5970
S. A. Carvalho et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5967–5970
T. cruzi. On the other hand, we are able to identify the
interesting profile of 3,4-dihydroxy derivative (5e),
which in spite of the absence of the nitro-heterocyclic
framework was able to kill the trypomastigote forms
of T. cruzi with an IC50 = 63.4lM, indicating clearly
the compensatory effect promoted by introduction of
the arylhydrazone subunit.
9. Maya, J. D.; Bollo, S.; Nunez-Vergara, L. J.; Squella, J.
A.; Repetto, Y.; Morello, A.; Perie, J.; Chauviere, G.
Biochem. Pharmacol. 2003, 65, 999–1006.
0. Nesslany, F.; Brugier, S.; Mouries, M. A.; Le, C. F.;
Marzin, D. Mutat. Res. 2004, 560, 147–158.
1. Poli, P.; Mello, M. A.; Buschini, A.; Mortara, R. A.;
Albuquerque, C. N.; Silva, S.; Rossi, C.; Zucchi, T. M. A.
D. Biochem. Pharmacol. 2002, 64, 1617–1627.
1
1
1
2. Chauvi e` re, G.; Bouteille, B.; Enanga, B.; Albuquerque, C.;
Croft, S. L.; Dumas, M.; P e´ ri e´ J. Med. Chem. 2003, 46,
427–440.
13. Messeder, J. C.; Tinoco, L. W.; Figueroa-Villar, J. D.;
Souza, E. M.; Santa Rita, R.; de Castro, S. L. Bioorg.
Med. Chem. Lett. 1995, 5, 3079–3084.
To acquire preliminary information about the radical
scavenger activity of the 3,4-dihydroxy derivative (4k)
we evaluated by UV spectrometry its effect over stable
DPPH radical. In fact, hydrazone (4k) was able
to inhibit in 91% the UV absorption of DPPH radical
while megazol (2) used as standard inhibited 32%, at
the same molar concentration (0.1mM). This result
indicated that, as anticipated in the design of series
2
3
1
4. Mahy, J. P.; Gaspard, S.; Mansuy, D. Biochemistry 1993,
2, 4014.
3
1
5. Prusis, P.; Dambrova, M.; Andrianov, V.; Rozhkov, E.;
Semenikhina, V.; Piskunova, I.; Ongwae, E.; Lundstedt,
T.; Kalvinsh, I.; Wikberg, J. E. S. J. Med. Chem. 2004, 47,
(
4) and (5), the introduction of arylhydrazone
framework in megazol structure (2) changed its redox
behaviour and could eventually improve its therapeutic
profile and safety.
3
105–3110.
16. Inter alia: (a) Cerecetto, H.; DiMaio, R.; Gonzalez, M.;
Risso, M.; Sagrera, G.; Seoane, G.; Denicola, A.; Peluffo,
G.; Quijano, C.; Stoppani, A. O. M.; Paulino, M.; Olea-
Azar, C.; Basombrio, M. A. Eur. J. Med. Chem. 2000, 35,
As concluding remarks, we discovered the new potent
hydrazone-containing trypanocide prototype (4k),
named brazilizone A, which possibly acts through the
interference in some step of the oxidative metabolism
of trypomastigote T. cruzi forms.
3
43–350; (b) Caffrey, C. R.; Schanz, M.; Nkemgu-Njink-
eng, J.; Brush, M.; Hansell, E.; Cohen, F. E.; Flaherty, T.
M.; McKerrow, J. H.; Steverding, D. Int. J. Antimicrob.
Agents 2002, 19, 227–231; (c) Du, X.; Guo, C.; Hansell, E.;
Doyle, P. S.; Caffrey, C. R.; Holler, T. P.; McKerrow, J.
H.; Cohen, F. E. J. Med. Chem. 2002, 45, 2695–2707; (d)
Aguirre, G.; Cabrera, E.; Cerecetto, H.; DiMaio, R.;
Gonz a´ lez, M.; Seoane, G.; Duffaut, A.; Denicola, A.; Gil,
M. J.; Matinez-Merino, V. Eur. J. Med. Chem. 2004, 39,
Acknowledgements
4
21–431.
Thanks are due to CNPq (BR.) for financial support and
fellowships (to C.A.M.F. and S.L.C.).
1
1
7. (a) Megazol was prepared by reproducing the experimen-
tal conditions described in: Albright, J. D.; Shepherd, R.
G. J. Heterocycl. Chem. 1973, 10, 899–907; (b) Papaioan-
nou, C. G. U.S. Patent 3,682,942, 1972; Chem. Abstr.
1972, 77, 152193.
8. Weiss, M. J.; Remers, W. A.; Gibs, G. J. J. Heterocycl.
Chem. 1969, 6, 835–840.
19. Foroumadi, A.; Daneshtalab, M.; Shafiee, A. Arzneim.-
Forsch. 1999, 49, 1035–1038.
20. Turner, S.; Myers, M.; Gadie, B.; Nelson, A. J.; Pape, R.;
Saville, J. F.; Doxey, J. C.; Berridge, T. L. J. Med. Chem.
1988, 31, 902–906.
21. Todeschini, A. R.; Miranda, A. L. P.; Silva, K. C. M.;
Parrini, S. C.; Barreiro, E. J. Eur. J. Med. Chem. 1998, 33,
189–199.
References and notes
1
. Urbina, J. A.; DoCampo, R. Trends Parasitol. 2003, 25,
95–501.
4
2
. Brener, Z.; Andrade, Z.; Barral-Netto, M. In Trypano-
soma cruzi e Doen c¸ a de Chagas; Guanabara Koogan: Rio
de Janeiro, 1999; 431pp.
3
. Higuchi, M. L.; Benvenuti, L. A.; Reis, M. M.; Metzger,
M. Cardiovasc. Res. 2003, 60, 96–107.
4
. Coura, J. R.; Castro, S. L. Mem. I. Oswaldo Cruz 2002, 97,
3–24.
5
6
. Berkelhammer, G.; Asato, G. Science 1968, 162, 1146.
. Lages-Silva, E.; Filardi, L. S.; Brener, Z. Mem. I. Oswaldo
Cruz 1980, 85, 401.
22. (a) Karabatsos, G.; Graham, J. D.; Vane, F. M. J. Am.
Chem. Soc. 1962, 84, 753–755; (b) Karabatsos, G.;
Shapiro, B. L.; Vane, F. M.; Fleming, J. S.; Ratka, J. S.
J. Am. Chem. Soc. 1963, 85, 2784–2788; (c) Karabatsos,
G.; Vane, F. M.; Taller, R. A.; Hsi, N. J. Am. Chem. Soc.
1964, 86, 3351–3357.
7
8
. Filardi, L. S.; Brener, Z. Ann. Trop. Med. Parasitol. 1982,
76, 293.
. Viod e´ , C.; Bettache, N.; Cenas, N.; Krauth-Siegel, R. L.;
Chauvi e` re, G.; Bakalara, N.; P e´ ri e´ , J. Biochem. Pharmcol.
23. Tait, A.; Ganzerli, S.; Di Bella, M. Tetrahedron 1996, 52,
12587–12596.
1999, 57, 549–557.