Synthesis and antitubercular activity of ferrocenyl diaminoalcohols and diamines

Article abstract of DOI:10.1016/j.bmc.2008.09.030

A total of 21 ferrocenyl and benzyl diaminoalcohols and diamines were synthesized and evaluated against Mycobacterium tuberculosis H37Rv. Interestingly, ferrocenyl diamines exhibit better activities than ferrocenyl diaminoalcohols.

Full text of DOI:10.1016/j.bmc.2008.09.030

Bioorganic & Medicinal Chemistry 16 (2008) 9546–9553
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and antitubercular activity of ferrocenyl diaminoalcohols
and diamines
a
b
a
Dimby Andrianina Ralambomanana , Dorothée Razafimahefa-Ramilison , Andry Clément Rakotohova ,
Jeanne Maugein , Lydie Pélinski
a
c
a,
*
Université des Sciences et Technologie de Lille, Unité de Catalyse et de Chimie du Solide, UMR CNRS 8181, ENSCL, B.P. 108, 59652 Villeneuve d’Ascq, France
Université d’Antananarivo, Faculté des Sciences, Laboratoire de Chimie Appliquée aux Substances Naturelles, BP 906, Antananarivo 101, Madagascar
CHU de Bordeaux, Laboratoire de Bactériologie, Hôpital du Haut-Lévêque, Ave de Magellan, 33 604 Pessac, France
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 May 2008
Revised 8 September 2008
Accepted 10 September 2008
Available online 13 September 2008
A total of 21 ferrocenyl and benzyl diaminoalcohols and diamines were synthesized and evaluated
against Mycobacterium tuberculosis H37Rv. Interestingly, ferrocenyl diamines exhibit better activities
than ferrocenyl diaminoalcohols.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Ferrocene
Ethambutol
Mycobacterium tuberculosis
Diamine
1
. Introduction
Tuberculosis (TB), an infectious disease caused by Mycobac-
cause its very low toxicity and its chemical simplicity.5 Studies
concerning the structural modification of EMB have focused on
the diamine or diaminoalcohol analogues with enhanced efficiency
6
–11
terium tuberculosis, still remains the leading cause of world-
wide death among infectious diseases.1 Two billion people
are infected with latent TB and are at risk for developing the
active disease, and annually, approximately eight million of
these infected people develop active TB more. TB kills nearly
two million people over the world every year. Even though
improved methods of prevention, detection, diagnosis and
treatment have greatly reduced the number of people who
contract the disease and unfortunately die from it, the emer-
gence of multidrug-resistant (MDR) strains and the global hu-
man immunodeficiency virus (HIV) pandemic have amplified
the incidence of TB. Currently, TB chemotherapy is composed
by a cocktail of the first-line drugs, isoniazid (INH), rifampin
compared to EMB.
Among diamines, compounds SQ 109, SQ
775 and SQ 786 (Fig. 1) exhibit enhanced activities in comparison
7
,8
to EMB.
The use of metal complexes capable of enhancing the activ-
ity of biological compounds has become a relevant strategy of
research in both communities of organometallic chemists and
1
2
biologists. Ferroquine (SSR97193), resulting from the incorpo-
ration of a metallocenic moiety into chloroquine, proved to be
a
new effective drug with
a
powerful antimalarial activity
1
3,14
in vitro and in vivo.
In particular, the high lipophilicity
and electrochemical behaviour (redox potential of the ferro-
cene/ferrocinium couple, = +0.400V vs saturated calomel
electrode) of ferrocene render it very attractive for designing
E
0
1
5
(
RIF), pyrazinamide (PZA) and ethambutol (EMB), given for
antimalarial drugs. This strategy, which consists of incorpo-
rate a ferrocenyl moiety into a ‘standard’ drug offers new pos-
sibilities in therapeutic applications and reversal of drug
six months. The increasing problem of MDR-TB has focused
attention on developing new drugs that are not only active
against drug resistant TB, but also shorten the lengthy therapy.
Consequently, there is urgent need and significant interest in
developing new TB drugs.2
1
6–18
resistances.
In a preliminary communication, we reported the synthesis of
ferrocenyl diamines and the evaluation of their antitubercular
–4
1
9
Despite its modest efficiency against M. tuberculosis, ethambu-
tol (EMB) (Fig. 1) is still a first-line drug used against TB in part be-
activity. Herein we describe the full details of our investigations.
A strategy based on the modification of ethambutol is presented
here: insertion of ferrocene between the two amine functions,
insertion of ferrocene between alcohol and amine, replacement
of alcohol by ferrocene: synthesis of diamines (Fig. 2).
*
Corresponding author. Tel.: +33 3 20434893; fax: +33 3 20436585.
E-mail address: Lydie.Pelinske@ensc-lille.fr (L. Pélinski).
0
968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.09.030

D. Andrianina Ralambomanana et al. / Bioorg. Med. Chem. 16 (2008) 9546–9553
9547
OH
dimethylaminomethylferrocenecarbox-aldehyde 1 was first re-
acted with acetic anhydride to give 2 in 89% yield. The saponifica-
tion of ester 2 was carried out in the presence of sodium hydroxide
H
N
20
in methanol providing 3 in 89% yield after work-up.
N
H
The ferrocenyl amino alcohols were then obtained in two steps.
2 2
First, the hydroxy aldehyde 3 was reacted in CH Cl with commer-
Ethambutol
OH
cially available diamines giving the corresponding imines. Then, a
reduction with sodium borohydride in methanol provided the ami-
no alcohols 4, 5 and 6 in 42%, 66% and 88% overall yields, respec-
tively. Compounds 4–6 were obtained as mixtures of
diastereomers. To simplify, only the meso form of 4–6 has been
H
N
N
H
represented on Scheme 1.
SQ 109
0
Ferrocene-1,1 -dicarboxaldehyde 7 was reacted in CH
2
Cl
2
with
commercially available (R)-(ꢀ) and (S)-(+) 2-amino-1-butanol in
the presence of molecular sieves providing the corresponding imi-
nes. Then, a reduction of the crude reaction mixtures with sodium
borohydride in methanol provided respectively the amino alcohols
8
and 9 in 76–85% overall yields after work-up (Scheme 2). Follow-
N
N
ing the same procedure from ferrocene-1,2-dicarboxaldehyde 10,
the amino alcohols 11 and 12 were obtained in 70–88% overall
yields (Scheme 3).
SQ 775
2
.2. Synthesis of ferrocenyl and benzyl diamines
To increase the structural diversity of EMB analogues and to as-
N
N
sess the influence of a modified linker on the activity of structurally
diverse diamines against M. tuberculosis, we prepared derivatives
incorporating a series of ferrocenyl and alkyl substituents in the
spacer between the two amino alcohol residues.
SQ 786
The condensation of diamines with ferrocene carboxaldehyde,
0
OBn
ferrocene-1,1 -dicarboxaldehyde 7, ferrocene-1,2-dicarboxalde-
hyde 10 or benzaldehyde in methanol followed by reduction with
Figure 1. Structure of ethambutol (EMB) and three analogues.
NaBH
4
led to the ferrocenyl diamines 13–23 or benzyl diamines
2
1–23
2
4–26 in 25–84% global yields (Table 1).
Intercalation
Replaced
OH
of ferrocene
by ferrocene
H
N
R1
R2
N
H
Replaced
by ferrocene
R1
R2
R2
OH
OH
CHO H N
2
OH
Ethambutol
OH
N
Fe
CH Cl
2
2
Fe
H
H
N
Figure 2. Chemical modifications of EMB.
CHO
then NaBH4
MeOH
2
2
. Results and discussion
R1
.1. Synthesis of ferrocenyl amino alcohols
7
R1 = H, R2 = Et
R1 = Et, R2 = H
8
9
The racemic ferrocenyl diamino alcohols 4–6 were synthesized
according to the reported procedure (Scheme 1). Racemic 2-N,N-
Scheme 2. Synthesis of ferrocenyl-1,1’-diaminoalcohols.
CHO
CHO
OAc
CHO
(
H CCO) O
NaOH
3
2
Fe
NMe2
Fe
Fe
OH
1
00 ºC, 1h
MeOH
1
2
3
(CH2)n
N
N
H
H
H2N-(CH2)n-NH2, EtOH
then NaBH , MeOH
Fe
OH
HO
Fe
4
n = 2
n = 4
n = 6
4
5
6
Scheme 1. Synthesis of ferrocenyl diamino alcohols 4–6.

9
548
D. Andrianina Ralambomanana et al. / Bioorg. Med. Chem. 16 (2008) 9546–9553
R1
R2
Tertiary diamine 27 was obtained by reductive N-methylation
of 13 in the presence of formaldehyde and NaBH CN (Scheme 4)
3
in 16% yield after purification.
R1
R2
OH
CHO
N
H H
N
H2N
OH
Fe
CHO
Fe
OH
2.3. Biological activity
then NaBH4
R1
R2
The in vitro antimycobacterial activity of ferrocenyl diaminoal-
cohols and diamines for tuberculosis inhibition against M. tuber-
culosis H37Rv strain was carried out using the Mycobacteria
1
0
R1 = H, R2 = Et
R1 = Et, R2 = H
11
12
Growth Indicator Tube system (MGIT) at a concentration of 2 lg/
Scheme 3. Synthesis of ferrocenyl-1,2-diaminoalcohols.
mL. The minimum inhibitory concentration (MIC,
l
g/mL) was de-
Table 1
Structure and yields of ferrocenyl (Fc = ferrocene) and benzyldiamines
Compound
Aldehyde
Amine or diamine
Ferrocenyl or benzyl diamine
Yield (%)
76
(CH2)2
1
3
FcCHO
H
2
2 2
N(CH ) NH
2
FcCH2
N
H
N
H
CH Fc
2
(
CH2)3
CH2)4
CH2)6
1
1
1
4
5
6
FcCHO
FcCHO
FcCHO
H
2
H
2
H
2
N(CH
N(CH
N(CH
2 3
) NH
2 4
) NH
2 6
) NH
2
2
2
FcCH2
FcCH2
FcCH2
N
H
N
CH Fc
54
77
46
2
H
(
(
N
H
N
CH Fc
2
H
N
H
N
H
CH Fc
2
Me
Me
1
7
FcCHO
25
H N
2
NH2
FcCH2 NH
HN CH2Fc
1
1
2
2
8
9
0
1
FcCHO
FcCHO
FcCHO
FcCHO
H2N
H2N
NH2
FcCH2
N
H
N
H
CH2Fc
77
41
48
62
Me
Me
Me
Me
NH2
NHCH2Fc
FcCH2HN
H N
FcCH HN
2
2
H2N
FcCH2HN
NH
NCH2Fc
HN
FcCH2N
CHO
i
NH Pro
i
2
2
2
3
Fe
Fe
H
2
N Pro
Fe
48
72
i
NH Pro
CHO
CHO
i
NH Pro
i
i
CHO
H
2
N Pro
Fe
NH Pro
(
CH2)2
2
2
4
5
PhCHO
PhCHO
H
2
2
N(CH
2
)
2
NH
NH
2
2
PhCH2
PhCH2
N
N
H
CH Ph
69
84
2
H
(
CH2)6
H
N(CH
2
)
6
N
H
N
H
CH Ph
2
Me
Me
2
6
PhCHO
67
H N
NH2
PhCH2 NH
HN CH2Ph
2

D. Andrianina Ralambomanana et al. / Bioorg. Med. Chem. 16 (2008) 9546–9553
9549
N
H
N
H
HCHO
NaBH CN
N
N
Me
Me
Fe
Fe
Fe
Fe
3
1
4
27
Scheme 4. Synthesis of tertiary diamine.
tected by BACTEC 960. The MIC, defined at the lowest concentra-
tion of compound inhibiting 90% of the inoculum relative controls,
is summarized in Table 2.
4. Experimental
4.1. General methods
It appeared that compounds with ferrocenyl groups 13 and 14
having only two or three carbon atoms spacer between the two
amino functions are more active than the analogue 24 with two
phenyl groups. This proves the beneficial effect of the presence of
ferrocenyl residue on EMB analogues. We observed also that the
substitution of the spacer in 17 or the amine in 27 affects the activ-
ities of these analogues of compound 13.
It would have been interesting to compare the activity of the ferr-
ocenyl piperazine 21 with SQ786 (Fig. 1). Unfortunately, the low sol-
ubility of 21 did not allow the evaluation of the biological activity.
A weak activity was obtained in the presence of cyclohexyl as
the spacer between the two amines in 19 and 20.
The H and 13C NMR spectra were recorded on a Bruker AC300
spectrometer using tetramethylsilane (TMS) as the internal stan-
dard and CDCl , MeOH-d or DMSO-d as the solvents. MS-MALDI
1
3
4
6
TOF spectra were obtained using a Vision 2000 time-of-flight
instrument (Finnigan MAT, Bremen, Germany) equipped with a
nitrogen laser operating at wavelength of 337 nm. The matrix used
was trihydroxyacetophenone (thap). Thin layer chromatography
(TLC) was carried out on aluminium-baked Macherey-Nagel silica
gel 60. Column chromatography was performed on silica gel (35–
70 mesh). Melting points were determined on a Kofler apparatus
and are uncorrected.
No antimycobacterial activity was observed when the ferrocene
was placed between the two amines (compounds 22 and 23).
Moreover, it appears that the presence of the hydroxymethyl group
in ferrocenyl diaminoalcohols 6, 8–9 and 11–12 inhibited the bio-
logical activity (MIC > 64).
4.2. 2-(Acetoxymethylferrocene)carboxaldehyde 2
A mixture of 2-(N,N-dimethylaminomethylferrocene) carboxal-
dehyde 1 (206 mg, 0.75 mmol) and acetic anhydride (2.5 mmol)
was stirred at 100 °C for 10 h. The solution was allowed to room
3
. Conclusion
2 2
temperature. After addition of CH Cl (10 mL), the organic layer
was washed by aqueous solution of sodium hydroxide (0.5 N).
The solvent was evaporated from the filtrate under reduced pres-
sure. After purification by column chromatography (eluent: ethyl
In conclusion we have synthesized and evaluated a series of
ferrocenyl diamines and diaminoalcohols as inhibitors of M. tuber-
culosis H37Rv. This study has revealed that the presence of a ferr-
ocenyl moiety in the structure of diamines is essential for a good
antimycobacterial activity. The best activity was obtained for ferr-
ocenyl diamines having only a two or three carbon atoms spacer
between the two amino functions. Other studies are currently
underway in our laboratories to better understand the importance
of the presence of a ferrocenyl unit on TB drugs.
2
0 1
acetate), the ester 2 is obtained as a red oil (89%). H NMR (CDCl
d 10.05 (s, 1H, CHO), 5.17 (m, 2H, CH O), 4.79 (m, 1H, Cp), 4.68 (m,
1H, Cp), 4.57 (m, 1H, Cp), 4.26 (s, 5H, Cp ), 2.04 (s, 3H, CH
NMR (CDCl ) d 193.3, 170.8, 83.4, 77.6, 75.4, 72.3, 71.6, 70.2,
3
)
2
0
13
3
).
C
3
+
+
+
60.6, 20.9. MS (m/z): 325 (M +K), 309 (M +Na), 286 (M ).
4.3. 2-(Hydroxymethylferrocene)carboxaldehyde 3
A
mixture of 2-(acetoxymethylferrocene)carboxaldehyde
(136 mg, 0.475 mmol) and sodium hydroxide 1 N (6 mL) in MeOH
14 mL) was stirred at room temperature. After 1 h, the solvent is
2
Table 2
Antimycobacterial in vitro activity against Mycobacterium tuberculosis H37Rv
(
Compound
MIC H37Rv (lg/mL)
NDa
32
>64
>64
>64
>64
>64
8
8
32
32
16
evaporated under reduced pressure. Dichloromethane (20 mL)
was added to the residue. The organic mixture was washed by
4
5
6
8
9
water and the organic layer was dried over Na
tion under reduced pressure, the oil was purified by column chro-
matography (eluent: CH Cl /MeOH: 15–1) to give 3 as red crystals
89%). Mp 92 °C. H NMR (CDCl ) d 9.92 (s, 1H, CHO), 4.70 (d, 1H,
Cp, J = 2.7 Hz), 4.67 (m, 1H, Cp), 4.53 (m, 2H, CH O), 4.47 (m, 1H,
) d 196.2, 90.5, 74.9, 73.3,
2 4
SO . After evapora-
2
2
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
20
1
(
3
2
0
13
Cp), 4.32 (s, 5H, Cp ). C NMR (CDCl
3
+
+
+
71.7, 70.3, 59.4. MS (m/z): 283 (M +K), 267 (M +Na), 244 (M ).
4
.4. General procedure for the synthesis of ferrocenyl amino
alcohols 4–6
64
64
32
ND
64
A mixture of 2-(hydroxymethylferrocene)carboxaldehyde 3
810 mg, 3.32 mmol) and the appropriate diamine (1.6 mmol) in
(
64
anhydrous ethanol (50 mL) containing molecular sieves (4 A, 5 g)
was stirred at room temperature. After 6 h, the mixture was fil-
tered through Celite 545. The solvent was evaporated from the fil-
trate under reduced pressure. The residue was dissolved in MeOH
30 mL) and NaBH
The mixture was stirred at room temperature for 1 h, hydrolysed
by addition of a saturated solution of NH Cl (50 mL) and extracted
>64
>64
>64
64
EBM
2
(
4
(20 mg, 0.5 mmol) was added in small portions.
a
ND, not determinated. Compounds 4 and 21 were not completely dissolved in
MeOH and DMSO.
4

9
550
D. Andrianina Ralambomanana et al. / Bioorg. Med. Chem. 16 (2008) 9546–9553
with CH
2
Cl
2
(3 ꢁ 30 mL). An aqueous solution of HCl (1 N, 40 mL)
4
dissolved in MeOH (30 mL) and NaBH (0.15 g, 4.2 mmol) was
added in small portions. The mixture was stirred at room temper-
ature for 1 h, hydrolysed by addition of a saturated solution of
was added to the organic layer. The mixture was extracted by
diethyl ether (3 ꢁ 100 mL). Sodium carbonate was then added to
the aqueous layer until neutralisation. The product was then ex-
tracted by CH
sodium sulfate before removing the solvent under reduced pres-
sure. The oil was purified by column chromatography (CH Cl
MeOH/Et N = 88:2:10).
NH
4
Cl (50 mL) and extracted with CH
2
Cl
2
(3 ꢁ 30 mL). The solvent
2
Cl
2
(3 ꢁ 100 mL). The organic layer was dried over
was removed from the combined organic layers and the residue
purified by column chromatography (petroleum ether/diethyl
ether/triethyl-amine = 80:10:10).
2
2
/
3
0
4
.9. (R,R)-Bis [N-2-(1-hydroxy)butyl]-1,1 -ferrocenylmethyl
4
.5. 1,2-Bis[2-(hydroxymethyl)ferrocenylmethylamino]ethane 4
diamine 8
0
Following the general procedure starting from 2-(hydroxym-
Following the general procedure starting from ferrocene-1,1 -
ethylferrocene)carboxaldehyde 3 (810 mg, 3.32 mmol) and 1,2-
ethylenediamine (99.5 mg, 1.66 mmol), 1,2-bis[2-(hydroxy-
dicarboxaldehyde 7 (200 mg, 0.83 mmol) and (R)-(ꢀ)-2-amino-1-
0
butanol (221 mg, 2.5 mmol), (R,R)-bis[N-2-(1-hydroxy)butyl]-1,1 -
methyl)ferrocenylmethylamino]ethane 4 was obtained as yellow
ferrocenylmethyldiamine 8 was obtained as yellow oil (273 mg,
1
2
1
crystals (360 mg, 42%). Mp 90 °C. H NMR (CDCl
3
) d 4.62 (d, 2H,
O,
J = 12.2 Hz), 4.07 (m, 2H, Cp), 4.04 (s, 10H, Cp ), 3.99 (m, 2H, Cp),
85%). ½
a
ꢂ 0 ꢀ6 (c 0.36, CHCl
3
). H NMR (CDCl
3
) d 4.23 (m, 2H,
N,
N, 11,0 Hz), 3.29
O), 2.63 (m, 2H, CH), 1.52 (m, 2H, CH ), 1.36 (m, 2H,
) d 87.9, 68.6,
68.2, 68.1, 67.9, 62.9, 60.7, 45.7, 24.0, 10.5. MS (m/z): 427
D
CH
2
O, J = 12.2 Hz), 4.15 (m, 2H, Cp), 4.15 (d, 2H, CH
2
Cp), 4.14 (m, 2H, Cp), 4.10 (m, 4H, Cp), 3.68 (d, 2H, CH
2
0
J = 11.0 Hz), 3.51 (m, 2H, CH
(m, 2H, CH
3 3
CH ), 0.91 (t, 6H, CH , J = 7.5 Hz). C NMR (CDCl
2 2
O), 3.36 (d, 2H, CH
3
2
6
5
.78 (d, 2H, FcCH
2
, J = 12.5 Hz), 3.36 (d, 2H, FcCH
2
, J = 12.5 Hz),
2
2
1
3
13
.65 (s, 4H, CH
2
N). C NMR (CDCl
3
) d 87.1, 84.9, 70.3, 69.7, 68.8,
2
+
+
5.8, 59.6, 48.6, 47.7. MS (m/z): 555 (M+K) , 541, 539 (M+Na) ,
+
+
+
+
27, 517 (MH) . Anal. Calcd for C26
H32Fe
2
N
2
O
2
: C, 60.49; H, 6.25;
(M +K), 411 (M +Na), 389 (MH ). Anal. Calcd for C20
H
32FeN
2
O
2
:
N, 5.43. Found: C, 60.82; H, 6.36; N, 5.62.
C, 61.86; H, 8.31; N, 7.21. Found: C, 61.42; H, 8.03; N, 7.34.
0
4
.6. 1,2-Bis[2-(hydroxymethyl)ferrocenylmethylamino]butane 5
4.10. (S,S)-Bis [N-2-(1-hydroxy)butyl]-1,1 -ferrocenylmethyl
diamine 9
Following the general procedure starting from 2-(hydroxym-
ethylferrocene)carboxaldehyde 3 (800 mg, 3.28 mmol) and 1,4-
diaminobutane (131 mg, 1.49 mmol), 1,2-bis[2-(hydroxy-
0
Following the general procedure starting from ferrocene-1,1 -
dicarboxaldehyde 7 (150 mg, 0.62 mmol) and (S)-(+)-2-amino-1-
0
methyl)ferrocenylmethylamino]butane 5 was obtained as yellow
butanol (154 mg, 1.7 mmol), (S,S)-bis[N-2-(1-hydroxy)butyl]-1,1 -
crystals (535 mg, 66%). Mp decomposition before fusion. 1H NMR
ferrocenylmethyldiamine 9 was obtained as yellow oil (182 mg,
2
(
CDCl
3
) d 4.68 (d, 2H, CH
2
O, J = 12.4 Hz), 4.18 (d, 2H, CH
2
O,
76%). ½
a
ꢂ 0 6 (c 0.36, CHCl
3
).
D
0
J = 12.4 Hz), 4.17 (m, 2H, Cp), 4.10 (m, 2H, Cp), 4.07 (s, 10H, Cp ),
4
.01 (m, 2H, Cp), 3.81 (d, 2H, CH
CH N, J = 12.4 Hz), 2.57 (t, 4H, CH N, J = 7.1 Hz), 1.45 (t, 4H, CH
J = 7.1 Hz). C NMR (CDCl
2
N, J = 12.4 Hz), 3.79 (d, 2H,
4.11. (R,R)-Bis [N-2-(1-hydroxy)butyl]-1,2-ferrocenylmethyl
diamine 11
2
2
2
,
1
3
3
) d 87.4, 84.9, 70.2, 69.7, 68.8, 65.6,
+
+
5
9.7, 48.5, 47.8, 27.2. MS (m/z): 583 (M +K), 567 (M +Na), 545
Following the general procedure starting from ferrocene-1,2-
dicarboxaldehyde 10 (223 mg, 0.84 mmol) and (R)-(ꢀ)-2-amino-
1-butanol (245 mg, 2.75 mmol), (R,R)-bis[N-2-(1-hydroxy)butyl]-
+
+
(
MH ), 544 (M ). Anal. Calcd for C28
H36Fe
2
N
2
O
2
: C, 61.79; H,
6
.67; N, 5.15. Found: C, 61.43; H, 6.33; N, 5.03.
1
,2-ferrocenylmethyldiamine 11 was obtained as yellow oil
2
1
4
6
.7. 1,2-Bis[2-(hydroxymethyl)ferrocenylmethylamino]hexane
(286 mg, 88%). ½
a
ꢂ 0 ꢀ62 (c 0.81, CHCl
3
). H NMR (CDCl
3
) d 4.16
D
0
(m, 1H, Cp), 4.14 (m, 1H, Cp), 4.05 (s, 5H, Cp ), 4.02 (m, 1H, Cp),
3
.93 (d, 1H, CH
3.57 (d, 1H, CH
3.37 (m, 4H, CH
(m, 4H, CH ), 0.91 (t, 6H, CH
84.6, 70.5, 69.9, 69.0, 66.4, 63.2, 63.0, 61.0, 59.7, 44.9, 24.2, 23.5,
2
N, J = 12.5 Hz), 3.67 (d, 1H, CH
2
N, J = 12.9 Hz),
N, J = 12.5 Hz),
Following the general procedure starting from 2-(hydroxym-
2
N, J = 12.9 Hz), 3.45 (d, 1H, CH
2
ethylferrocene)carboxaldehyde 3 (864 mg, 3.54 mmol) and 1,6-
diaminohexane (187 mg, 1.61 mmol), 1,2-bis[2-(hydroxy-
methyl)ferrocenylmethylamino]hexane 6 was obtained as yellow
2
O), 2.63 (m, 1H, CH), 2.47 (m, 1H, CH), 1.44–1.42
1
3
2
3 3
, J = 7.5 Hz). C NMR (CDCl ) d 85.1,
1
+
+
crystals (810 mg, 88%). Mp 106 °C. H NMR (CDCl
3
) d 4.69 (d, 2H,
24.2, 23.5, 10.6, 10.5. MS (m/z): 427 (M +K), 411 (M +Na), 389
(MH ). Anal. Calcd for C20
+
CH
2
O, J = 12.3 Hz), 4.15 (d, 2H, CH
2
O, J = 12.3 Hz), 4.14 (m, 2H,
2 2
H32FeN O : C, 61.86; H, 8.31; N, 7.21.
0
Cp), 4.09 (m, 2H, Cp), 4.07 (s, 10H, Cp ), 3.99 (m, 2H, Cp), 3.78 (d,
Found: C, 62.21; H, 8.12; N, 7.48.
2
H, FcCH
2
, J = 11.3 Hz), 3.44 (d, 2H, FcCH
2
, J = 11.3 Hz), 2.58 (t,
), 1.28–1.27 (m, 4H,
) d 87.6, 85.3, 70.2, 69.6, 68.6, 65.4, 59.8,
4
H, CH N, J = 7.1 Hz), 1.43–1.41 (m, 4H, CH
2
3
2
4.12. (S,S)- Bis [N-2-(1-hydroxy)butyl]-1,2-ferrocenylmethyl
diamine 12
1
CH
4
2
). C NMR (CDCl
3
+
+
8.8, 47.9, 29.5, 26.9. MS (m/z): 611 (M +K), 595 (M +Na), 573
+
+
(
MH ), 572 (M ). Anal. Calcd for C30
H40Fe
2
N
2
O
2
: C, 62.96; H,
Following the general procedure starting from ferrocene-1,2-
dicarboxaldehyde 10 (314 mg, 1.18 mmol) and (S)-(+)-2-amino-1-
butanol (336 mg, 3.77 mmol), (S,S)-bis[N-2-(1-hydroxy)butyl]-
7
.04; N, 4.89. Found: C, 62.48; H, 6.85; N, 4.62.
4
.8. General procedure for the synthesis of ferrocenyl amino
1,2-ferrocenylmethyldiamine 12 was obtained as yellow oil
2
alcohols 8–9 and 11–12
(279 mg, 61%). ½
a
ꢂ 0 65 (c 0.72, CHCl
3
).
D
0
A mixture of ferrocene-1,1 -dicarboxaldehyde 7 or ferrocene-
,2-dicarboxaldehyde 10 (200 mg, 0.83 mmol) and the appropriate
4.13. General procedure for the synthesis of ferrocenyl
diamines
1
2 2
amino alcohol (2.5 mmol) in anhydrous CH Cl (50 mL) containing
molecular sieves (4 A, 5 g) was stirred under reflux for 10 h. The
mixture was filtered through Celite 545. The solvent was evapo-
rated from the filtrate under reduced pressure. The residue was
A mixture of ferrocenecarboxaldehyde (4.50 mmol) and the
appropriate diamine (2.2 mmol) in anhydrous MeOH (50 mL) was
stirred at room temperature. After 4 h, NaBH (4.2 mmol) was
4

D. Andrianina Ralambomanana et al. / Bioorg. Med. Chem. 16 (2008) 9546–9553
9551
*
added in small portions. The mixture was stirred at room temper-
ature for 1 h, hydrolysed by addition of a saturated solution of
NH Cl (50 mL) and extracted with CH Cl
solution of HCl (1 N, 40 mL) was added to the organic layer. The
mixture was extracted by diethyl ether (3 ꢁ 100 mL). Sodium car-
bonate was then added to the aqueous layer until neutralisation.
J = 12.9 Hz), 3.40 (2H, s, Fc-CH
J = 12.9 Hz), 2.76 (1H, m, CH–N), 2.64 (1H, dd, N–CH
11.7 Hz,), 2.47 (1H, dd, N–CH , J = 8.8 and 11.7 Hz), 1.05 (3H, d,
). C NMR (CDCl ) d 87.2, 86.9, 68.4, 67.8, 67.7,
55.0, 52.1, 48.8, 46.27, 18.56. MS (m/z) 470 (M ). Anal. Calcd for
2
–N), 3.34 (1H, d, Cp-CH
2
–N–C ,
2
, J = 3.9 and
4
2
2
(3 ꢁ 30 mL). An aqueous
2
1
3
J = 6.4 Hz, –CH
3
3
+
C
26
H32Fe
2
N
2
: C, 63.86; H, 6.43; N, 5.96. Found: C, 63.93; H, 6.77;
The product was then extracted by CH
ganic layer was dried over sodium sulfate before removing the sol-
vent under reduced pressure. The residue was purified by column
2
Cl
2
(3 ꢁ 100 mL). The or-
N, 5.69.
0
4.19. 1,3-Diamino-N,N -(diferrocenylmethyl)-2,2-dimethylprop
chromatography (CH
2
Cl
2 3
/MeOH/Et N = 19:1:1).
ane 18
0
4
.14. 1,2-Diamino-N,N -di(ferrocenylmethyl)ethane 13
Following the general procedure starting from ferrocenecarboxal-
dehyde (1.40 g, 6.54 mmol) and 1,3-diamino-2,2-dimethylpropane
0
Following the general procedure starting from ferrocenecarbox-
(0.337 mL,
2.8 mmol),
1,3-diamino-N,N -di(ferrocenylmethyl)-
1
aldehyde (1.268 g, 5.92 mmol) and 1,2-ethylenediamine (0.2 mL,
2,2-dimethylpropane 18 was obtained as yellow oil (1.07 g, 77%). H
0
2
.96 mmol), 1,2-diamino-N,N -di(ferrocenylmethyl)ethane 13 was
NMR (CDCl
3
) d 4.18–4.16 (4H, m, Cp), 4.13–4.10 (4H, m, Cp), 4.12
2
1,22 1
0
obtained as yellow oil (1.02 g, 76%).
H NMR (CDCl
3
) d 4.19–
(10H, s, Cp ), 3.49 (4H, s, Cp-CH
2
–N), 2.52 (4H, s, CH
) d 85.1, 68.8, 68.6, 68.2, 59.2, 49.3, 34.0, 24.8.
MS (m/z) 498 (M ). Anal. Calcd for C27 : C, 65.08; H, 6.88; N,
2
–N), 0.96 (6H, s,
0
13
4
(
6
.17 (4H, m, Cp), 4.12 (10H, s, Cp ), 4.11–4.09 (4H, m, Cp), 3.49
–N). C NMR (CDCl
8.7, 68.6, 48.7, 48.6. MS (m/z) 456 (M ).
3 3
CH ). C NMR (CDCl
13
+
4H, s, Fc-CH
2
-N), 2.74 (4H, s, CH
2
3
) d 86.7,
2 2
H34Fe N
+
5.62. Found: C, 64.80; H, 6.75; N, 5.76.
0
0
4
.15. 1,3-Diamino-N,N -di(ferrocenylmethyl)propane 14
4.20. trans-1,4-Diamino-N,N -(diferrocenylmethyl)cyclohexane
1
9
Following the general procedure starting from ferrocenecarbox-
aldehyde (1.268 g, 5.92 mmol) and 1,3-propanediamine (0.25 mL,
Following the general procedure starting from ferrocenecarbox-
0
2
.96 mmol), 1,3-diamino-N,N -di(ferrocenylmethyl)propane 14
aldehyde (1.40 g, 6.54 mmol) and trans -1,4-diaminocyclohexane
23
1
0
was obtained as yellow oil (751 mg, 54%).
3
H NMR (CDCl ) d
(354 mg,
3.11 mmol),
1,4-diamino-N,N -(diferrocenylmeth-
0
4.18–4.16 (4H, m, Cp), 4.11 (10H, s, Cp ), 4.10–4.08 (4H, m, Cp),
yl)cyclohexane 19 was obtained as yellow crystals (0.65 g, 41%).
1
3
CH
.49 (4H, s, Fc-CH
2
–N), 2.67 (4H, t, CH
2
–N, J = 6.3 Hz), 1.67 (4H, q,
) d 85.6, 68.7, 68.5, 48.6, 47.7,
: C, 63.90; H, 6.40; N, 6.00. Found:
Mp 110 °C. H NMR (CDCl
3
) d 4.18–4.16 (4H, m, Cp), 4.11–4.08
1
3
0
2
, J = 6.3 Hz). C NMR (CDCl
3
(4H, m, Cp), 4.09 (10H, s, Cp ), 3.52 (4H, s, CH
CH), 1.92–1.88 (4H, m, CH ), 1.29 (2H, m, CH
2 2
). C NMR (CDCl
5.3, 32.1. MS (m/z) 510 (M ). Anal. Calcd for C28H34Fe N : C,
2
–N), 2,45 (2H, m,
), 1.18 (2H, m,
) d 87.3, 68.4, 68.3, 67.7, 56.0, 50.5, 46.4,
3
9.2. Anal. Calcd for C25
H30Fe
2
N
2
1
3
C, 63.70; H, 6.20; N, 5.80.
CH
3
2
3
+
2 2
0
4
.16. 1,4-Diamino-N,N -di(ferrocenylmethyl)butane 15
65.91; H, 6.72; N, 5.49. Found: C, 65.81; H, 6.52; N, 5.54.
0
Following the general procedure starting from ferrocenecarbox-
4.21. (1R,2R) 1,2-Diamino-N,N -di(ferrocenylmethyl)cyclohe
aldehyde (1.40 g, 6.54 mmol) and 1,4-butanediamine (268 mg,
xane 20
0
3
.04 mmol), 1,4-diamino-N,N -di(ferrocenylmethyl)butane 15 was
1
obtained as yellow crystals (1.13 g, 77%). Mp 98 °C. H NMR
Following the general procedure starting from ferrocenecarbox-
aldehyde (1.40 g, 6.54 mmol) and (1R,2R) 1,2-diaminocyclohexane
(354 mg, 3.11 mmol), (1R,2R) 1,2-diamino-N,N -(diferrocenylmeth-
yl)cyclohexane 20 was obtained as yellow crystals (0.76 g, 48%).
0
(
CDCl
3
) d 4.15–4.14 (4H, m, Cp), 4.11 (10H, s, Cp ), 4.11–4.09 (4H,
0
m, Cp), 3.56 (4H, s, Fc-CH
2
–N), 2.63 (4H, t, CH
). C NMR (CDCl ) d 86.1, 68.7, 68.5, 48.7,
8.2, 27.6. MS (m/z) 484 (M ). Anal. Calcd for C26 : C,
2
–N, J = 6.1 Hz),
13
1
4
6
.61–1.56 (4H, m, CH
2
3
+
1
H
32Fe
2
N
2
Mp 188 °C. H NMR (CDCl
3
) d 4.19–4.17 (4H, m, Cp), 4.11 (10H, s,
–N, J = 12.9 Hz), 3.35 (2H, d,
–N, J = 12.9 Hz), 2.24 (1H, m, CH–N), 2.10 (1H, m, CH–N), 1.92
(2H, s, NH), 1.75–1.71 (4H, m, CH ), 1.24 (2H, m, CH ), 1.04 (2H,
) d 88.0, 68.4, 68.1, 68.0, 67.5, 61.4, 46.1,
0
4.49; H, 6.66; N, 5.78. Found: C, 63.90; H, 6.87; N, 5.56.
Cp ), 4.08 (4H, s, Cp), 3.62 (2H, d, CH
2
CH
2
0
4
.17. 1,6-Diamino-N,N -di(ferrocenylmethyl)hexane 16
2
2
1
3
2 3
m, CH ). C NMR (CDCl
+
Following the general procedure starting from ferrocenecarbox-
31.8, 25.1. MS (m/z) 510 (M ). Anal. Calcd for C28H34Fe N : C,
2 2
aldehyde (1.46 g, 6.82 mmol) and 1,6-hexanediamine (344 mg,
65.91; H, 6.72; N, 5.49. Found: C, 66.30; H, 7.95; N, 5.63.
0
2
.96 mmol), 1,6-diamino-N,N -di(ferrocenylmethyl)hexane 16 was
1
0
obtained as yellow crystals (697 mg, 46%). H NMR (CDCl
3
) d
4.22. N,N -Diferrocenylmethylpiperazine 21
0
4.19–4.17 (4H, m, Cp), 4.11 (10H, s, Cp ), 4.11–4.09 (4H, m, Cp),
3
.53 (4H, s, Fc-CH
2
–N), 2.61 (4H, t, CH
2
–N, J = 7.2 Hz), 1.53–1.49
Following the general procedure starting from ferrocenecarbox-
aldehyde (1.480 g, 6.91 mmol) and piperazine (354 mg,
(
4H, m, –CH –), 1.35–1.30 (4H, m, –CH
2
2
–). 13C NMR (CDCl
3
) d
+
0
8
7.1, 68.5, 68.4, 49.7, 49.1, 30.1, 27.4. MS (m/z) 512 (M ). Anal.
3.23 mmol), N,N -diferrocenylmethylpiperazine 21 was obtained
1
Calcd for C28
H, 7.22; N, 5.61.
H36Fe
2
N
2
: C, 65.65; H, 7.08; N, 5.47. Found: C, 63.98;
as yellow crystals (0.965 g, 62%). Mp 106 °C. H NMR (CDCl
3
) d
0
4.24–4.19 (4H, m, Cp), 4.18–4.14 (4H, m, Cp), 4.11 (10H, s, Cp ),
+
3
.35 (4H, s, FcCH
Anal. Calcd for C26
4.91; H, 6.32; N, 5.74.
2
N), 2.61–2.35 (8H, m, CH
2
). MS (m/z) 482 (M ).
: C, 64.76; H, 6.27; N, 5.81. Found: C,
0
4
.18. 1,2-Diamino-N,N -di(ferrocenylmethyl)propane 17
2 2
H30Fe N
6
Following the general procedure starting from ferrocenecarbox-
0
0
aldehyde (1.479 g, 6.91 mmol) and 1,2-propanediamine (0.250 mL,
4.23. N,N -Diisopropyl-1,1 -ferrocenylmethyldiamine 22
0
2
.93 mmol), 1,2-diamino-N,N -di(ferrocenylmethyl)propane 17
1
0
was obtained as yellow crystals (344 mg, 25%). Mp 188 °C.
H
Following the general procedure starting from ferrocene-1,1 -
dicarboxaldehyde (1.09 g, 4.5 mmol) and isopropylamine
(0.77 mL, 9.0 mmol), N,N -diisopropyl-1,1 -ferrocenylmethyldi-
NMR (CDCl
3
) d 4.19 (2H, m, Cp), 4.14 (2H, m, Cp), 4.12 (5H, s,
7
0
0
*
0
0
Cp ), 4.09 (5H, s, Cp ), 4.02 (4H, m, Cp), 3.60 (1H, d, Fc-CH
2
–N–C ,

9
552
D. Andrianina Ralambomanana et al. / Bioorg. Med. Chem. 16 (2008) 9546–9553
amine 22 was obtained as yellow oil (709 mg, 48%). 1H NMR
CDCl ) d 4.15–4.11 (4H, m, Cp), 4.08–4.05 (4H, m, Cp), 3.49 (4H,
s, CH ), 2.84 (2H, s, CH, J = 6.1 Hz), 1.07 (12H, d, CH , J = 6.1 Hz).
C NMR (CDCl ) d 87.3, 68.9, 68.4, 48.3, 46.5, 22.9. MS (m/z):
28 (M ). Anal. Calcd for C18 28FeN : C, 65.86; H, 8.60; N, 8.53.
raphy, eluting with diethyl ether: petroleum ether: triethylamine
(80:10:10). Compound 27 was obtained as yellow crystals (16%).
(
3
1
2
3
Mp 130 °C. H NMR (CDCl
3
) d 4.13–4.12 (4H, m, Cp), 4.10–4.09
1
3
0
3
(4H, m, Cp), 4.09 (10H, s, Cp ), 3.36 (2H, s, Fc-CH
2
–N), 3.35 (2H, s,
–N), 2.14 (3H, s,
) d 82.6, 70.3, 68.4,
+
3
H
2
Fc-CH
–CH ), 2.12 (3H, s, –CH
7.9, 57.3, 53.7, 42.1. MS (m/z): 484 (M ). Anal. Calcd for
: C, 64.49; H, 6.66; N, 5.78. Found: C, 64.21; H, 6.57;
2 2 2
–N), 2.38 (2H, s, CH –N), 2.36 (2H, s, CH
1
3
Found: C, 65.97; H, 8.50; N, 8.40.
3
3
). C NMR (CDCl
3
+
6
C
0
4
.24. N,N -Diisopropyl-1,2-ferrocenylmethyldiamine 23
26 2 2
H32Fe N
N, 5.69.
Following the general procedure starting from ferrocene-1,2-
dicarboxaldehyde 10 (371 mg, 1.53 mmol) and isopropylamine
4.29. Activity against M. tuberculosis H37Rv strain
0
(
0.326 mL, 3.8 mmol), N,N -diisopropyl-1,2-ferrocenylmethyldi-
1
amine 23 was obtained as yellow oil (360 mg, 72%). H NMR
(
Susceptibility testing with the BACTEC MGIT 960 system (Bec-
ton Dickinson) was performed according to the manufacturer’s rec-
ommendations. Test compounds were dissolved in dimethyl
0
CDCl
3
) d 4.12 (2H, m, Cp), 4.04 (5H, s, Cp ), 3.99 (1H, m, Cp),
3
2
.66 (2H, d, CH
2
N, J = 12.3 Hz), 3.40 (2H, d, CH
, J = 6.3 Hz), 1.02 (6H, d, CH
) d 86.0, 71.1, 71.0, 68.9, 65.6, 48.3,
2
N, J = 12.3 Hz),
.78 (2H, m, CH), 1.05 (6H, d, CH
3
3
,
sulfoxide or in methanol. 390 ll of diluted test compounds was
1
3
J = 6.3 Hz). C NMR (CDCl
2
5.6, 23.3, 22.5. MS (m/z) 328 (M ). Anal. Calcd for C18H28FeN :
3
added to MGIT 7 ml tubes supplemented with 0.8 ml of the pro-
vided enrichment solution. Susceptibility testing was performed
by minimal inhibitory concentration (MIC) determination. Serial
twofold dilution of a 1280 mg/l solution of each drugs were added
to MGIT tubes to achieve final concentration ranging from 64 to
+
4
C, 65.86; H, 8.60; N, 8.53. Found: C, 65.97; H, 8.78; N, 8.41.
0
4
.25. N,N -Dibenzyl-1,2-diaminoethane 24
0
.25 mg/l. All the drug-containing tubes were inoculated with
Following the general procedure starting from benzaldehyde
0.5 ml of the positive broth culture. Mycobacterial suspensions
were used undiluted from 2 days following the detection of
growth, while the suspensions were diluted 1:5 with sterile saline
from days 3 to 5. A SIRE drug-free control was inoculated with
0.5 ml of a 10 dilution of the positive culture broth in sterile sal-
ine. The tubes were then placed in an BACTEC 960 set carrier and
incubated in the instrument. The tubes were continuously moni-
tored until the results indicating susceptibility or resistance were
automatically interpreted and reported using predefined algo-
rithms that compared growth in the drug-containing tube to that
in the control tube.
(
4
1.22 mL, 11.8 mmol) and 1,2-ethylenediamine (0.332 mL,
0
.9 mmol), N,N -dibenzyl-1,2-diaminoethane 24 was obtained as
1
yellow oil (811 mg, 69%). H NMR (CDCl
3
) d 7.39–7.25 (6H, m,
–N), 2.74 (4H, s,
) d 140.3, 128.4, 128.0,
ꢀ2
Ph), 7.24–7.22 (4H, m, Ph), 3.76 (4H, s, Ph–CH
2
CH
1
2
–N), 2.01 (2H, s, NH). 13C NMR (CDCl
3
+
26.9, 54.0, 51.9. MS (m/z): 240 (M ).
0
4
.26. N,N -Dibenzyl-1,6-diaminohexane 25
Following the general procedure starting from benzaldehyde
(
1.22 mL, 11.8 mmol) and 1,6-hexanediamine (572 mg, 4.9 mmol),
0
N,N -dibenzyl-1,6-diaminohexane 25 was obtained as yellow oil
Acknowledgements
1
(
(
1.22 g, 84%). H NMR (CDCl
4H, m, Ph), 7.21 (2H, m, Ph), 3.75 (4H, s, Ph–CH
–N), 1.52–1.47 (4H, m, –CH –), 1.35–1.29 (4H, m, –
–). C NMR (CDCl ) d 140.6, 128.4, 128.1, 126.9, 54.1, 49.5,
3
) d 7.31–7.28 (4H, m, Ph), 7.24–7.22
2
–N), 2.59 (4H, t,
The authors are thankful to the ‘Ministère des Affaires Etrangè-
res’, the ‘Centre National de la Recherche Scientifique’ and the
‘Ambassade de France à Madagascar’ for financial support and
Francine Agbossou-Niedercorn for helpful discussions.
J = 7.1 Hz, CH
CH
2
2
1
3
2
3
+
3
0.1, 27.3. MS (m/z): 296 (M ).
0
4
.27. N,N -Dibenzyl-1,2-diaminopropane 26
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2
3
.
.
.
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Following the general procedure starting from benzaldehyde
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4
1.22 mL, 11.8 mmol) and 1,2-propanediamine (0.43 mL,
0
.9 mmol), N,N -dibenzyl-1,2-diaminopropane 26 was obtained as
1
4. Barry, P. J.; O’Connor, T. M. Curr. Med. Chem. 2007, 14, 2000.
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3
) d
5
.
*
7
3
2
2
2
.27–7.20 (10H, m, Ph), 3.83 (1H, d, Ph–CH –N–C , J = 15 Hz,),
8
*
.70 (2H, s, Ph–CH
.73 (1H, m, CH–N), 2.61 (1H, dd, N–CH
2
–N) 3.65 (1H, d, Ph–CH
2
–N–C , J = 15 Hz),
6. Sherpherd, R. G.; Baughn, C.; Cantrall, M. L.; Goodstein, B.; Thomas, J. P.;
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*
2
–C , J = 3.9 and 11.9 Hz),
.47 (1H, dd, N–CH –C , J = 8.6 and 11.9 Hz), 1.05 (3H, d,
2
) d 140.8, 140.6, 128.3, 128.1,
28.0, 126.9, 126.8, 55.1, 53.9, 51.8, 51.3, 18.5. MS (m/z): 254 (M ).
*
1
3
J = 6.1 Hz, –CH
3
). C NMR (CDCl
3
+
1
4
9, 3045.
9.
Tripathi, R. P.; Saxena, N.; Tiwari, V. K.; Verma, S. S.; Chaturvedi, V.; Manju, Y.
K.; Srivastva, A. K.; Gaikwad, A.; Sinha, S. Bioorg. Med. Chem. 2006, 14, 8186.
0
0
4
.28. N,N -Diferrocenylmethyl-N,N -dimethyl-1,2-
diaminoethane 27
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