S. Kantevari et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4316–4319
4319
Table 3
Physical data and antitubercular evaluation of 6a–e against M. tuberculosis H37RV
Entry
Aldehyde 4
R
Product 6
Yielda (%)
Mp ( °C)
Log P/C Log Pb
MIC (lg/mL)
1
2
3
4
5
4a
4b
4c
4d
4e
H
Cl
Br
OCH3
6a
6b
6c
6d
6e
85
90
90
81
76
126
130
192
189
167
3.61/4.489
4.16/5.202
4.43/5.352
3.48/4.408
3.23/3.789
3.13
1.56
1.56
6.25
12.5
3,4,5-Tri OCH3
a
Isolated yields.
Calculated using Chemdraw Ultra 12.0
b
4. (a) Koul, A.; Arnoult, E.; Lounis, N.; Guillemont, J.; Andries, K. Nature 2011, 469,
483; (b) Ginsberg, A. M.; Spigelman, M. Nat. Med. 2007, 13, 290; (c) Check, E.
Nat. Med. 2007, 13, 266.
5. (a) Kumar, A.; Srivastava, S.; Gupta, G.; Chaturvedi, V.; Sinha, S.; Srivastava, R.
ACS Comb. Sci. 2011, 13, 65; (b) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Angew.
Chem., Int. Ed. 2003, 42, 3996.
liphophilic nature is needed for amidoalkyl dibenzofuranols to be
active against M. tuberculosis H37Rv (MTB) and cyclized oxazinone
analogues are structurally better correlates with liphophilic nature
and showed better activity.
In conclusion we have synthesized a new class of amidoalkyl
dibenzofuranols 5a–k and 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxa-
zin-3(2H)-ones 6a–e through polyphosphoric acid supported on
silica (PPA–SiO2) catalyzed one-pot three component condensation
of 2-dibenzofuranol; aromatic aldehydes and acetamide or benz-
amide or urea under solvent free conditions in very good yields.
At 160 °C condensation with urea proceeded to cyclization to give
1H-benzo[2,3] benzofuro[4,5-e][1,3] oxazin-3(2H)-ones 6a–e.
Screening all these new derivatives against M. tuberculosis H37Rv
(MTB) resulted amidoalkyl dibenzofuranols 5h, 5i, 6a (MIC
6. (a) Stoll, A. Experientia 1947, 3, 11; (b) Klosa, J. Pharmazie 1953, 8, 435; (c)
Müller, K. Appl. Microbiol. Biotechnol. 2001, 56, 9; (d) Ingólfsdóttir, K.; Chung, G.
A. C.; Skúlason, V. G.; Gissurarson, S. R.; Vihelmdóttir, M. Eur. J. Pharm. Sci. 1998,
6, 141; (e) Lombaert, S. D.; Blanchard, L.; Stamford, L. B.; Tan, J.; Wallace, E. M.;
Satoh, Y.; Fitt, J.; Hoyer, D.; Simonsbergen, D.; Moliterni, J.; Marcopoulos, N.;
Savage, P.; Chou, M.; Trapani, A. J.; Jeng, A. Y. J. Med. Chem. 2000, 43, 488.
7. (a) Khouri, T. I.; Gaslonde, T.; Prado, S.; Saint-Joanis, B.; Bardoud, F.;
Amanatiadou, E. P.; Vizirianakis, I. S.; Kordulakova, J.; Jackson, M.; Brosch, R.;
Janin, Y. L.; Daffé, M.; Tillequin, F.; Michel, S. Eur. J. Med. Chem. 2010, 45, 5833;
(b) Prado, S.; Ledeit, H.; Michel, S.; Koch, M.; Darbord, J. C.; Cole, S. T.; Tillequin,
F.; Brodin, P. Bioorg. Med. Chem. 2006, 14, 5423; (c) Prado, S.; Janin, Y. L.; Saint-
Joanis, B.; Brodin, P.; Michel, S.; Koch, M.; Cole, S. T.; Tillequin, F.; Bost, P. E.
Bioorg. Med. Chem. 2007, 15, 2177.
3.13 lg/mL) and oxazin-3(2H)-ones 6b and 6c (MIC 1.56 lg/mL)
as most potent antitubercular agents.
8. (a) Kantevari, S.; Patpi, S. R.; Sridhar, B.; Yogeeswari, P.; Sriram, D. Bioorg. Med.
Chem. Lett. 2011, 14, 1214; (b) Sriram, D.; Yogeeswari, P.; Dinakaran, M.;
Banerjee, D.; Bhat, P.; Gadhwal, S. Eur. J. Med. Chem. 2010, 45, 120; (c)
Manikannan, R.; Muthusubramanian, S.; Yogeeswari, P.; Sriram, D. Bioorg. Med.
Chem. Lett. 2010, 20, 3352.
Acknowledgments
9. Kantevari, S.; Bantu, R.; Nagarapu, L. J. Mol. Catal. A: Chem. 2007, 269, 53.
10. (a) Kantevari, S.; Yampala, T.; Vuppalapati, S. N. V. Synthesis 2010, 959; (b)
Kantevari, S.; Putapatri, S. R. Synlett 2010, 2251; (c) Kantevari, S.; Addala, D.;
Sridhar, B. Synthesis 2010, 3745.
Authors are thankful to Dr. J. S. Yadav, Director and
Dr. V. V. N. Reddy, Head, Organic Chemistry Division-II, IICT,
Hyderabad for their continuous support, encouragement and
financial assistance from MLP projects. T.Y. is thankful to CSIR
for fellowship (SRF).
11. Representative
furanyl)methyl]urea (5h). Light yellow solid; mp 68 °C. IR (KBr): 3384, 3063,
2922, 2852, 1701, 1638, 1590, 1461, 1431, 1216, 1154, 1092 cmÀ1 1H NMR
spectral
data:
[(4-Chlorophenyl)(2-hydroxydibenzo
.
(300 MHz, DMSO-d6): d = 9.32 (s, 1H), 8.15 (d, J = 6.9 Hz, 1H), 7.75 (s, 1H), 7.50
(d, J = 8.1 Hz, 1H), 7.40 (t, 1H), 7.32–7.10 (m, 7H), 7.0 (d, J = 8.6 Hz, 1H), 5.55 (s,
2H). HRMS (ESI): m/z calcd for: C20H15O3N2ClNa [(M+Na)+]: 389.0668; found:
389.0685. [(4-Bromophenyl)(2-hydroxydibenzofuranyl)methyl] urea (5i)
White solid; mp 82 °C. IR (KBr): 3374, 2923, 2853, 1647, 1597, 1528, 1454,
Supplementary data
1429, 1369, 1219, 1181, 1076 cmÀ1 1H NMR (300 MHz, DMSO-d6): d = 9.50 (s,
.
Supplementary data (complete experimental procedures and
copies of 1H, 13C NMR and mass (HRMS) spectra of compounds
5c,d, and 6c,d CCDC 823486 (for 6d) contain the crystallographic
data and can be obtained free of charge from the Cambridge Crys-
quest/cif) associated with this article can be found, in the online
1H), 8.20 (br, 1H), 7.6 (d, J = 8.1 Hz, 1H), 7.5–7.23 (m, 5H), 7.20 (d, J = 8.3 Hz,
2H), 7.0 (s, 3H), 5.80 (s, 2H).13C NMR (75 MHz, DMSO-d6): d = 158.4, 156.1,
151.2, 149.2, 142.7, 130.8, 129.0, 128.0,127.2, 121.8, 122.7, 122.4, 122.1, 119.2,
116.0, 111.7, 110.8, 49.3. HRMS (ESI): m/z calcd for C20H15O3N2BrNa [(M+Na)+]:
433.0163; found: 433.0152. 1-(4-chlorophenyl)-1H-benzo[2,3]benzofuro[4,5-
e][1,3]oxazin-3(2H)-one (6b) White solid; mp 130 °C. IR (KBr): 3252, 2923,
1728, 1431, 1386, 1216, 1163, 1090 cmÀ1 1H NMR (300 MHz, DMSO-d6):
.
d = 8.75 (s, 1H), 7.60 (m, 3H), 7.43 (t, 1H), 7.25–7.36 (m, 5H), 7.2 (t, 1H), 6.2 (s,
1H). HRMS (ESI): m/z calcd for C20H12O3NClNa [(M+Na)+]: 372.0403; found:
372.0399.
1-(4-bromophenyl)-1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-
References and notes
3(2H)-one (6c) White solid; mp 192 °C. IR (KBr): 3259, 29225, 1729, 1433,
1217, 1082, 1003 cmÀ1 1H NMR (500 MHz, DMSO-d6): d = 8.7 (s, 1H), 7.5–7.6
.
1. (a) Russell, D. G.; Barry, C. E.; Flynn, J. L. Science 2010, 328, 852; (b) Russell, D. G.
Nat. Rev. Microbiol. 2007, 5, 39; (c) Kaufmann, S. H. E.; McMichael, A. J. Nat. Med.
2005, 11, 578; (d) Manabe1, Y. C.; Bishai1, W. R. Nat. Med. 2000, 6, 1327.
2. (a) World Health Organization. Multidrug and Extensive Drug Resistant
Tuberculosis: 2010 Global Report on Surveillance and Response, 2010.; (b)
(m, 3H), 7.48–7.4 (m, 3H), 7.30–7.15 (m, 4H), 6.14 (s, 1H). 13C NMR (75 MHz,
CDCl3+ DMSO-d6): d = 156.0, 151.7, 49.4, 45.4, 139.3, 131.3, 131.2, 128.2, 126.9,
122.2, 121.8, 121.5, 121.3, 115.2, 113.4, 111.5, 111.1, 53.5. MS (EI): m/z for
C
20H12O3NBr: 393 [M+], 395 [(M+2)+].
12. Crystal data: C21H15NO4, M = 345.34, triclinic, space group P1;, a = 8.3749(10) Å,
b = 9.9268(12) Å, c = 11.6531(14) Å, = 112.558 (2)°, b = 92.821(2) °,
100.038(2)° V = 873.77 (18) Å3, Z = 2, Dcalcd = 1.313 mg mÀ3
T = 294(2) K,
= 0.092 mmÀ1
F(0 0 0) = 360, k = 0.71073 Å. Data collection yielded 8350
Global tuberculosis control:
a short update to the 2009 report <http://
a
c =
3. (a) Nikalie, A. G.; Mudassar, P. Asian J. Biol. Sci. 2011, 4, 101; (b) Sacchettini, J. C.;
Rubin, E. J.; Freundlich, J. S. Nat. Rev. Microbiol. 2008, 6, 41; (c) Showalter, H. D.
H.; Denny, W. A. Tuberculosis 2008, 88, S3–S17; (d) Duncan, K.; Barry, C. E., III
Curr. Opin. Microbiol. 2004, 7, 460; (e) Muddassar, M.; Jang, J. W.; Gon, H. S.;
Cho, Y. S.; Kim, E. E.; Keum, K. C.; Oh, T.; Cho, S.-N.; Pae, A. N. Bioorg. Med. Chem.
2010, 18, 6914.
,
l
,
reflections resulting in 3059 unique, averaged reflections, 2632 with I >2(I).
Full-matrix least-squares refinement led to a final R = 0.0393, wR = 0.1048 and
GOF = 1.042. Intensity data were measured on Bruker Smart Apex with CCD
area detector.