Acknowledgments
The valuable support and financial assistance for this research by
the Council of Scientific and Industrial Research (VK) (Grant
No. 02(0293)/17/EMR-II) and by the Department of Science and
Technology (DST) under the INSPIRE fellowship programme
2 4
over anhydrous Na SO and concentrated under vacuum. The
compound was purified via column chromatography using
chloroform : methanol (95:5) to yield the desired compound 4-(3-
(Shalini, IF160180) are immensely acknowledged.
(
7
CH
CH
4
2-methyl-5-nitro-1H-imidazol-1-yl)propyl)morpholine (6b).Yield
1
5%; Brown oil; H NMR (CDCl
2
3
, 500MHz): 1.93-1.98 (m, 2H,
), 2.32 (t, J = 6.5 Hz, 2H, CH ), 2.40-2.42 (m, 4H, CH -N-
), 2.45 (s, 3H, CH ), 3.70 (t, J = 4.5 Hz, 4H, CH -O-CH ),
), 7.72 (s, 1H, imidazole-H); C NMR
): 146.44, 144.86, 119.81, 66.83, 54.15, 53.45,
References and notes:
2
2
2
3
2
1
2
1
2
3
.
.
.
Lonnroth, K.; Jaramillo, E.; Williams, B. G.; Dye C.; Raviglione,
M. Soc. Sci. & Med. 2009, 68, 2240-2246.
World Health Organization (WHO), Treatment of Tuberculosis:
Guidelines forNationalProgrammes, fourth ed., WHO Press,
Geneva, Switzerland, 2009.
Ambrosio, L. D’; Centis, R.; Sotgiu G.; Pontali E.; Spanevello A.;
Migliori G. B. ERJ open Res. 1, 2015 1-15.
Gandhi N. R.; Nunn P.; Dheda K.; Schaaf H. S.; Zignol M.;
Sooligen D. van; Jensen P.; Bayona J.; Lancet, 2010, 375,
3
.03 (t, J = 6.8 Hz, 2H, CH
2
(125 MHz, CDCl
3
+
4
18 4 3
4.48, 26.55, 13.02. HRMS calcd for C11H N O 254.1379 [M]
found 254.1385.
2
4. Synthesis of 7-chloro-4-(4-(3-(2-methyl-5-nitro-1H-imidazol-1-
yl)propyl)piperazin-1-yl)quinoline (11b): To the suspension of
0
NaH (2 equiv) in dry DMF at 0 C, was added dropwise the
4
5
.
.
solution of 10 (1 equiv) in dry DMF. After the generation of
anion as evident from the appearance of a bright yellow
colouration, the solution of 5b (1.3 equiv) in dry DMF was added
dropwise. The reaction was allowed to stir at room temperature for
1
830−1843.
2
h and the progress was monitored by TLC. After the completion
6
.
Cohen J. Infectious disease. Approval of novel TB drug
celebrated-with restraint, Science, 2013, 339, 130.
Mahajan R. Int J App Basic Med Res, 2013, 3, 1-2.
Ryan N. J.; Lo J. H. Drugs, 2014, 74, 1041-1045.
Sutherland H. S.; Blaser A.; Kmentova I.; Franzblau S. G.; Wan
B.; Wang Y.; Ma Z.; Palmer B. D.; Denny W. A.; Thompson A.
M. J. Med. Chem. 2010, 53, 855−866.
of the reaction, it was quenched by adding water and the crude
was extracted using ethyl acetate (2 × 20mL). The combined
organic layers were dried over anhydrous Na
concentrated under reduced pressure. The compound was purified
via column chromatography using chloroform : methanol (95:5) to
yield the desired hybrid 7-chloro-4-(4-(3-(2-methyl-5-nitro-1H-
7
8
9
.
.
.
2
SO
4
and
imidazol-1-yl)propyl)piperazin-1-yl)quinoline (11b). Yield 68%;
1
1
0. Tonelli M.; Simone M.; Tosso B.; Novelli F.; Biodo V. Bioorg.
Med. Chem. 2010, 18, 2937−2953.
1. Lin P. L.; Dartois V.; Johnston P. J.; Janssen C.; Via L.; Goodwin
M. B.; Klein E.; Barry III C. E.; Flynn J. L. Proc. Natl. Acad. Sci.
U.S.A. 2012, 109, 14188−14193.
1
Brown oil; H NMR (CDCl
3
, 500MHz): 1.98-2.05 (m, 2H,
+ CH ), 2.71 (s, 4H, CH -N-CH ),
), 4.05 (t, J = 8.5 Hz, 2H, CH ), 6.83 (d,
CH
2
), 2.44-2.48 (m, 5H, CH
-N-CH
2
3
2
2
3
.27 (s, 4H, CH
2
2
2
2
4
J= 6.4 Hz, 1H, H ), 7.40 (dd, J =2.7 Hz, 10.9 Hz, 1H, H ), 7.73 (s,
3
1
H, imidazole-H), 7.88 (d, J = 11.3 Hz, 1H, H ), 8.04 (d, J = 2.7
1
2. Chetty S.; Ramesh M.; Pillay A.S.; Soliman M. E. S. Bioorg. &
5
1
1
3
Hz, 1H, H ), 8.67 (d, J = 6.4 Hz, 1H, H ); C NMR (125 MHz,
CDCl ): 157.12, 151.24, 149.37, 146.54, 144.98, 135.48, 128.33,
26.51, 125.28, 121.64, 119.97, 108.93, 53.86, 52.94, 52.07,
4.62, 29.78, 13.20. HRMS calcd for C20 414.1571
Med. Chem. Lett. 2017, 27, 370-386.
3
1
1
1
1
1
1
3. Nguta J. M.; Appiah-Opong R.; Nyarko A.K.; Yeboah-Manu D.;
Addo P.G.A. Int. J. Mycobacteriol. 2015, 4, 165-183.
4. Worley M. V.; Estrada S. J. Pharmacother.: The J. Human
Pharm. & Drug Ther. 2014, 34, 1187-1197.
1
4
H
6 2
23ClN O
+
+
[
M] found 414.1562, [M+2] 416.1542 found 416.1550.
5. Diacon A. H.; Pym A.; Grobusch M. P. N. Engl. J. Med. 2014,
3
71, 723-732.
6. Singh A.; Viljoen A.; Kremer L.; Kumar V. Fut. Med. Chem.
017, 9, 1701-1708.
7. Singh A.; Biot C.; Viljoen A.; Dupont C.; Kremer L.; Kumar K.;
Kumar V. Chem. Bio. & Drug Des. 2017, 89, 856-861.
Supplementary Material
General procedure for the synthesis of 5a-e, 6b-j, 11b-e
2
1
13
and H and C spectral data of 6b-j, 11b-e along with
1
13
8. Raj R.; Biot C.; Carrere-Kremer S.; Kremer L.; Guerardel Y.; Gut
J.; Rosenthal P. J.; Kumar V. Chem. Bio. & Drug Design, 2014,
scanned H and C NMR spectra of 7+5a, 6b-j and 11c-
e.
8
3, 191-197.
1
2
2
2
9. Kumar K.; Biot C.; Carrere-Kremer S.; Kremer L.; Guerardel Y.;
Roussel P.; Kumar V. Organometallics, 2013, 32, 7386-7398.
0. Kumar K.; Carrere-Kremer S.; Kremer L.; Guerardel Y.; Biot C.;
Kumar V. Organometallics, 2013, 32, 5713-5719.
1. Bhovi M. G.; Tanwar P.; Yadav G. C. Indian J. Heterocycl. Chem.
2
010, 19, 215.
2. Synthesis of 5a-e: To a stirred suspension of activated K
2
3
CO (2
equiv) in dry DMF was added dropwise solution of 4 (1 equiv) in
dry DMF. After the generation of anions as evident by appearance
of bright yellow colouration, di-bromo alkane (1.2 equiv) was
added. The reaction mixture was allowed to stir at room
temperature for 6h and the progress of the reaction was monitored
by TLC. After the completion of the reaction, the reaction mixture
was concentrated under reduced pressure and crude product was
then extracted with ethyl acetate (2 × 20mL). The combined
organic layers were dried over anhydrous Na
2
SO
4
and
concentrated under vacuum. The compound was then purified via
column chromatography using ethyl acetate : hexane (30:70) as
eluent.
2
3. Synthesis
yl)propyl)morpholine (6b): To a stirred suspension of activated
CO (2 equiv) in dry DMF was added secondary amine
of
4-(3-(2-methyl-5-nitro-1H-imidazol-1-
K
2
3
Morpholine (2 equiv). After 15-20 min, a solution of alkylated
nitroimidazoles, 5b (1equiv) in dry DMF was added dropwise and
the reaction was allowed to stir at room temperature for 6h. The
progress of the reaction was monitored using TLC and on
completion of the reaction, the reaction mixture was concentrated
under reduced pressure and the crude product was extracted with
ethyl acetate (2 × 20mL). The combined organic layers were dried
4