P. M. Chaudhary et al. / Bioorg. Med. Chem. 17 (2009) 2433–2440
2439
6. Isono, K.; Asahi, K.; Suzuki, S. J. Am. Chem. Soc. 1969, 91, 7490.
7. Isono, K.; Suzuki, S. Heterocycles 1979, 13, 333.
8. Uramoto, M.; Kobinata, K.; Isono, K.; Higashijima, T.; Isono, K.; Miyazawa, T.;
Jenkins, E. E.; McCloskey, J. A. Tetrahedron Lett. 1980, 21, 3395.
9. Zhang, D.; Miller, M. J. Curr. Pharm. Des. 1999, 5, 73.
10. Deshpande, M. V. In Wealth and Sustainable Environment; Varma, A., Ed.;
Malhotra Publishing House: New Delhi, 1998; pp 281–291.
11. Muzzarelli, R. A. A. Chitin; Pergamon: Oxford, 1977.
12. Obi, K.; Uda, J. I.; Iwase, K.; Sugimoto, O.; Ebisu, H. Biorg. Med. Chem. Lett. 2000,
10, 1451.
13. Behr, J-B.; Gourlain, A. H.; Guillerm, G. Biorg. Med. Chem. Lett. 2003, 13, 1713.
14. Ondeyka, J. G.; Zink, D. L.; Dombrowaski, A. W.; Polishook, J. D.; Felock, P. J.;
Hazuda, D. J.; Singh, S. B. J. Antibiot. 2003, 56, 1018.
15. Baek, S. H.; Oh, H. J.; Lim, J. A.; Chun, H. J.; Lee, H. O.; Ahn, J. W.; Perry, N. B.;
Kim, H. M. Bull. Korean Chem. Soc. 2004, 25, 195.
16. Chen, Q.; Yang, F.; Du, Y. Carbohydr. Res. 2005, 340, 2476.
17. Varma, G. B.; Fatope, M. O.; Marwah, R. G.; Deadman, M. E.; At-Rawahi, F. K.
Phytochemistry 2006, 67, 1925.
18. Ladmiral, V.; Mantovani, G.; Clarkson, G. J.; Cauet, S.; Irwin, J. L.; Haddleton, D.
M. J. Am. Chem. Soc. 2006, 128, 4823.
19. Bock, V. D.; Perciaccante, R.; Jansen, T. P.; Hirmstra, H.; Van Maarseveen, J. H.
Org. Lett. 2006, 5, 919.
20. Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128.
21. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004.
22. Huisgen, R. In 1,3-Dipolar cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New
York, 1984.
23. Sasaki, T.; Minamoto, K.; Suzuki, T.; Sugiura, T. J. Org. Chem. 1979, 44, 1424.
24. Gholap, A. R.; Toti, K. S.; Shirazi, F.; Kumari, R.; Bhat, M. K.; Deshpande, M. V.;
Srinivasan, K. V. Bioorg. Med. Chem. 2007, 15, 6705.
25. Salunke, D. B.; Hazra, B. G.; Pore, V. S.; Bhat, M. K.; Nahar, P. B.; Deshpande, M.
V. J. Med. Chem. 2004, 47, 1591.
26. National Committee for Clinical Laboratory Standard. Reference Method for
Broth Dilution Antifungal susceptibility Testing of Yeast, Approved Standard.
Document M27-A; National Committee for Clinical Laboratory Standards:
Wayne, PA, USA, 1997.
27. National Committee for Clinical Laboratory Standard. Reference Method for
Broth Dilution Antifungal Susceptibility Testing of Conidium Forming
Filamentous Fungi: Proposed Standard. Document M38-P; National
Committee for Clinical Laboratory Standard: Wayne, PA, USA, 1998.
28. Yamamoto, N.; Fujita, J.; Shinzato, T.; Hig, F.; Tateyama, M.; Tohyama, M.;
Nakasone, I.; Yamaneb, N. Int. J. Antimicrob. Agents 2006, 27, 171.
29. Ghormade, V.; Deshpande, M. V. Naturwissenschaften 2000, 87, 236.
30. Deshpande, M. V.; Donnell, R. O.; Gooday, G. W. FEMS Microbiol. Lett. 1997, 152, 327.
31. Lucero, A. H.; Kuranda, J. M.; Bulik, A. D. Anal. Biochem. 2002, 305, 97.
32. Yarden, J. C.; Gonneau, M.; Sarthou, P.; Le Goffic, F. J. Bacteriol. 1984, 160, 884.
33. General experimental protocol for the synthesis of 1,2,3-triazoles 19a–19g and
21a–21g: To the stirred solution of 17 (1 mmol) and propargyl ethers 18a–18g
(1 mmol) or propargyl esters 20a–20g (1 mmol) in 10 mL of tertiary butanol/
water (8:2) was added copper sulfate (24 mg, 5 mol %) and sodium ascorbate
(40 mg, 10 mol %). Reaction mixture was stirred at 28 °C for 4–12 h.
Completion of the reaction was monitored by TLC. Tertiary butanol was
removed under reduced pressure, reaction mixture was partitioned between
ethyl acetate and water. Organic phase was washed successively with water,
brine, and dried over sodium sulfate and concentrated to furnish compounds
19a–19g or 21a–21g, yields ranging from 50% to 83%.
synthase activity at 4 ppm concentration against B. poitrasii were
compared (Table 4). With nikkomycin, for instance, inhibition of
chitin synthase activity and% germ tube formation were >95% while
that of growth was 45% (Table 4). This indicated that nikkomycin
uptake by B. poitrasii was high enough to show antifungal activity,
unlike earlier report of low nikkomycin uptake by C. albicans.32
Based on the in vitro inhibition of chitin synthase activity all the
compounds were divided in 3 groups (Table 4). From group I how-
ever 19e did not show growth inhibition comparable to other two
parameters which could be attributed to less uptake by the cells.
While compounds 19c and 21a showed higher inhibition of germ
tube formation as compared to chitin synthase activity. These com-
pounds may be acting on some additional targets. The compound
21b must be acting on some other target since it showed lesser inhi-
bition of chitin synthase activity as compared to other two assays.
Obi et al. reported that in case of synthesized nikkomycin ana-
logues anti-chitin synthase activity was found to be enhanced by
introducing b-dimethyl group as b-methyl group of nikkomycin.12
Furthermore, introduction of hydroxyl group in terminal aryl moi-
ety resulted in significantly enhanced anti-chitin synthase activity.
In present investigation introduction of methyl group at meta posi-
tion of benzene ring of compound 19f showed higher anti-chitin
synthase activity. Whereas in compound 21b decrease in anti-chi-
tin synthase activity was observed, which may be attributed to
ortho position of methyl group on benzene ring. Unlike reported
by Obi et al. in case of compound 21c introduction of hydroxyl
group in benzene ring did not show significant increase in anti-chi-
tin synthase activity.
In conclusion the current endeavor enables a practical, reliable
and efficient synthesis of several novel 1,4-disubstituted-1,2,3-
triazolyluridine derivatives by ‘click chemistry’ approach, most of
which showed significant antifungal activity. Compound 19a
showed potent antifungal activity as compared to all three stan-
dards used against C. neoformans with MIC of
(0.018 mol). Compounds 19c, 19d, 21a, and 21b demonstrated
potent antifungal activity in comparison to nikkomycin with MIC
value of 24–32 g/mL (0.048–0.067 mol) against C. albicans. Com-
8 lg/mL
l
l
l
pounds 19b, 19c, 19g, 21a, and 21f have profound suppressive ef-
fect on yeast-hypha transition, exhibiting >70% inhibition at
concentration 4
ited >80% inhibition of chitin synthase activity comparable to that
of nikkomycin at a concentration 4 g/mL. Comparing the results
lg/mL. Compounds 19d, 19e, 19f, and 21f exhib-
l
34. Spectral data and elemental analysis for 50-deoxy-20,30-O-(methylethylidene)-50-
{4-[(3-methoxyphenoxy)methyl]-1,2,3-triazol-1-yl}uridine (19c): 1H NMR (CDCl3,
200 MHz): d = 9.82 (s, 1H), 7.61 (s, 1H), 7.05 (d, 1H, J = 8 Hz), 6.84 (q, 4H,
J = 8 Hz), 5.17 (d, 1H, J = 8 Hz), 5.50 (s, 1H), 5.12 (s, 2H), 5.03 (dd, 1H, J = 1.6 Hz),
4.98 (m, 1H), 4.67 (br s, 2H), 4.48 (m, 1H), 3.74 (s, 3H), 1.52 (s, 3H), 1.32 (s, 3H).
13C (CDCl3, 50 MHz): 174.9, 163.8, 154.2, 152.3, 150.3, 144.3, 143.4, 125.0,
115.8, 114.7, 102.8, 96.1, 86.2, 84.2, 81.8, 62.6, 55.6, 51.8, 27.0, 25.2, 20.7 ppm.
of all three types of assays, compounds 19a, 19b, 19f, 21c, 21f,
and 21g can be identified as lead chitin synthase inhibitors for fur-
ther modifications to increase their antifungal as well as applica-
tion potential in health care and in agriculture.
MS m/z: (MH+) 472.10; IR (CHCl3)
m: . Anal. Calcd for
1714, 1693 cmꢂ1
Acknowledgments
C22H25N5O7: C, 56.05; H, 5.35; N, 14.85. Found: C, 56.00; H, 5.25; N, 14.55.
35. Spectral data and elemental analysis for 50-{4-[(4-hydroxyphenylacetoxy)methyl)]-
-1,2,3-triazol-1-yl}-50-deoxy-20,30-O-(methylethylidene)uridine (21c): 1H NMR
(CDCl3, 200 MHz): d = 9.88. (s, 1H), 7.41 (s, 1H), 7.05 (d, 1H, J = 8 Hz), 7.01 (d,
1H, J = 6 Hz), 6.73 (d, 2H, J = 6 Hz), 5.07 (d, 1H, J = 8 Hz), 5.47(s, 1H), 5.20 (s,
2H), 5.04 (dd, 1H, J = 1.6 Hz), 4.89 (m, 1H), 4.64 (m, 2H), 4.45 (m, 1H), 3.63 (s,
2H), 1.53 (s, 3H), 1.33 (s, 3H). 13C (CDCl3, 50MHz): 176.2, 168.2, 159.8, 154.2,
147.6, 146.6, 134.2, 129.0, 128.4, 119.3, 118.7, 106.5, 100.0, 90.0, 88.1, 85.7,
Authors are thankful to CSIR, New Delhi, for the financial sup-
port. Ms. P.C. and Mr. F.S. are thankful to CSIR for senior research
fellowship.
Supplementary data
61.5, 55.8, 44.0, 30.7, 28.9 ppm. MS m/z: (MH+) 501.03; IR (CHCl3)
m: 3338,
1683, 1693 cmꢂ1. Anal. Calcd for C23H25N5O8: C, 55.31; H, 5.05; N, 14.02.
Found: C, 55.00; H, 4.99; N, 14.00.
Supplementary data associated with this article can be found, in
36. Spectral data and elemental analysis data for the characterization of compounds
19a, 19b, 19d–19g and 21a, 21b, 21d–21g have been incorporated as
Supplementary data.
References and notes
37. Crystallographic data for 50-{4-[(4-chlorophenoxy)methyl]-1,2,3-triazol-1-yl}-50-
deoxy-20,30-O-(methylethylidene)uridine (19d): The single-crystal diffraction
1. Zhou, L.; Amer, A.; Korn, M.; Burda, R.; Balzarini, J.; Clercq, E. D.; Kern, E. R.;
Torrence, P. F. Antiviral Chem. Chemother. 2005, 16, 375.
2. Kosiova, I.; Kovackova, S.; Kois, P. Tetrahedron 2007, 63, 312.
3. Epple, R.; Kudirka, R.; Greenberg, W. A. J. Comb. Chem. 2003, 5, 292.
4. Akri, K. E.; Bougrin, J.; Faraj, A.; Benhida, R. Bioorg. Med. Chem. Lett. 2007, 17, 6656.
5. Patil, R. S.; Deshpande, A. M.; Natu, A. A.; Nahar, P.; Chitnis, M.; Ghormade, V.;
Laxman, R. S.; Rokade, S.; Deshpande, M. V. J. Biol. Control 2001, 15, 157.
data were collected on
297(2) K. The X-ray generator was operated at 50 kV and 30 mA using
graphite-monochromatized (Mo = 0.71073 Å) radiation. Data were
collected with scan width of 0.3° and with four different settings of
a Bruker AXS Smart Apex CCD diffractometer at
K
a
x
u (0°, 90°, 180° and 270°) keeping the sample-to-detector distance fixed at
6.145 cm and the detector position (2h) fixed at ꢂ28°. C21H22Cl1N5
O6: M = 475.89, crystal dimensions 0.62 ꢁ 0.38 ꢁ 0.19 mm3, T = 297(2) K,