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Table 1 (continued)
Compound
Structure
MIC (lM)
F
H
N
COOH
COOH
11c
0.3
N
H
H
N
COOH
COOH
N
H
11d
11e
8.6
1.7
0.6
0.6
OH
H
N
COOH
N
H
2
COOH
OCH3
H
N
2 HCl
N
H
11f
F
H
N
2 HCl
N
H
SQ109
The first objective of this investigation was to immediately syn-
thesize a variety of derivatives with alkyl attached geranylamine
moiety or substituted admantanamine moiety. Synthesis of com-
pounds 7a–e were outlined in Scheme 1. The starting material
(E)-3,7-dimethylocta-2,6-dienal 1 was converted to 2a–e by treat-
ment with corresponding Grignard reagents in yields 93–97%. And
these alcohols were treated with phthalimide in the presence of
Ph3P and DIAD to give intermediates 3a–e, which were converted
to corresponding amines 4a–e by treatment with methylamine.
The yields of these two steps from 2a–e to 4a–e were 37–49%.
Chloroacylation of 4a–e using chloroacetyl chloride and pyridine
in THF gave 5a–e in 96–98% yield. Reaction of 2-admantylamines
with 5a–e afforded intermediates 6a–e with yields of 64–73%. Fi-
nally, 6a–e were treated with Red-Al in THF to provide the 1,2-dia-
mines, and these diamines were treated with maleic acid or
hydrochloride to afford target compounds 7a–e in 52–63% yield.
Derivatives with substituted admantane ring were synthesized as
Scheme 2. The starting material 8 was synthesized according to
the method described by Lee et al.4 and it was converted to 10a–
f by treatment with corresponding substituted admantylamines
9a–f and K2CO3 in THF at reflux temperature with yields of 67–
75%. Then 10a–f were treated with Red-Al in THF to provide the
1,2-diamines, and these diamines were treated with maleic acid
or hydrochloride to give target compounds 11a–f in 55–67% yield.
The chemical structures of compounds 7a–e and 11a–f were deter-
mined by 1H NMR and HR-MS.9
ple compound 7d and 7e, the antituberculosis potency reduced
about 5–9 fold. It was interesting that removal of the substituted
group of benzyl (7c vs 7e) led to a fivefold increase in antitubercu-
losis potency.
To further improve the antituberculosis potency, we also inves-
tigated the requirement for the 2-admantylamine moiety of
SQ109. Guided by the metabolism information of SQ109, we at-
tached the hydroxyl, halide, methoxyl group to the 1 and 5 position
of the 2-admantylamine nucleus. As shown in Table 1, for the 5-
substituted 2-admantylamine, 5-fluorine-2-admantylamine deriv-
ative 11f showed MIC value of 0.6 lM, the same potency to the
SQ109, whereas 14 fold increase in antituberculosis potency over
5-hydroxyl-2-admantylamine derivative 11d. For the 1-substi-
tuted 2-admantylamine, as exemplified by compound 11c, no sig-
nificant change was observed compared to SQ109, MIC values of
those compounds ranged from 0.3 to 0.6 lM. As far as the substi-
tution of 2-admantylamine nucleus was concerned the fluorine ap-
pears to be the most favorable group. Among all tested compounds,
compound 11c showed the most potent antituberculosis activity
with MIC value of 0.3 lM against M. tuberculosis H37Rv strain.
In summary, guided by the metabolism information of SQ109,
derivatives of SQ109 with substituted geranylamine moiety or
substituted admantane ring were synthesized and evaluated as
an anti-tuberculosis agent. Among all tested compounds, com-
pound 11c showed the most potent antituberculosis activity with
MIC value of 0.3 lM against M. tuberculosis H37Rv.
All of the synthesized compounds 7a–e and 11a–e were evalu-
ated for tuberculosis inhibition against M. tuberculosis H37Rv strain
(ATCC 27294, susceptible both to rifampin and isoniazid) using
microbroth dilution assay described by Lee et al.4 and results are
summarized in Table 1.
References and notes
1. Dye, C. Lancet 2006, 367, 938.
2. Nayyar, A.; Jain, R. Curr. Med. Chem. 2005, 12, 1873.
3. Laughon, B. E. Curr. Top. Med. Chem. 2007, 7, 463.
Our initial work focused on exploring variants to the geranyl-
amine moiety of SQ109. As shown in Table 1, by introducing an al-
kyl group, such as methyl, ethyl, to the geranylamine moiety of
SQ109, compounds 7a and 7b displayed similar potency against
4. Lee, R. E.; Protopopova, M.; Crooks, E.; Slayden, R. A.; Terrot, M.; Barry, C. E. J.
Comb. Chem. 2003, 5, 172.
5. Protopopova, M.; Hanrahan, C.; Nikonenko, B.; Samala, R.; Chen, P.; Gearhart, J.;
Einck, L.; Nacy, C. A. J. Antimicrob. Chemother. 2005, 56, 968.
6. Chen, P.; Gearhart, J.; Protopopova, M.; Einck, L.; Nacy, C. A. J. Antimicrob.
Chemother. 2006, 58, 332.
M. tuberculosis H37Rv with the 1.2
lM compared with 0.6 lM of
7. Jia, L.; Tomaszewski, J. E.; Hanrahan, C.; Coward, L.; Noker, P.; Gorman, G.;
Nikonenko, B.; Protopopova, M. Br. J. Pharmacol. 2005, 144, 80.
SQ109. However when substituted benzyl was attached, for exam-
Meng, Qingyi
