T. Moreira Osório et al. / Bioorg. Med. Chem. Lett. 22 (2012) 225–230
229
droxy-30-prenyl-chalcone), 30 (2,20,40-trihydroxy-chalcone) and
31 (20,4,40,60-tetrahydroxy-dihydrochalcone). These three anti-
MRSA compounds have in common a hydroxyl group at positions
20,40 and 4. In addition to the hydroxyl substituents, the bioactive
chalcone 14 also has a prenyl substituent at position 30. The antimi-
crobial activity of natural compounds structurally related to this
chalcone has been previously described; for erypostyrene minimal
cones increases their cytotoxic effect; dihydrochalcone 31 contains
four hydroxyl groups, and is the most toxic compound among
those tested in this study. This indicates that hydrazones may be
more promising than chalcones in terms of their future potential
as antibacterial drugs.
In summary, the genotypic characterization of the MRSA iso-
lates revealed that the mecA gene was found in 12 of the 14 iso-
lates, and the randomly amplified polymorphic DNA (RAPD)
reaction allowed the discrimination of nosocomial bacteria from
community isolates. The tested compounds can be distributed into
three categories related to the spectrum of activity: compounds
inactive against S. aureus, compounds active against sensitive S.
aureus and compounds active against methicillin-resistant isolates.
Chalcones 14 and 30, dihydrochalcone 31 and hydrazones 52 and
53 were the compounds which were most active against MRSA iso-
lates, and hydrazones showed the best selectivity indices. From the
65 tested compounds, 52 and 53 are potentially promising as anti-
biotic-like substances, and microbiological studies to better evalu-
ate them should be continued.
inhibitory concentration (MIC) values of 50
in relation to Candida albicans and MRSA, respectively, and for ang-
olensin an MIC of 50 g/mL in relation to MRSA have been re-
lg/mL and 6.25 lg/mL
l
ported.32 Chalcones 21 and 22, despite having hydroxyl groups in
the same positions of the active compounds 14, 30 and 31, have
a geranyl substituent at position 30, which interfere with their ac-
tion against MRSA strains probably due to their considerable size.
Of the three chalcones which were active against the MRSA iso-
lates, dihydrochalcone 31 was the least active, possibly due to a
loss of rigidity of the molecule, resulting in a difficulty in maintain-
ing the conformation required for interaction with the biological
target.
The presence of the hydroxyl group at position 20 is important
due to its intramolecular interaction with the carbonyl group,
and the hydroxyl group at position 40 activates the region that in-
Acknowledgments
cludes the neighboring hydroxyl group at 20 and the
a
,b-unsatu-
This work was supported by FAPESC (Fundação de Apoio à Pes-
quisa Científica e Tecnológica do Estado de Santa Catarina), CAPES
(Coordenação de Aperfeiçoamento de Pessoal de Nível Superior)
and CNPq (Conselho Nacional de Desenvolvimento Científico e Tec-
nológico). The authors would like to thank the University Hospital
of the Federal University of Santa Catarina and Santa Luzia Labora-
tory for donation of the MRSA isolates, and the Chemistry Depart-
ment of the Federal University of Santa Catarina for access to
equipment for the chemical characterization.
rated carbonyl group.33 Nielsen and col. assayed licochalcone
A analogues against S. aureus and concluded that the presence of
hydroxyl group at 40 position is important to antibacterial activ-
ity.34 This may be the reason for the low activity of dihydrochal-
cone 28 against the MSSA strain and absence of activity against
the MRSA isolates, since it lacks the hydroxyl groups in these posi-
tions, as well as the double bond.
Chalcone 18 showed very good antimicrobial activity against
the MSSA strain, but surprisingly was inactive against the MRSA
isolates; the only difference between 18 and 14 is the presence
of a methoxyl group instead of hydroxyl group at position 40. How-
ever, erypostirene, active compound against MRSA in a previous
work,32 also has a methoxy group at position 40.
Supplementary data
Supplementary data associated with this article can be found, in
All compounds that showed a bacteriostatic effect on the MRSA
isolates were also evaluated in terms of their lytic activity. The MIC
values were the same as those obtained for the minimum bacteri-
cidal concentration (MBC).13,35 The cytotoxicity of the five active
compounds against the MRSA isolates (14, 30, 31, 52 and 53), at
References and notes
1. Walsh, C. Antibiotics: actions origins resistance; SM Press: Washington, 2003.
2. Maranan, M. C.; Moreira, B.; Boyle-Vavra, S.; Daum, R. S. Infect Dis. Clin. North
Am. 1997, 11, 813.
3. (a) Vivone, A. M.; Moreira, B. M. Memórias do Instituto Oswaldo Cruz 2005, 100,
693; (b) Chambers, H. F.; Deleo, F. R. Nature Rev. 2009, 7, 629.
4. Oliveira, D. C.; Tomasz, A.; de Lencastre, H. Lancet Infect. Dis. 2002, 2, 180.
5. Velázquez-Meza, M. E. Salud Pública de México 2005, 47, 381.
6. (a) Wise, R. J. Antim. Chemotherapy 2003, 51, ii5; (b) Veronesi, R.; Focaccia, R.
Tratado de Infectologia, 2nd ed.; Atheneu: São Paulo, 2004; (c) Moreillon, P. Clin.
Microbiol. Infect. 2008, 14, 32.
7. Dewick, P. M. Medicinal Natural Products: A Biosinthetic Approach; John Wiley &
Sons: Cichestes, 1997. Chapter 4.
8. (a) Won, S. J.; Liu, C. T. Eur. J. Med. Chem. 2005, 40, 103; (b) Nowakowska, Z. A.
Eur. J. Med. Chem. 2007, 42, 125; (c) Ni, L.; Meng, C. Q.; Sikorski, J. A. Expert Opin.
Ther. Pat. 2004, 14, 1669.
concentrations equal to or less than 500 lg/mL, was evaluated
against VERO cells using the MTT method.36 The results are shown
in Table 3 and from these values it was possible to calculate the
selectivity index (SI), to assess whether the compounds are toxic
at the minimal inhibitory concentration. A high IS value indicates
low toxicity of the compound. Thus, based on the IS indices ob-
tained, it is possible to suggest that the hydrazones studied are
clinically safer than chalcones and dihydrochalcone. This result is
in agreement with the findings of Dimmock et al.,37 who reported
that the presence of hydroxyl groups in the structure of the chal-
9. Okada, K.; Takamura, Y.; Yamamoto, M.; Inoue, Y.; Takagaki, R.; Takahashi, K.;
Demizu, S.; Kajiyama, K.; Hiraga, Y.; Kinoshita, T. Chem. Pharm. Bull. 1989, 37,
2528.
10. (a) Rollas, S.; Küçükgüzel, S. G. Molecules 2007, 12, 1910; (b) Borchhardt, D. M.;
Mascarello, A.; Chiaradia, L. D.; Nunes, R. J.; Oliva, G.; Yunes, R. A.; Andricopulo,
A. D. J. Braz. Chem. Soc. 2010, 21, 142.
11. Jin, L.; Chen, J.; Song, B.; Chen, Z.; Yang, S.; Li, Q.; Hu, D.; Xu, R. Bioorg. Med.
Chem. 2006, 16, 5036.
Table 3
Cytotoxicity of chalcones and hydrazones toward VERO cells
Compounds
VERO cells CC50
(
l
g/mL SD)
IC50 (lg/mL)
ISc
a
b
14
30
31
52
53
726.82 14.63
463.65 53.00
735.47 68.83
488.71 67.13
856.71 15.13
31.25
31.25
125.00
7.81
23.25
14.80
5.90
62.60
109.70
12. Grinholc, M.; Kawiak, A.; Kurlenda, J.; Graczyk, A.; Bielawski, K. P. Acta Biochim.
Pol. 2008, 55, 85.
13. Ávila, H. P.; Smânia, E. F. A.; Delle Monache, F.; Smânia Júnior, A. Bioorg. Med.
Chem. 2008, 16, 9790.
14. Chiaradia, L. D.; dos Santos, R.; Vitor, C. E.; Vieira, A. A.; Leal, P. C.; Nunes, R. J.;
Calixto, J. B.; Yunes, R. A. Bioorg. Med. Chem. 2008, 16, 658.
15. Tsai, S.; Klinmam, J. P. Bioorg. Chem. 2003, 31, 172.
7.81
a
Average of three independent assays standard deviation; statistical test was
16. Högberg, T.; Bengtsson, S.; Paulis, T. De.; Johansson, L.; Ström, P.; Hall, H.;
Ögren, S. O. J. Med. Chem. 1990, 33, 1155.
17. Pérez-Melero, C.; Maya, A. B. S.; del Rey, B.; Peláez, R.; Caballero, E.; Medarde,
M. Bioorg. Med. Chem. Lett. 2004, 14, 3771.
conducted to assess the significance of the results, with p = 0.05, all results were
significant.
b
IC50 = concentration that showed 50% cellular cytotoxic effect.
c
IS = CC50/IC50
.
Moreira Osório, Thaís
