4408
N. Singh et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4404–4408
and glycogen phosphorylase. It was also observed that these 2-
aminopyrimidine derivatives with fused cyclohexyl moiety show
Lucknow, for providing the spectral data. This is CDRI Communica-
tion No. 7862
better
analogues.
In order to gain further insight into the antitubercular action of
a-glucosidase inhibitory activities than their cycloheptyl
Supplementary data
these compounds, molecular docking studies of M. tuberculosis
DHFR (PDB 1DF7) were carried out and docking energies are shown
in Table 1. Interestingly, docking energy obtained through molecu-
lar modeling studies correlate well with the experimentally deter-
Supplementary data associated with this article can be found, in
References and notes
mined MIC values. For instance, compounds 23 (MIC 12.5
lg/mL),
1. Lagoja, I. M. Chem. Biodivers. 2005, 2, 1.
31 (MIC 6.25 g/mL) and 40 (MIC 3.12 g/mL) display good bind-
l
l
2. Ackermann, P.; Stierli, D.; Jung, P. M. J.; Maienfisch, P.; Cederbaum, F. E. M.;
Wenger, J. F. Int. Pat. Appl. WO 03/047347 A1, 2003.
ing affinities with docking energies of À16.665, À15.755 and
21.392 kcal/mol, respectively. Interestingly, the most potent com-
pound 40 has the most favored docking energy and suggested that
compounds with naphthalene ring are likely to exhibit greater
inhibition. This further adds to the confidence level of the present
analysis.
Four top scorer compounds from docking studies, 23, 31, 39 and
40 were further analyzed for their interactions with the protein in
silico. These compounds occupy a long groove, largely lined by
hydrophobic residues, adjacent to the NADP binding site of the pro-
tein (Fig. 3a–d). In addition to making several hydrophobic interac-
tions, compounds utilize their amino head group to interact with
the protein through some hydrogen bonds also (Fig. 3e). Interac-
tions involving Phe31 seem to be particularly important. The resi-
}
3. Bretschneider, T.; Es-Sayed, M.; Fischer, R.; Maurer, F.; Erdelen, C.; Losel, P. Int.
Pat. Appl. WO 02/067684 A1, 2002.
4. Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Nat. Rev. Drug
Discov. 2002, 1, 493.
5. Sehon, C. A.; Lee, D.; Goodman, K. B.; Wang, G. Z.; Viet, A. Q. Int. Pat. Appl. WO
2006/009889 A1, 2006.
6. Goff, D. A.; Harrison, S. D.; Nuss, J. M.; Ring, D. B.; Zhou, X. A. U.S. Pat. 6,417,185
B1, 2002.
7. Kung, Pei-Pei; Casper, M. D.; Cook, K. L.; Wilson-Lingardo, L.; Risen, L. M.;
Vickers, T. A.; Ranken, R.; Blyn, L. B.; Wyatt, J. R.; Cook, P. D.; Ecker, D. J. J. Med.
Chem. 1999, 42, 4705.
8. (a) Fry, D. W.; Garrett, M. D. Curr. Opin. Oncol. Endocr. Met. Invest. Drugs 2000, 2,
40; (b) Garrett, M. D.; Fattaey, A. Curr. Opin. Genet. Dev. 1999, 9, 104.
9. (a) Agarwal, K. C.; Sharma, V.; Shakya, N.; Gupta, S. Bioorg. Med. Chem. Lett.
2009, 19, 5474; (b) Chen, M. J.; Shimada, T.; Moulton, A. D.; Harrison, M.;
Nienhuis, A. W. Proc. Natl. Acad. Sci. U.S.A. 1982, 79, 7435.
10. Argyrou, A.; Vetting, M. W.; Aladegbami, B.; Blanchard, J. S. Nat. Struct. Mol. Biol.
2006, 13, 408.
11. (a) Kumar, A.; Siddiqui, M. I. J. Mol. Graph. Model. 2008, 27, 476; (b) Hawser, S.;
Lociuro, S.; Islam, K. Biochem. Pharmacol. 2006, 71, 941.
due, in most of the cases, is involved in the p–p interactions with
the aromatic ring of the compound. The groove already has been
shown to provide interaction site to methotrexate (MTX), another
known inhibitor for the mycobacterial DHFR.25 The compound 40
simultaneously occupies the NADP binding site and the MTX bind-
ing site (Fig. 3f). This simultaneous utilization, presumably, leads to
the greater in vitro inhibition by the molecule. Although compound
39 shows the comparable docking energy with compounds 32 and
31, it exhibits weaker inhibition in in vitro studies. The reason be-
hind this anomaly becomes evident when the docked structure is
analyzed. The molecule, on account of substitution at second posi-
tion, does not remain in the extended conformation as the com-
pounds with substitution at the first position. Hence the molecule
fails to occupy both the sites simultaneously and results in higher
MIC value. Comparative analysis of docking data and in vitro studies
indicate that the data can be used for the design of novel inhibitors
with high degree of confidence.
12. Jhone, S.; Jucker, E. Birkauser Verlag: Basel 1982, 26, 259.
13. Brown, D. J. The Chemistry of Heterocyclic Compounds; John Wiley and Sons:
New York, 1996.
14. (a) Nichols, G. P. Am. Rev. Tuberc. 1957, 76, 1016; (b) Silwer, H.; Oscarsson, P. N.
Acta Med. Scand. Suppl. 1958, 335, 1; (c) Patel, J. C. Ind. J. Med. Sci. 1989, 43, 177.
15. Edsall, J.; Collins, J.; Gray, J. Am. Rev. Respir. Dis. 1970, 102, 725.
16. (a) Singh, N.; Pandey, J.; Yadav, A.; Chaturvedi, V.; Bhatnagar, S.; Gaikwad, A.
N.; Sinha, S. K.; Kumar, A.; Shukla, P. K.; Tripathi, R. P. Eur. J. Med. Chem. 2009,
44, 1705; (b) Tripathi, R. P.; Pandey, J.; Kukshal, V.; Ajay, A.; Mishra, M.; Dube,
D.; Chopra, D.; Dwivedi, R.; Chaturvedi, V.; Ramchandran, R. Med. Chem.
Chaturvedi, V.; Anand, N.; Misra, M.; Sharma, R.; Kumar, B.; Dwivedi, R.;
Singh, S.; Sinha, S. K.; Gupta, V.; Mishra, P. R.; Dwivedi, A. K.; Tripathi, R. P. Eur.
J. Med. Chem. 2010, 46, 5965; (d) Ajay, A.; Singh, V.; Singh, S.; Pandey, S.;
Gunjan, S.; Dubey, D.; Sinha, S. K.; Singh, B. N.; Chaturvedi, V.; Tripathi, R.;
Ramachandran, R.; Tripathi, R. P. Bioorg. Med. Chem. 2010, 18, 8289.
17. (a) Tewari, N.; Tiwari, V. K.; Mishra, R. C.; Tripathi, R. P.; Srivastava, A. K.;
Ahmad, R.; Srivastava, R.; Srivastava, B. S. Bioorg. Med. Chem. 2003, 11, 2911; (b)
Bisht, S. S.; Fatima, S.; Tamrakar, A. K.; Rahuja, N.; Jaiswal, N.; Srivastva, A. K.;
Tripathi, R. P. Bioorg. Med. Chem. Lett. 2009, 19, 2699.
18. Yu, M.; Pochapsky, S. S.; Snider, B. B. J. Org. Chem. 2008, 73, 9065.
19. (a) Saito, H.; Tomioka, H.; Sato, K.; Emori, M.; Yamane, T.; Yamashita, K.
Antimicrob. Agents Chemother. 1991, 35, 542; (b) McClatchy, J. K. Lab. Med. 1978,
9, 47.
20. Cory, A. H.; Owen, T. C.; Barltrop, J. A.; Cory, J. G. Cancer Commun. 1991, 3, 207.
21. Mosmann, T. J. Immunol. Methods 1983, 65, 55.
22. Skinner, P. S.; Furney, S. K.; Kleinest, D. A.; Orme, I. M. M. Antimicrob. Agents
Chemother. 1995, 39, 750.
23. (a) Cogoli, A.; Mosimann, H.; Vock, C.; Balthazar, A. K. V.; Semenza, G. Eur. J.
Biochem. 1972, 30, 7; (b) Matsui, T.; Yoshimoto, S.; Osajima, K.; Oki, T.; Osajima,
Y. Biosci. Biotech. Biochem. 1996, 60, 2019; (c) Hubscher, G.; West, G. R. Nature
1965, 205, 799.
In conclusion, we have synthesized cycloalkyl fused aminopyr-
imidines with potent antitubercular,
a-glucosidase and glycogen
phosphorylase inhibitory activities. The docking studies with
mycobacterial DHFR show very strong correlation with their
in vitro inhibition results. Thus the synthesized compounds with
dual antitubercular and antidiabetic may offer new prototypes to
develop drugs for diabetic tuberculosis.
Acknowledgments
24. (a) Rall, T. W.; Sutherland, E. W.; Barthet, J. J. Biol. Chem. 1957, 224, 463; (b) Van
Teeffelen, J. W.; Brands, J.; Stroes, E. S.; Vink, H. Trends Cardiovasc. Med. 2007,
17, 101; (c) Nieuwdorp, M. J. Appl. Physiol. 2008, 104, 845.
25. Rongbao, L.; Sirawaraporn, R.; Chitnumsub, P.; Sirawaraporn, W.; Wooden, J.;
Athappilly, F.; Turley, S.; Hol, W. G. J. J. Mol. Biol. 2000, 295, 307.
The authors thank DRDO New Delhi, CSIR New Delhi and DBT
New Delhi, for financial assistance. N.S. and N.A. are thankful to
CSIR New Delhi for SRF and S.K.P. is thankful to CSIR New Delhi
for RA fellowship. The authors sincerely thank SAIF Division, CDRI