Journal of Medicinal Chemistry
Article
3-carboxylic acid (200 mg, 0.67 mmol) was taken in DCM (10 mL). 1-
Propanephosphonic acid cyclic anhydride (427 mg, 1.34 mmol) was
added, followed by the addition of triethyl amine (339 mg, 3.35 mmol)
and cyclopropylmethanamine (95 mg, 1.34 mmol). The reaction mass
was stirred at RT for overnight. After the completion of the reaction,
water was added and extracted with DCM. The organic layer was
washed with water and brine slution. The organic layer was separated
and dried over sodium sulfate. The organic layer was evaporated to get
the residue, which was purified by column chromatography to get the
pure compound (yield 74%). ES + MS m/z: 352.38 (M + 1). 1H NMR
(300 MHz, DMSO-d6) δ ppm 0.02 (q, J = 4.58 Hz, 2 H) 0.18−0.31
(m, 2 H) 0.83 (t, J = 6.88 Hz, 1 H) 2.00 (s, 3 H) 2.98−3.11 (m, 3 H)
3.69 (s, 3 H) 5.43 (s, 2 H) 7.00 (dd, J = 8.29, 4.71 Hz, 1 H) 7.68 (dd, J
= 8.29, 1.13 Hz, 1 H) 7.98 (s, 1 H) 8.17 (s, 1 H) 8.24 (dd, J = 4.71,
1.13 Hz, 1 H) 8.55 (t, J = 5.75 Hz, 1 H). 13C NMR (400 MHz,
DMSO-d6) δ ppm 167.2, 162.7, 161.2, 154.9, 143.3, 142.5, 136.9,
130.2, 119.3, 117.1, 114.6, 109.8, 54.1, 48, 42.4, 11.2, 9.4, 3.1.
Author Contributions
#P.S.S. and M.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the analytical support provided by S. Rudrapatna and
the analytical team. Our sincere thanks to the PD Bangalore,
CMG, Global DMPK, Safety, Biosciences (AZ Boston, USA),
and Discovery Sciences (AZ, Alderly Park, UK) for technical
support in various assays. We thank M. Panda for preliminary
docking studies. We also thank Rajkumar and Subhash for
animal welfare support. We sincerely thank G. Riccardi
(University of Pavia) for providing the DprE1 expression
plasmid. We thank Sudha R. for her contributions towards
DprE1 overexpression strain. We acknowledge N. Dinesh and
S. Ghorpade for scientific discussions. We also thank V.
Balasubramanian, P. Warner, R. Tommasi, and M. Perros for
their constant inspiration, support, and encouragement. This
research was supported by the Global Alliance for Tuberculosis
(GATB).
N-(2-Fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)-
methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
(5). 1-((6-Methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-
pyrrolo[3,2-b]pyridine-3-carboxylic acid (0.190 g, 0.61 mmol), 2-
fluoroethanamine (0.077 g, 1.22 mmol), and TEA (0.254 mL, 1.83
mmol) was added in DCM. After 3 min, 1-propanephosphonic acid
cyclic anhydride (0.484 g, 1.52 mmol) was added. The resulting
reaction mixture was stirred at rt for 50 min. The reaction was diluted
with DCM and water. The DCM layer was extracted and washed with
brine and dried over sodium sulfate and concentrated. Purification was
performed on Waters RP system to get product N-(2-fluoroethyl)-1-
((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo-
[3,2-b]pyridine-3-carboxamide (0.090 g, 41.4%). ES + MS m/z:
ABBREVIATIONS USED
■
TB, tuberculosis; Mtb, Mycobacterium tuberculosis; DprE1,
decaprenylphosphoryl-β-D-ribose2′-epimerase 1; MDR-TB,
multidrug-resistant tuberculosis; BTZs, nitro-benzothiazinones;
DPR, decaprenylphosphoryl-β-D-ribose; DPA, decaprenylphos-
phoryl-β-D-arabinofuranose; DPX, decaprenylphosphoryl-2-
keto-β-D-erythro-pentofuranose; MBC, minimum bactericidal
concentration; MIC, minimum inhibitory concentration; SAR,
structure−activity relationship; Msm, Mycobacterium smegmatis;
DMPK, drug metabolism and pharmacokinetic; Clint, intrinsic
clearance; PPB, plasma protein binding; CL, clearance; LBF,
liver blood flow; CYP, cytochrome P450 enzymes
1
358.36. H NMR (300 MHz, DMSO-d6) δ ppm 2.17−2.30 (3, 3 H)
2.40 (s, 3 H) 3.59−3.73 (m, 1 H) 3.73−3.83 (m, 1 H) 3.94 (s, 3 H)
4.50 (t, J = 4.99 Hz, 1 H) 4.66 (t, J = 4.99 Hz, 1 H) 5.64 (s, 2 H) 7.76
(s, 1 H) 8.15 (s, 1 H) 8.35 (s, 1 H) 8.42 (s, 1 H) 8.87 (t, J = 5.84 Hz, 1
H). 13C NMR (400 MHz, DMSO-d6) δ ppm 167.1, 163.1, 161.3, 155,
144.4, 140.6, 136.4, 130.3, 126.6, 119, 114.5, 109.3, 83.8, 82.2, 54.1,
47.9, 38.6, 18.3, 9.4.
N-(2-Hydroxyethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)-
methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
(6). 1-((6-Methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-
pyrrolo[3,2-b]pyridine-3-carboxylic acid (75 mg, 0.24 mmol) was
added to dichloromethane (10 mL) to give a suspension. Triethyl
amine (66.9 mL, 0.48 mmol) was added, followed by 1-propane-
phosphonic acid cyclic anhydride (286 mL, 0.48 mmol). The reaction
mixture was stirred at RT for 5 min. Ethanol amine (29.0 mL, 0.48
mmol) was added, and the mixture was stirred at RT overnight. After
completion of the reaction, the mixture was diluted with DCM and
washed with water and brine. The DCM layer was dried over sodium
sulfate and evaporated to give the crude product, which was purified by
column chromatography using methanol/dichloromethane as eluent
REFERENCES
■
(1) Raviglione, M.; Marais, B.; Floyd, K.; Lonnroth, K.; Getahun, H.;
̈
Migliori, G. B.; Harries, A. D.; Nunn, P.; Lienhardt, C.; Graham, S.;
Chakaya, J.; Weyer, K.; Cole, S.; Kaufmann, S. H.; Zumla, A. Scaling
up interventions to achieve global tuberculosis control: progress and
new developments. Lancet 2012, 379, 1902−1913.
(2) Global Tuberculosis Report; World Health Organization: Geneva,
2012.
(3) Cohen, J. Approval of novel TB drug celebrated with restraint.
Science 2013, 339, 130−131.
1
(yield 52.7%). ES + MS m/z: 356.4 (M + 1). H NMR (300 MHz,
DMSO-d6) δ ppm 2.23 (s, 3 H) 2.39 (s, 3 H) 3.39−3.65 (m, 4 H) 3.93
(s, 3 H) 4.84 (t, J = 5.09 Hz, 1 H) 5.63 (s, 2 H) 7.74 (s, 1 H) 8.12 (s, 1
H) 8.33 (s, 1 H) 8.41 (s, 1 H) 8.80 (t, J = 5.65 Hz, 1 H). 13C NMR
(400 MHz, DMSO-d6) δ ppm 167.1, 163, 161.3, 155, 144.3, 140.6,
136.2, 130.3, 126.4, 118.9, 114.5, 109.8, 60.3, 54.1, 47.9, 41, 18.3, 9.4.
(4) Trefzer, C.; Rengifo-Gonzalez, M.; Hinner, M. J.; Schneider, P.;
Makarov, V.; Cole, S. T.; Johnsson, K. Benzothiazinones: prodrugs
that covalently modify the decaprenylphosphoryl-β-D-ribose 2′-
epimerase DprE1 of Mycobacterium tuberculosis. J. Am. Chem. Soc.
2010, 132, 13663−13665.
̌ ́
(5) Mikusova, K.; Huang, H.; Yagi, T.; Holsters, M.; Vereecke, D.;
ASSOCIATED CONTENT
D’Haeze, W.; Scherman, M. S.; Brennan, P. J.; McNeil, M. R.; Crick,
D. C. Decaprenylphosphoryl arabinofuranose, the donor of the D-
arabinofuranosyl residues of mycobacterial arabinan, is formed via a
two step epimerization of decaprenylphosphoryl ribose. J. Bacteriol.
2005, 187, 8020−8025.
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S
* Supporting Information
Details of the synthesis of all compounds and biological assays.
This material is available free of charge via the Internet at
̌ ́
(6) Makarov, V.; Manina, G.; Mikusova, K.; Mollmann, U.; Ryabova,
̈
O.; Saint-Joanis, B.; Dhar, N.; Pasca, M. R.; Buroni, S.; Lucarelli, A. P.;
Milano, A.; De Rossi, E.; Belanova, M.; Bobovska, A.; Dianiskova, P.;
Kordulakova, J.; Sala, C.; Fullam, E.; Schneider, P.; McKinney, J. D.;
Brodin, P.; Christophe, T.; Waddell, S.; Butcher, P.; Albrethsen, J.;
Rosenkrands, I.; Brosch, R.; Nandi, V.; Bharath, S.; Gaonkar, S.;
Shandil, R. K.; Balasubramanian, V.; Balganesh, T.; Tyagi, S.; Grosset,
J.; Riccardi, G.; Cole, S. T. Benzothiazinones kill Mycobacterium
AUTHOR INFORMATION
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Corresponding Authors
23621212. Fax: +91 080 23621214.
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dx.doi.org/10.1021/jm401382v | J. Med. Chem. XXXX, XXX, XXX−XXX