Synthesis and evaluation of carbamate prodrugs of SQ109 as antituberculosis agents

Article abstract of DOI:10.1016/j.bmcl.2009.03.091

The low bioavailability of SQ109 in rats, resulting from first-pass effect in the liver, may be remedied by prodrug strategy. Based on esterase-sensitive carbamate prodrug strategy, a novel series of prodrugs of SQ109 has been reported. Bioavailability of

Full text of DOI:10.1016/j.bmcl.2009.03.091

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2808–2810
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of carbamate prodrugs of SQ109
as antituberculosis agents
Qingyi Meng a, Huibing Luo b, Yibin Liu b, Wei Li c, Wen Zhang c, Qizheng Yao a,
*
a Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
b Shanghai Sun-sail Pharmaceutical Science and Technology Company, Shanghai 201203, China
c Nanjing C&O Pharmaceutical Technology Company, Nanjing 210022, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The low bioavailability of SQ109 in rats, resulting from first-pass effect in the liver, may be remedied by
prodrug strategy. Based on esterase-sensitive carbamate prodrug strategy, a novel series of prodrugs of
SQ109 has been reported. Bioavailability of SQ109 after administration of prodrug 7a was 91.4% com-
pared with 21.4% after oral administration of SQ109. After oral administration of compound 7a, the par-
ent drug SQ109 exhibited preferential tissue distribution into lung and spleen, the target organs of
tubercular infection and replication.
Received 13 January 2009
Revised 5 March 2009
Accepted 23 March 2009
Available online 26 March 2009
Keywords:
Anti-tuberculosis
SQ109
Ó 2009 Elsevier Ltd. All rights reserved.
Prodrug
Bioavailability
Among infectious diseases, tuberculosis (TB) still remains the
leading single-agent killer in the world, claiming over three million
lives each year. The major challenges for tuberculosis control are
the development of multidrug-resistant tuberculosis (MDR-TB)
strains and the increasing numbers of immunocompromised indi-
viduals with HIV infectious who are highly susceptible to the dis-
ease. Consequently, there is an urgent need to develop new,
potent, fast-acting antituberculosis drugs with low toxicity profiles
that can be given in conjunction with other drugs used to treat HIV
infection. Despite the increasing worldwide incidence of TB and its
alarming threat toward the public health, no novel antituberculosis
drugs have been introduced into clinical practice over the past four
decades. Only within the last few years have several promising
drug candidates emerged.1,2
Figure 1. Structure of SQ109.
of SQ109 might result from the effect of first-pass metabolism in
the liver.7
Prodrug strategy as a chemical/biochemical approach is often
used to overcome various barriers which can hinder drug delivery,
including minimization of the first-pass effect to improve oral bio-
availability. Carbamate-based esterase-sensitive prodrug system
has been used for prodrugs of amines and amidines.8–12 The pio-
neering work in this area was done by Alexander and co-work-
ers.13,14 The results from these studies indicated that carbamate-
based prodrugs had good chemical stability and were substrates
of plasma esterases.
Herein, we report the synthesis and evaluation of compounds
7a–d, carbamate prodrugs of SQ109, as antituberculosis agents.
Synthesis of prodrugs 7a–d is outlined in Scheme 1. The starting
material geranylchloride 1 was converted to N-geranyl-2-amino-
ethanol 2 by treatment with 2-aminoethanol at ambient tempera-
ture, and then 2 was acylated to afford intermediates 4a–d by
treatment with corresponding chloroformates 3a–d and triethyl-
amine in THF at ambient temperature. Oxidation of 4a–d by Swern
oxidation procedure gave corresponding aldehydes 5a–d. Reduc-
tive amination of these aldehydes with 2-admantylamine and NaB-
H(OAc)3 yielded compounds 6a–d. These intermediates were then
N-Geranyl-N0-(2-adamantyl)ethane-1,2-diamine (SQ109, Fig. 1),
a second-generation agent from the first-line drug ethambutol, en-
tered clinical trail stage in 2005 and completed its phase Ia trial in
2007.3–5 SQ109 exhibited potent activity against Mycobacterium
tuberculosis including multi-drug resistant mutants both in vitro
and in vivo.6 Unfortunately, SQ109 showed poor oral bioavailabil-
ity, only 12% in rats and 3.8–5% in dogs. The metabolism study of
SQ109 by Jia et al. in human liver microsomes suggested that the
predominant metabolisms of SQ109 were oxidation, epoxidation
and N-dealkylation. It also indicated that the low bioavailability
* Corresponding author. Tel.: +86 25 83271445; fax: +86 25 86634730.
E-mail address: qz_yao@yahoo.com.cn (Q. Yao).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.091

Q. Meng et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2808–2810
2809
Scheme 1. Reagents and conditions: (a) 2-aminoethanol, 25 °C, 24 h; (b) triethylamine, THF, 0 °C, 2 h; (c) oxalyl chloride, dimethylsulfide, CH2Cl2, ꢀ60 °C, 30 min; then
triethylamine, 15 min; (d) 2-admantylamine, NaBH(OAc)3, 1,2-dichloroethane, 25 °C, 0.5 h; (e) maleic acid, ethanol, 25 °C, 0.5 h.
treated with maleic acid to yield the target compounds 7a–d. The
chemical structures of compounds 7a–d were determined by 1H
NMR, LR-MS, and elemental analysis.15
With compounds 7a–d in hand, we first examined their phar-
macokinetic profiles. Unfortunately, compounds 7c and 7d were
hydrolyzed with pH 7.4 Sorensen’s buffer at room temperature in
the chemical stability experiment. Then 7a and 7b were selected
for further pharmacokinetic studies in rats. The analytical method
for determining SQ109 in various biomatrices and the method for
pharmacokinetic studies with 7a and 7b were similar to that de-
scribed by Jia et al.7 Plasma concentration–time profiles of SQ109
after oral administration of compounds 7a, 7b and SQ109 were
shown in Figure 2. After oral administration of compounds 7a
and 7b, the prodrug was rapidly metabolized so that 7a and 7b
could not be detected in the plasma samples, and the plasma con-
centration of SQ109 was higher than that after administration of
SQ109 in the same dosage. Some relevant pharmacokinetic param-
eters are listed in Table 1. Oral bioavailability of SQ109 in rats was
21.9%, whereas bioavailability of SQ109 was 91.4% and 72.6% after
oral administration of compounds 7a and 7b, respectively. Based
on the Student’s t-test (P < 0.01), bioavailability of SQ109 after
administration of prodrugs 7a and 7b was significantly greater
than that after oral administration of SQ109. Given compounds
7a and 7b being prodrugs of SQ109, the increased bioavailability
might result from minimization of the first-pass effect in the liver.
After administration of compounds 7a and 7b (13 mg/kg, po) to
rats, the concentration of SQ109 in lung, liver, spleen and plasma
were showed respectively in Figures 3 and 4. The concentration
of SQ109 in lung was higher than that in liver, spleen and plasma.
Especially compound 7a, at 4 h after po administration of 13 mg/kg
Figure 2. Mean plasma SQ109 concentration–time curves after administration of
SQ109 (1.5 mg/kg iv and 13 mg/kg po) and administration of prodrugs (13 mg/kg
po) in rats (n = 4).
dosage, the concentration of SQ109 in lung was 35.08
lg/g, which
was about 76-fold higher than the concentration in plasma; at
Table 1
Pharmacokinetic parameters of SQ109 after administration of compounds 7a, 7b and SQ109.
(n = 4)
SQ109 (iv) 1.5 mg/kg
SQ109 (po) 13 mg/kg
7a (po) 13 mg/kg
7b (po) 13 mg/kg
cmax (ng/mL)
tmax (h)
888.76 386.44
naa
498.61 125.31
0.75 0.29
1309.3 797.5
1.0 0.71
585.6 126.8
1.4 0.8
t1/2 (h)
5.06 0.35
1.05 0.13
1228.16 314.14
na
3.71 0.47
4.94 0.77
2326.05 1086.99
21.9 10.2
4.58 2.53
2.49 0.84
5441.2 1773.5
91.4 29.8
5.6 0.8
3.0 0.8
4224.8 1143.0
72.6 19.6
Cl (L/kg/h)
AUC0 ? 24 (ng h/mL)
F%b
a
Not available.
b
F% = (AUC0 ? 24 (po) * MTD/13 mg/kg)/(AUC0 ? 24 (iv) * MSQ109/1.5 mg/kg). MTD means the molecular weight of the tested drug, and MSQ109 means the molecular weight of
SQ109. Values are expressed as mean S.D.

2810
Q. Meng et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2808–2810
In summary, based on esterase-sensitive carbamate prodrug
strategy, a novel series of prodrugs of SQ109 has been reported.
Bioavailability of SQ109 after administration of prodrug 7a was
91.4% compared with 21.4% after oral administration of SQ109.
After oral administration of compound 7a, the parent drug SQ109
exhibited preferential tissue distribution into lung and spleen,
the target organs of tubercular infection and replication. Further
in vivo efficacy evaluation of compound 7a is ongoing in our
laboratories.
References and notes
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Einck, L.; Nacy, C. A. J. Antimicrob. Chemother. 2005, 56, 968.
Figure 3. Mean administration of SQ109 in tissues after administration of 7a
(13 mg/kg, po) in rats, S.D. for n = 4.
5. Chen, P.; Gearhart, J.; Protopopova, M.; Einck, L.; Nacy, C. A. J. Antimicrob.
Chemother. 2006, 58, 332.
6. Jia, L.; Tomaszewski, J. E.; Hanrahan, C.; Coward, L.; Noker, P.; Gorman, G.;
Nikonenko, B.; Protopopova, M. Br. J. Pharmacol. 2005, 144, 80.
7. Jia, L.; Noker, P. E.; Coward, L.; Gorman, G. S.; Protopopova, M.; Tomaszewski, J.
E. Br. J. Pharmacol. 2006, 145, 1.
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Chen, S. H. Bioorg. Med. Chem. Lett. 2001, 11, 1881.
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R.; Giardino, E. C.; Damiano, B. P. Chem. Biol. Drug. Des. 2006, 68, 29.
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Koch, T. H. J. Med. Chem. 2006, 49, 7002.
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Vijaykumar, D.; Stephens, R.; Liu, L.; Pan, L.; Mordenti, J.; Green, M. J.;
Sukbuntherng, J. Bioorg. Med. Chem. Lett. 2006, 16, 2224.
12. Rahmathullah, S. M.; Tidwell, R. R.; Jones, S. K.; Hall, J. E.; Boykin, D. W. Eur. J.
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14. Gogate, U. S.; Repta, A. J.; Alexander, J. Int. J. Pharm. 1987, 40, 235.
15. Compound 7a: white powder, mp: 151–153 °C; 1H NMR (400 MHz, DMSO-d6):
d 1.09 (d, J = 7.0 Hz, 6H), 1.56–1.60 (m, 5H), 1.64–1.74 (m, 10H), 1.85 (s, 4H),
1.90–2.12 (m, 8H), 2.55–2.61 (m, 1H), 3.05–3.10 (m, 3H), 3.43–3.53 (m, 2H),
3.84 (d, J = 6.0 Hz, 1H), 3.89 (d, J = 5.6 Hz, 1H), 5.06–5.11 (m, 2H), 5.71 (s, 2H),
6.01 (s, 2H), 8.20–8.40 (br s, 2H); ESI-MS (m/e): 475 (M+H)+; Anal. Calcd for
C32H50N2O8: C, 65.06; H, 8.53; N, 4.74. Found: C, 64.93; H, 8.46; N, 4.63.
Compound 7b: white powder, mp: 164–166 °C; 1H NMR (400 MHz, DMSO-d6):
d 1.44 (s, 9H), 1.56–1.74 (m, 15H), 1.84–2.09 (m, 12H), 3.01–3.09 (m, 2H), 3.45–
3.51 (m, 3H), 3.83 (d, J = 6.4 Hz, 1H), 3.90 (d, J = 6.6 Hz, 1H), 5.06–5.11 (m, 2H),
5.71 (s, 2H), 6.03 (s, 2H), 8.31 (br s, 2H); ESI-MS (m/e): 489 (M+H)+; Anal. Calcd
for C33H52N2O8: C, 65.54; H, 8.67; N, 4.63. Found: C, 65.53; H, 8.71; N, 4.47.
Figure 4. Mean administration of SQ109 in tissues after administration of 7b
(13 mg/kg, po) in rats, S.D. for n = 4.
10 h, the concentration of SQ109 in lung was still 29.03 lg/g,
which was about 60-fold higher than the minimum inhibitory con-
centration (MIC) of SQ109. This tissue distribution experiment sug-
gested that after oral administration of compounds 7a and 7b, the
parent drug SQ109 preferentially distributed into lung and spleen,
the target organs of tubercular infection and replication. It is also in
accordance with the result of tissue distribution experiment of
SQ109 by Jia et al.6