Synthesis and antimycobacterial activity of ferrocenyl ethambutol analogues and ferrocenyl diamines

Article abstract of DOI:10.1016/j.bmcl.2005.03.004

A new series of ferrocenyl diamino alcohols and diamines were synthesized and their inhibitory potencies were probed with Mycobacterium tuberculosis. Interestingly, ferrocenyl diamines 6a and b display significant activities against M. tuberculosis H37Rv.

Full text of DOI:10.1016/j.bmcl.2005.03.004

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2301–2303
Synthesis and antimycobacterial activity of ferrocenyl
ethambutol analogues and ferrocenyl diamines
a,b
Dorothee Razafimahefa, Dimby Andrianina Ralambomanana,c,b
´
d
b,
b
d
*
´
Lies Hammouche, Lydie Pelinski, Sylvia Lauvagie, Christiane Bebear,
Jacques Brocardb and Jeanne Maugeind
a
´ ´
Laboratoire de Chimie Appliquee aux Substances Naturelles, Faculte des Sciences d’Antananarivo, B.P. 906, 101
Antananarivo, Madagascar
`
b
´
´
´
Laboratoire de Catalyse de Lille—Groupe de Syntheses Asymetriques et Molecules Therapeutiques, UMR CNRS 8010,
´
ENSCL, Universite des Sciences et Technologie de Lille, B.P. 108, 59652 Villeneuve d’Ascq, France
c
´
Laboratoire de Chimie Organique ‘Substances Marines’, Faculte des Sciences d’Antananarivo,
101 Antananarivo, Madagascar
d
´ ˆ ´ ˆ
Laboratoire de Bacteriologie, CHU de Bordeaux, Hopital du Haut-Leveque, Ave de Magellan, 33 604 Pessac, France
Received 22 December 2004; revised 28 February 2005; accepted 2 March 2005
Abstract—A new series of ferrocenyl diamino alcohols and diamines were synthesized and their inhibitory potencies were probed
with Mycobacterium tuberculosis. Interestingly, ferrocenyl diamines 6a and b display significant activities against M. tuberculosis
H37Rv.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
was developed.9 The presence of ferrocene remarkably
enhanced the antimalarial activity of the synthetic com-
pound.10 Moreover, the stability and the lipophilic
properties of the ferrocenyl moiety are of particular
interest renderingsuch drugs compatible with almost
any other. In continuation of our efforts to show the
ability of ferrocene to enhance biological effect, we be-
came interested in the synthesis of new antimycobacte-
rial ferrocenyl ethambutol analogues. In this paper, we
wish to report on the synthesis of a new series of ferroce-
nyl diamino alcohols and diamines and on the results of
biologic activities against M. tuberculosis H37Rv.
Tuberculosis (TB) an infection of Mycobacterium tuber-
culosis is a contagious disease with high worldwide mor-
tality.1,2 Every year, millions of people die worldwide
because of this epidemic disease and the problem is
amplified by the apparent synergism with HIV.3,4
First-line drugs, with superior efficacy and acceptable
toxicity, used for treatinginfections caused by M. tuber-
culosis include isoniazid, rifampicin, ethambutol, strep-
tomycin and pyrazinamide.
However, the increase of multidrug-resistant (MDR)
strains of M. tuberculosis, indicates the need for new
effective anti-tuberculosis drugs5,6 and for alternative
therapy regimens.7,8
2. Chemistry
The racemic ferrocenyl diamino alcohols 4a–c were syn-
thesized accordingto the reported procedure ( Scheme
1). The dimethylamino group was first replaced by an
acetoxy group by reaction of anhydride acetic on race-
mic 2-N-N-dimethylaminomethyl ferrocene carboxalde-
hyde 111 in 89% yield. The resolution of planar
chirality of compound 1 has not been realized. The
saponification of the ester function of 2 was carried
out in the presence of sodium hydroxide in methanol
Some years ago, a new strategy, based on incorporation
of a ferrocenyl moiety in the side chain of chloroquine,
Keywords: Ethambutol; Ferrocene; diamino alcohols; Diamines; Anti-
tuberculosis activity.
*
Correspondingauthor. Tel.: +33 3 20434893; fax: +33 3 20436585;
e-mail: lydie.pelinski@ensc-lille.fr
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.004

2302
D. Razafimahefa et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2301–2303
CHO
CHO
CHO
(CH3CO)2O
NaOH
MeOH
Fe
Fe
Fe
100°C, 1h
NMe2
OAc
OH
2
1
3
(CH2)n
N
H
N
H
H2N-(CH2)n-NH2
puis NaBH4
Fe
Fe
OH
n = 2
n = 4
n = 6
HO
4a
4b
4c
Scheme 1. Synthesis of ferrocenyl diamino alcohols 4a–c.
to lead to 3 in 89% yield. The ferrocenyl amino alcohols
were then obtained in two steps. First, hydroxy aldehyde
3 was reacted in CH2Cl2 with commercially available
diamine giving the corresponding imines. Then, a reduc-
tion with sodium borohydride in methanol provided the
amino alcohols 4a,b and c in 42%, 66% and 88% overall
yields, respectively. Only one of the enantiomer 4a–c has
been shown in Scheme 1.
(CH2)n
N
H
N
H
CHO
H2N-(CH2)n-NH2
then NaBH4
8a
8b
n = 2
n = 6
7
Scheme 3. Synthesis of diamines 8a and b.
The condensation of diamines with ferrocene carboxal-
dehyde 5 followed by reduction with NaBH4 led to the
ferrocenyl diamines 6a,b,c and d in 76%, 54%, 77%
and 46% global yields, respectively (Scheme 2).
Table 1. Antimycobacterial in vitro activity against Mycobacterium
tuberculosis H37Rv
Compounds
MIC (lg/mL)
Followingthe same procedure while startingfrom benz-
aldehyde 7, the diamines 8a and b were obtained in 69%
and 84% yields, respectively (Scheme 3).
4a
4b
ND
>64
>64
8
4c
6a
6b
6c
8
32
3. Antimycobacterial activity
6d
8a
32
>64
>64
2
The antimycobacterial in vitro activity of ferrocenyl
compounds 4a–c, 6a–d and 8a–b for tuberculosis inhibi-
tion against M. tuberculosis H37Rv strain was carried
out usingthe mycobacteria growth indicator tube sys-
tem (MGIT) at a concentration of 2 lg/mL. The mini-
mum inhibitory concentration (MIC, lg/mL) was
detected by BACTEC 960. The MIC, defined at the low-
est concentration of compound inhibiting90% of the
inoculum relative to controls, are summarized in Table
1.
8b
EBM
Surprisingly, the suppression of the hydroxy group in
the diamines 6a–c involves an increase of the antimyco-
bacterial activity. Particularly, ferrocenyl diamines 6a
and b exhibited excellent inhibitory activity against M.
tuberculosis H37Rv strain and produced MIC value of
8 lg/mL.12 It is observed that increasingthe carbon
chain between both amino groups of the diamines in-
duces a decrease of the antimycobacterial activity (com-
pare 6a and d). In recent studies, Barry III and Coll have
Ferrocenyl diamino alcohols 4b and c appeared to have
low inhibitory antimycobacterial activity against drug-
sensitive M. tuberculosis H37Rv strain.
(CH2)n
CHO
N
H
N
H
H2N-(CH2)n-NH2
Fe
Fe
Fe
then NaBH4
6a
n = 2
n = 3
n = 4
n = 6
5
6b
6c
6d
Scheme 2. Synthesis of ferrocenyl diamines 6a–d.

D. Razafimahefa et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2301–2303
2303
also obtained equal or higher activities from [1,2]-
diamines.13
References and notes
1. Murray, C. J. L.; Styblo, K.; Rouillon, A. In Disease
Control Priorities in Developing Countries; Jamison, D. T.,
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2. World Health Organization, Report On Global Tubercu-
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3. Harries, A. D.; Mahler, D. TB/HIV A Clinical Manual;
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4. Whalen, C.; Horsburgh, C. R.; Hom, D. Am. J. Respir.
Crit. Care Med. 1995, 151, 129.
We can then confirm the importance of the introduction
of the ferrocene in the diamine structure regarding the in
vitro antimycobacterial activity. Indeed, the replace-
ment of the ferrocenyl group with the phenyl group re-
sults in complete loss of the anti-tuberculosis activity
(compare 6a with 8a and 6d with 8b).
4. Conclusion
5. Luna-Herrera, J.; Reddy, M. V.; Gangadharam, P. R. J.
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1997, 40, 319.
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12. The compounds 6a–c were not completely dissolved in
MeOH or DMSO for biological tests.
In the present study we have presented the simple and
efficient synthesis of new ferrocenyl diamino alcohols
and diamines and their promisinganti-tuberculosis
activity against M. tuberculosis H37Rv strain. Further
studies to acquire more information about structure–
activity are in progress in our laboratory.
Acknowledgements
`
The authors are thankful to the ÔMinistere des Affaires
EtrangeresÕ, the ÔCentre National de la Recherche Scien-
tifiqueÕ and the Ôambassade de France a MadagascarÕ for
financial support and Kelly Chibale for helpful
discussions.
`
`
13. Lee, R. E.; Protopopova, M.; Crooks, E.; Slayden, R. A.;
Terrot, M.; Barry, C. E., III. J. Comb. Chem. 2003, 5, 172.