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;
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.004