential quinolone compounds in hand, we could
easily convert them to the diamino compounds 22a–d as shown in
Scheme 2, in which the chlorine atom was replaced with the azide
moiety via the standard nucleophilic aromatic substitution. The
structure of compounds 21a–d is supported by spectral (NMR and
MS) data which are in agreement with the literature data. In the
1H NMR spectra, there is not any difference in the chemical shift
compared to the compounds 20a–d. In the 13C NMR spectra there
is a small difference for C-7, which appears downfield in
compounds 21a–d (ꢀ128 ppm) compared to the corresponding C-
7 in 20a–d due to the replacement of –Cl by the azide group.
Reduction of the particular ethyl 7-azido-1-(alkyl/aryl)-6-
fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate (21a–d)
with anhydrous stannous chloride in concentrated hydrochloric
acid afforded the respective 7,8-diamino compounds (22a–d)
in good yield (78–85%). The effective reduction of 21a–d to
afford 22a–d was deduced from the presence of NH band at
3462–3295 cmꢂ1 in the IR spectra. The IR spectra of 22a–d also
show absorption bands (1672, 1632 cmꢂ1), which indicate the
presence of a conjugated keto group, while the carboxy group
absorbs at 1718 cmꢂ1. The structure of 22a–d is further
Results and discussion
Chemistry
Our synthesis banks on the reported strategy used by us and others
in building the quinolone skeleton. Scheme 1 shows the synthesis
of our N-aryl/alkyl substituted quinolones, in which the benzoic
acid derivative 17 was converted to the benzoyl chloride via
interaction with thionyl chloride under reflux conditions. The
resulting benzoyl chloride was reacted with ethyl 3-(N,N-
dimethylamine)acrylate in benzene to produce the intermediate
18 which was reacted with the desired amino compound to get the
respective 19a–d as the predominant Z isomers.
1
supported by NMR spectral data. The H NMR spectra of 22a–
d indicate the appearance of the amine protons signals at 5.05
(NH2 on C-8) and 5.43 (NH2 on C-7), while H-5 appears as a
doublet at 7.19 ppm, and is thus shielded compared to its position
in 21a–d. The 13C NMR spectra show the C-8 and C-5 resonating
around 125.7 and 100.6 ppm, respectively, which are shielded
compared to their positions in 21a–d (133.1 and 115.8 ppm,
respectively).
Cyclocondensation of the synthesized diamine 22a–d using thi-
onyl chloride produces the targeted bicyclic benzo[c][1,2,5]thia-
diazoles system 23/24 (Scheme 3). The driving force of formation
is due to: (i) strong electrophilicity of thionyl chloride, and
(ii) stability of the tricyclic product due to aromaticity. It is worth
mentioning that upon the workup procedure, where methanol was
used to destroy the excess thionyl chloride, trans-esterification of
the ethyl ester produced completely the methyl ester 23a, while a
1:1 ratio of methyl and ethyl esters were isolated for the product
23b/24b and 23d/24d. Compound 24c was isolated as the ethyl
ester only.
The structures of compounds 19a–d are supported by spectral
1
(NMR and MS) data. The various H and 13C NMR signals were
assigned based on DEPT and 2D NMR (HMQC) experiments.
1
The H NMR spectra show the methylene protons (O–CH2CH3)
as quartet in the range ꢀ 3.98–4.07 ppm, while the methyl protons
(O–CH2CH3) resonate as triplet in the range ꢀ 1.01–1.07 ppm.
The H-300 proton resonates as a doublet signal in the range ꢀ 8.19–
8.67 ppm (with J ¼ 11–14 Hz) indicating that the products are the
Z-isomers. The H-6 proton of this series is well characterized as a
3
sharp doublet in the range ꢀ 7.09–7.19 ppm, (with JH–F ¼ 8.0–
8.2 Hz) due to spin–spin coupling interaction with the vicinal
fluorine atom.
The 13C NMR spectra of compounds 19a–d reveal clearly the
presence of the fluorine atom and its effect on the adjacent
carbons; thus the following carbons showed through-bonds
coupling with the fluorine atom and appear as doublets (C-5,

784 R. A. Al-Qawasmeh et al.
J Enzyme Inhib Med Chem, 2014; 29(6): 777–785
The following changes constitute diagnostic criteria for ring at 12 mg/mL, whereas phenyl derivative 24b had some activity
1
closure: the H NMR spectra of compounds (23/24) indicate the against the same strain at the concentration of 100 mg/mL.
disappearance of the amine protons signals at 3.75–4.80 (NH2 on Compound 24c was the only ester that inhibited the growth of
C-8) and 5.29–5.61 (NH2 on C-7), while H-5 appears as a doublet H. influenzae and S. aureus (MIC 200–400 mg/mL, respectively).
at 8.09–8.32 ppm, and is thus deshielded compared to its position
All the newly synthesized compounds exhibited antibacterial
in (22a–d). The 13C-NMR spectra show the C-3a and C-9b around activity lower than that of ciprofloxacin used as reference
148.4 and 148.9 ppm, respectively, which are deshielded com- substance. Furthermore, no inhibition was exerted against
pared to their positions in 22a–d.
The hydrolysis of ethyl(methyl) 9-(aryl/alkyl)-4-fluoro-6-oxo- concentration of 400 mg/mL (data not shown; MICs of miconazole
6,9-dihydro[1,2,5]thiadiazolo- [3,4-h]quinoline-7-carboxylate 12 mg/mL, 6 mg/mL and 3 mg/mL, respectively).
(23/24a–d) gave the corresponding acid products (25a–d) in Structure–activity relationship shows that, among the
S. cerevisiae, C. tropicalis and A. niger fungal strains up to the
ꢀ90 % yield by using 12% aqueous HCl under reflux conditions. newly synthesized thiadiazoloquinolone acids and among their
The structures of 25a–d are supported by spectral (1H NMR corresponding esters, the N-4-fluorophenyl derivatives 24c and
1
and MS) data. The H NMR spectra show the disappearance of 25c exhibited the highest activity, followed, in the order, by
ethyl or the methyl protons signals (in previous esters 23/24b–d) N-ethyl- (23a and 25a), N-phenyl- (24–25b) and N-4-methox-
from the spectra and the appearance of a broad signal at 14.9 yphenyl- (24–25d) quinolones. However, these new thiadiazolo-
(exchangeable CO2H proton). 13C-NMR spectra show the dis- quinolones exhibited MIC values higher than those of the
appearance of ethyl or the methyl carbons signals (in previous N–Cyclopropyl acid 16 and its ethyl ester, confirming the current
esters 23/24b–d) from the spectra.
knowledge that the replacement of the cyclopropyl at the N-1
position of the quinolone ring with ethyl or substituted and
unsubstituted phenyl moiety plays a negative role on the
antibacterial properties. Likewise, the introduction of fluorine at
position C-6, in compound 25a, enhanced, by a factor four or two,
the activity of 14 against S. aureus and E. coli, respectively.
As concerns the intermediates 19/22a–d, only B. subtilis, the
most sensitive microorganism, was inhibited by 22c at 100 mg/mL
and by 7-chloro-8-nitroquinolines 20a and 20c at 200 mg/mL.
A low antibacterial activity appeared when compounds 19 cyclize
to quinolone structure 20. This inhibition disappeared in the
derivatives 21, probably owing to the loss of chlorine substituent.
Replacing the azido fragment with the amino group for substances
22 led to an increase in antibacterial properties of 4-fluorophenyl
derivative 22c against B. subtilis. The subsequent cyclization
of the two amino groups at 7 and 8 positions on the fused
thiadiazole ring (compounds 23a and 24b-d) enhanced the
activity. Compound 24c showed a MIC value of 12 mg/mL
towards B. subtilis and broadened the range of its inhibition
against S. aureus and H. influenzae. This change in the structure
resulted also in increased activity of 23a and 24b towards
B. subtilis (MIC 12 and 100 mg/mL, respectively).
Antimicrobial activity
The in vitro antimicrobial properties of the acids 25a–d, their
esters 23a and 24b–d and of the starting compounds 19/22a–d
were detected against Gram positive and Gram negative bacteria,
yeasts and mould.
Table 1 summarizes the results obtained when compounds 23a,
24b–d and 25a–d were assayed against B. subtilis and S. aureus
Gram positive bacteria and E. coli and H. influenzae Gram
negative ones. The antibacterial activity of desfluorinated
N-ethylquinolone acid 14 and of the 6-fluoro-N–Cyclopropyl
analogous 16 together with its ethyl ester is also reported for an
useful comparison.
The thiadiazoloquinolone acids 25a–d are the most active
compounds. N-ethyl derivative 25a and N-4-fluorophenyl deriva-
tive 25c had strong inhibitory effect on the growth of both Gram
positive and Gram negative tested strains (MIC 0.15–3 mg/mL).
Significant inhibition was also exhibited by phenyl derivative 25b
with MIC values in the 1.5–50 mg/mL range. A lower activity was
observed for 4-methoxyphenyl derivative 25d against B. subtilis
and S. aureus (MIC 100–200 mg/mL). Gram positive B. subtilis
was the most sensitive microorganism. Among thiadiazoloquino-
lone esters, N-ethyl derivative 23a and N-4-fluorophenyl deriva-
tive 24c showed good antimicrobial properties against B. subtilis
As expected, the sizeable increase of activity was observed in
the target compounds 25a–d, whose activity is discussed above,
by replacing the C-3 ester group with the carboxylate that is
considered critical and not yet improved by any change.
Table 1. In vitro antibacterial activity of thiadiazoloquinolones (minimum inhibitory concentration in mg/mL).
Microorganism
Bacillus subtilis
ATCC 6633
Staphylococcus aureus
ATCC 6538
Escherichia coli
ATCC 8739
Haemophilus influenzae
ATCC 19418
Compound
23a
24b
24c
24d
12
100
12
4400
4400
4400
400
4400
4400
4400
4400
4400
4400
200
4400
4400
25a
25b
25c
25d
0.15
1.5
0.15
100
1.5
12
1.5
3
50
3
1.5
6
0.7
200
4400
4400
14*
nty
3
0.07
0.03
6
50
0.7
0.3
6
100
0.7
nt
25
0.3
0.15
16 ethyl ester*
16*
Ciprofloxacin
0.015
*Results reported in previous article.19
yNot tested.

DOI: 10.3109/14756366.2013.855925
Thiadiazoloquinolone compounds 785
dihydro-4-oxoquinline-3-carboxylic acids. J Med Chem 1980;23:
1358–63.
Conclusion
The aim of this study is to investigate whether the thiadiazolo
fused ring, as a bridge between the critical 7 and 8 positions of the
fluoroquinolone scaffold, offers new insight into the structural–
activity relationship of the class of quinolones antibacterials. In
this study, 26 new compounds were successfully synthesized and
fully characterized. The synthesized thiadiazolofluoroquinolones
show broad spectrum of activity. The fluoroquinolone 25c was the
most active compound in this study. The activities of this class of
compounds were expected as a consequence of the modifications
at the positions 7 and 8 of the fluoroquinolone ring, and are in
agreement with the analogous previous generations of fluoro-
quinolones. This modification is expected to increase the
intracellular targets on the type II topoisomerase and to impair
the action of efflux pump, thus lowering the development of
quinolone resistance in Gram positive pathogens. Extensive
mechanism of action for this class of compounds will be
investigated.
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Acknowledgements
We wish to thank the Deanship of Scientific Research (The University of
Jordan, Amman, Jordan) for financial support.
Declaration of interest
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565–73.
The authors report no conflicts of interests. The authors alone are
responsible for the content and writing of this article.
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