C.R.M. D’Oca et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5255–5257
5257
mide (10c), palmitoylethanolamide (11a), and oleylethanolamide
Acknowledgments
(11c). Regarding the polar moiety (R1) of tested compounds, the low-
er MIC was found when used cyclic amines. The best results, also in
connection with a lipophilic factor, were found when unsaturated
chains were combined with cyclic amines, in special pyrrolidine
and morpholine (compounds 12c, 14c, 12d, 14d, and 12e). The chiral
compounds also demonstrated influence about antituberculosis
activity. In assay with racemic oleylmethylbenzylamide (10c), MIC
The authors thank CNPq (Universal, 478383/04-5) and CAPES
(PROCAD, 229/2007) for financial support and fellowship. We
thank Thomson Mass Spectrometry Laboratory (UNICAMP) by
mass spectral data.
Supplementary data
100 lg/mL was obtained for RMPr and any activity for H37Rv and
INHr. The compound (S)-10c was not active against M. tuberculsis,
but its enantiomer (R)-10c inhibited bacterial growth for RMPr
and INHr in MIC 50 and 12.5 lg/mL, respectively. This fact suggests
Supplementary data associated with this article can be found, in
that, to 10c probably the presence of (S)-enantiomer inhibits the ac-
tion of (R)-enantiomer. For the compounds linoleylmethylbenzyla-
mide (R)- and (S)-10e the lowest MIC were obtained for
(S)-enantiomer. In this case, probably the presence of polyunsatu-
rated chain exerts greater influence over (S)-isomer.
Finally, amides derivates from ricinoleic acid were tested. Ricin-
oleic acid (C18:1, OH) or 12-hydroxy-9-cis-octadecenoic acid is the
major constituent (80–90%) of castor oil (Ricinus comunnis)23 and is
an uncommon fatty acid which contains both a double bond and a
hydroxyl group in chain. Hydroxyl groups are rare in plant oils and
afford these oils some interesting chemical properties. The fatty
acid amides 9d, 10d, 12d, and 14d derived from ricinoleic acid
showed interesting results against tuberculosis strains. The com-
pound ricinoleylpyrrolidilamide, (R,R)-12d, showed the best anti-
References and notes
1. WHO Global Tuberculosis Control Report, 2008.
2. Palomino, J. C.; Martin, A.; Camacho, M.; Guerra, H.; Swings, J.; Portaels, F.
Antimicrob. Agents Chemother. 2002, 46, 2720.
3. Silva, P. E. A.; Aínsa, J. A. Drugs and drug interactions. In Tuberculosis 2007. From
basic science to patient care; Palomino, J. C.; Leão, S. C.; Ritacco, V., Eds.; http://
4. Kochi, A.; Vareldzis, B.; Styblo, K. Res. Microbiol. 1993, 144, 104.
5. Colangeli, R.; Helb, D.; Sridharan, S.; Sun, J.; Basil, M. V.; Hazbon, M. H.;
Harbacheuski, R.; Megjugorac, N. J.; Jacobs, W. R.; Holzenburg, A.; Sacchettini, J.
C.; Alland, D. Mol. Microbiol. 2005, 55, 1829.
6. Rastogi, N.; Goh, K. S. Antimicrob. Agents Chemother. 1990, 34, 2061.
7. Farrell, E. K.; Merkler, D. J. Drug Discovery Today 2008, 13, 558.
8. Khare, S. K.; Kumar, A.; Kuo, T. M. Bioresour. Technol. 2009, 100, 1482.
9. Pacher, P.; Bátkai, S.; Kunos, G. Pharmacol. Rev. 2006, 58, 389.
10. Di Marzo, V. Nat. Rev. Drug Discov. 2008, 7, 438.
11. Micale, V.; Mazzola, C.; Drago, F. Pharmacol. Res. 2007, 56, 382.
12. Pillarisetti, S.; Alexander, C. W.; Khanna, I. Drug Discovery Today 2009, 14, 1098.
13. Burstein, S.; Salmonsen, R. Bioorg. Med. Chem. 2008, 16, 9644.
14. Flygare, J.; Sander, B. Semin. Cancer Biol. 2008, 18, 176.
15. Berdyshev, E.; Boichot, E.; Lagente, V. J. Lipid Mediat. Cell 1996, 15, 49.
16. Driscoll, W.; Chaturvedi, S.; Mueller, G. J. Biol. Chem. 2007, 282, 22353.
17. Wallace, V. C. J.; Segerdahl, A. R.; Lambert, D. M.; Vandevoord, S.; Blackbeard, J.;
Pheby, T.; Hasnie, F.; Rice, A. S. C. Br. J. Pharmacol. 2007, 151, 1117.
18. Aviello, G.; Matias, I.; Capasso, R.; Petrosino, S.; Borrelli, F.; Orlando, P.;
Romano, B.; Capasso, F.; Di Marzo, V.; Izzo, A. J. Mol. Med. 2008, 86, 413.
19. Zhao, J.; Muhammad, J.; Dunbar, D. C.; Mustafa, J.; Khan, I. A. J. Agric. Food Chem.
2005, 53, 690.
tubercular activity, with MIC 12.5 and 6.25
strains.
lg/mL for resistance
Concluding, this study demonstrated for the first time, the fatty
acid amides activity as M. tuberculosis inhibitors. The compound
(R,R)-12d showed the best inhibitory activity, include for M. tubercu-
losis RMPr and INHr strains, presenting a MIC similar to pyrazina-
mide, ethambutol, and ofloxacin.3 Taking into account our
preliminary results on the evaluated families compounds, our ef-
forts are now focused on the understanding of the antimicrobial
activity of fatty acid chains, however, the fact that there were no sig-
nificant differences in antimicrobial activity against strains sensitive
and resistant to permit infer the absence of cross-resistance with rif-
ampicin and isoniazid, which is strongly positive for TB control-
resistant. Efforts are also undertaken towards elaboration of new
fatty acid compounds.
20. Di Marzo, V.; Bisogno, T.; De Petrocellis, L.; Melck, D.; Martin, B. R. Curr. Med.
Chem. 1999, 6, 721.
21. Boger, D. L.; Patterson, J. E.; Guan, X.; Cravatt, B. F.; Lerner, R. A.; Gilula, N. B.
Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 4810.
22. Lopes, C. R.; D’Oca, C. R. M.; Duarte, R. C.; Kurz, M. H. S.; Primel, E. G.;
Clementin, R. M.; Vilarreyes, J. A.; D’Oca, M. G. M.; Quim. Nova, in press.
23. Lakshminarayana, G.; Paulose, M. M.; Kumari, N. B. J. Am. Oil Chem. Soc. 1984,
61, 1871.