J IRAN CHEM SOC
13 hydrophobic interactions between additional methyl
group and Ala169 partially improve potency In comparison
with 14 with bulkier phenyl group, which causes steric
hindrance. 17 in comparison with its relative structure, 16,
demonstrate moderately improvement in inhibition potency
due to additional hydrophobic interaction of methyl group
in para-position and hydrophobic pocket that has been
confirmed by docking studies. The bonding energy of
earlier has been estimated -8.4 kcal mol-1. Finally,
effects of different substituent’s have been studied by
evaluate inhibition power of 15 and 18. Both compounds
have penetrated to the entrance of urease active site from
ring C, but 15 have penetrated more effectively and shows
DG° = -7.02 kcal mol-1 (Table 3). This part could be
more modified by chain groups, which make better diffu-
sion of compound to active site without steric hindrance.
This modification with lower efficiency is illustrate by
evaluating inhibition potency of compound 19 which
shows IC50 = 125 lM. Computational studies raveled that
19 (DG° = -6.65 kcal mol-1) has been oriented trough
active site from alkyl chain. Lower binding affinity of this
compound may due to deleting aromatic ring A in contrast
to 12 and 16. On the other hand, proper orientation of
chlorine in 15 causes hydrophobic interaction with Ala 169
which has been missed in 18.
inhibition among all. The binding pattern of this potential
inhibitor which is localized in active site could help us to
understand its inhibitory activity. Scaffold of b-aryl-b-
mercapto ketone urease inhibitors can be utilized in further
optimization to improve potency and selectivity by varia-
tions in the basic skeleton.
Acknowledgments The financial supports of the Research Council
of the Tehran University of Medical Science, and Deputy of Research
of Chemistry and Chemical Engineering Research Center of Iran are
gratefully acknowledged.
References
1. N.E. Dixon, C. Gazzola, R.L. Blakeley, B. Zerner, J. Am. Chem.
Soc. 97, 413 (1975)
2. P.A. Karplus, M.A. Pearson, R.P. Hausinger, Acc. Chem. Res.
30, 330 (1997)
3. M. Stola, F. Musiani, S. Mangani, P. Turano, N. Safarov, B.
Zambelli, S. Ciurli, Biochem. 45, 6495 (2006)
4. D. Scott, E.A. Marcus, D.L. Weeks, A. Lee, K. Melchers, G.
Sachs, Infect. Immun. 68, 470 (2000)
5. A.N. Somal, K.E. Coley, P.C. Molan, B.M. Hancock, J. Roy. Soc.
Med. 87, 9 (1994)
6. J.K. Xu, C.S. Goodwin, M. Cooper, J. Robinson, J. Infect. Dis.
161, 1302 (1990)
7. K. Nagata, T. Mizuta, Y. Tonokatu, Y. Fukuda, H. Okamura, T.
Hayashi, T. Shimoyama, T. Tamura, Infect. Immun. 60, 4826
(1992)
8. D.H. Shi, Z.L. You, C. Xu, Q. Zhang, H.L. Zhu, Inorg. Chem.
Commun. 10, 404 (2007)
9. Z.L. You, L. Zhang, D.H. Shi, X.L. Wang, X.F. Li, Y.P. Ma,
Inorg. Chem. Commun. 13, 996 (2010)
10. A.A. Bekhit, N.S. Habbib, A. el-Din, A. Bekhit, Boll. Chim.
Farm. 140, 297 (2001)
11. H.K. Hiseh, T.H. Lee, J.P. Wang, J.J. Wang, C.N. Lin, Pharm.
Res. 15, 39 (1998)
12. S.K. Kumar, E. Hager, C. Pettit, H. Gurulingppa, N.E. Davidson,
S.R. Khan, J. Med. Chem. 46, 2813 (2003)
13. S.F. Nielsen, S.B. Christensen, G. Cruciani, A. Kharazmi, T.
Liljefors, J. Med. Chem. 41, 4819 (1998)
In the last series, compounds 20–22 were synthesized.
Each type of substituent in para position of ring B (21 and
22 with IC50 = 135 and 181 lM, respectively) suppress
inhibition effect which has been demonstrated earlier.
However, in 20 with IC50 = 71 lM, hydrophobic interac-
tion of chlorine group with residues stabilize compound
tightly in the site apart of active site. All the interactions
were analyzed by LigandScout 3.03b software and can be
found in supplementary data.
This structure activity study on new scaffold of urease
inhibitors is expected to provide rational information for
the design of new potential inhibitors for urease. The
studies on novel urease inhibitors are essential not only for
the basic research on urease biochemistry, but also for the
possible development of a highly needed therapy for ure-
ase-mediated bacterial infections.
14. S.N. Lopez, M.V. Castelli, S.A. Zacchino, J.N. Dominguez, G.
Lobo, J. Chrris-Charriss, J.C. Cortes, J.C. Ribas, C. Devia, A.M.
Rodriguez, R.D. Enrizz, Bioorg. Med. Chem. 9, 1999 (2001)
15. S. Murakami, M. Muramatsu, H. Aihara, S. Otomo, Biochem.
Pharmacol. 42, 1447 (1991)
16. A.M. Deshpande, N.P. Argade, A.A. Natu, J. Eckman, Bioorg.
Med. Chem. 7, 1237 (1999)
17. S. Khatib, O. Nerya, R. Musa, M. Shmnel, S. Tamir, J. Vaya,
Bioorg. Med. Chem. 13, 433 (2005)
Conclusion
18. F. Severi, S. Benvenuti, L. Costantino, G. Vampa, M. Melegari,
L. Antolini, Eur. J. Med. Chem. 33, 859 (1999)
19. T.A. Nakib, V. Bezjak, S. Rashid, B. Fullam, M.J. Meegan, Eur.
J. Med. Chem. 26, 221 (1991)
20. S. Nencetti, M.R. Mazzoni, G. Ortore, A. Lapucci, J. Giuntini, E.
Orlandini, I. Banti, E. Nuti, A. Lucacchini, G. Giannaccini, A.
Rossello, Eur. J. Med. Chem. 46, 825 (2011)
21. H. Azizian, F. Nabati, A. Sharifi, F. Siavoshi, M. Mahdavi, M.
Amanlou, J. Mol. Model. 18, 2917 (2011)
22. R.S. Varma, V.V. Namboodiri, Chem. Commun. 37, 643 (2001)
23. S. Park, R.J. Kazlauskas, J. Org. Chem. 66, 8395 (2001)
We successfully developed an efficient, economical, and
practical method for the synthesis of a series of b-aryl-b-
mercapto ketone derivatives using inexpensive and readily
available [omim]Cl under mild conditions without any
acidic or basic catalysts. Synthesized compounds were
evaluated for inhibition activity trough urease of jack bean.
All of the compounds showed inhibitory properties through
urease. In this series, compound 3 showed excellent
123