Synthesis and biological activity of 2-hydroxynicotinoyl-serine-butyl esters related to antibiotic UK-3A

Article abstract of DOI:10.1016/j.bmcl.2010.05.104

Novel 2-hydroxynicotinoyl-serine-butyl esters have been synthesized. Three-step reactions from l-serine by esterification with n-butanol, amidation with 2-hydroxynicotinic acid and esterification with the corresponding carboxylic acids gave AD-1, AD-2 and AD-3. The toxicity level of esters were determined by Brine shrimp assay, and antibiotic activity was tested against Escherichia coli, Bacillus subtilis, Staphylococcus aureus and Candida albicans. AD-3 showed greater activity as a growth inhibitor of B. subtilis and S. aureus compared to Antimycin A₃.

Full text of DOI:10.1016/j.bmcl.2010.05.104

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4018–4020
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological activity of 2-hydroxynicotinoyl-serine-butyl esters
related to antibiotic UK-3A
b
c
a
a
Ade Arsianti a,c, , Muhammad Hanafi , Endang Saepudin , Tsumoru Morimoto , Kiyomi Kakiuchi
*
a Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), Takayama-cho, Ikoma, Nara 630-0192, Japan
b LIPI Research Center for Chemistry, Kawasan Puspiptek, Tangerang, Banten, Indonesia
c Department of Chemistry, Faculty of Mathematics and Science, University of Indonesia, Depok, Indonesia
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel 2-hydroxynicotinoyl-serine-butyl esters have been synthesized. Three-step reactions from L-serine
Received 1 April 2010
Revised 17 May 2010
Accepted 27 May 2010
Available online 2 June 2010
by esterification with n-butanol, amidation with 2-hydroxynicotinic acid and esterification with the cor-
responding carboxylic acids gave AD-1, AD-2 and AD-3. The toxicity level of esters were determined by
Brine shrimp assay, and antibiotic activity was tested against Escherichia coli, Bacillus subtilis, Staphylococ-
cus aureus and Candida albicans. AD-3 showed greater activity as a growth inhibitor of B. subtilis and
S. aureus compared to Antimycin A3.
Keywords:
Synthesis
Ó 2010 Elsevier Ltd. All rights reserved.
Serine-butyl ester
Antibiotic
UK-3A
Recently, research on antifungal antibiotic agents has become
more important in medicinal chemistry, because many infectious
diseases caused by fungi or bacteria have shown resistance to cur-
rent antibiotics. To meet this challenge, research and development
of new antifungal antibiotic agents is needed.1 However, random
development and synthesis of new antibiotic agents can be expen-
sive and time-consuming. Consequently, synthesis of antibiotic
analogues has emerged as a promising strategy to seek new antibi-
otic agents that are effective against pathogenic microorganisms.
Analogue synthesis is advantageous due to its short duration and
high probability of yielding a more active compound by modifying
the structure, and it also gives information about the structure–
activity relationship. In 1997, Ueki and co-workers succeeded in
isolating the novel UK-3A compound which demonstrated antibi-
otic and antifungal activity from Streptomyces sp. 517-02.2–4 The
structure of UK-3A that consist of a nine-membered dilactone is
similar to well-known Antimycin A3, an antibiotic and insecticide
which has also been isolated from Streptomyces sp. in 19495,6
(Fig. 1).
the side chain of the ester group and replacing 3-hydroxypicolinate
moiety to commercially available and inexpensive 2-hydroxynico-
tinate moiety.
We proposed a three-step synthesis reaction of 2-hydroxyni-
cotinoyl-serine butyl esters, compound AD-1, AD-2 and AD-3
(Scheme 1). The first step is the esterification of L-serine (1) with
n-butanol by using p-toluensulfonic acid as a catalyst, yielding
51% of serine-butyl ester p-TsOH (2). In the second step, the
combination of DCC and DMAP7–9 is used to the formation of
2-hydroxynicotinoyl-serine-butyl ester (4) from the coupling
reaction between
2 and 2-hydroxynicotinic acid (3). Subse-
quently, the third step proceeded with three different reactions,
in which 2-hydroxynicotinoyl-serine-butyl ester (4) is reacted
with acetic anhydride, 3-phenylpropionic acid and octanoic acid
to produce AD-1, AD-2 and AD-3 in 69%, 43% and 69% yields,
respectively.
Antibiotic activity of 2-hydroxynicotinoyl-serine-butyl esters
and Antimycin A3 are summarized in Table 1. Antibiotic activity
of each ester and Antimycin A3 (standard) were tested against
Escherichia coli, Bacillus subtilis, Staphylococcus aureus and Candida
albicans. The result showed that AD-1, which contains an acetyl
group, has lower antibiotic activity than Antimycin A3 on E. coli
and C. albicans, and is equally active with Antimycin A3 on B. sub-
tilis and S. aureus. AD-2 which bears a phenyl group, has lower
antibiotic activity than Antimycin A3 on all the microorganism
tested. Whereas, AD-3, which contains an octanoyl group with
MIC values of 50 ppm and 100 ppm on B. subtilis and S. aureus,
respectively, has higher antibiotic activity than Antimycin A3
The significant antibiotic antifungal activity of UK-3A,
prompted us to carry out the synthesis of 2-hydroxynicotinoyl-ser-
ine-butyl esters related to UK-3A which have simple structure, but
are expected to have higher bioactivities than the original com-
pound UK-3A. In this research, we modified the structure of UK-
3A by opening the nine-membered dilactone ring system, varying
* Corresponding author. Tel./fax: +81 743 72 6084.
E-mail address: a-arsianti@ms.naist.jp (A. Arsianti).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.05.104

A. Arsianti et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4018–4020
4019
O
O
N
H
N
Bn
H
N
Bu
O
O
O
O
O
O
OHCHN
O
O
HO
O
HO
O
O
O
UK-3A
Antimycin A3
Figure 1. Structure of Antimycin A3 and UK-3A.
N
OH
.
H2N
O
p-TsOH H2N
H
N
a
N
OH
b
OH
OH
OH
+
OH
O
51%
O
O
33%
O
CO2H
O
O
1
2
3
4
N
OH
N
OH
O
N
OH
H
H
c
d
N
H
N
O
R
O
N
OH
O
AD-2)
43% (
O
69%
O
O
O
O
O
69% (AD-3)
O
O
AD-2, R = C6H5C2H4
AD-3
AD-1
4
, R = C7H15
Scheme 1. Synthesis of 2-hydroxynicotinoyl-serine-butyl esters. Reagent and conditions: (a) n-butanol, p-TsOH, benzene, 110 °C, 24 h; (b) DCC, DMAP, pyridine, 55 °C, 24 h;
(c) acetic anhydride, pyridine, rt, 4 h; (d) RCO2H (AD-2, R = C6H5C2H4; AD-3, R = C7H15), DCC, DMAP, rt, 4 h.
Table 1
toxicity level of 2-hydroxynicotinoyl-serine-butyl esters. The mea-
sure of toxicity is reflected by LC50. LC50 value greater than 30 ppm
Antibiotic activity of AD-1, AD-2, AD-3 and Antimycin A3
for tested samples were considered inactive (non-toxic).10,11 As
shown in Table 2, AD-1, AD-2 and AD-3 have LC50 values over
30 ppm, so they were assigned as non-toxic compounds. The high-
est potency to cause toxicity in A. salina was displayed by AD-2
(LC50: 266.83 ppm), which resulted in 100% shrimp death at a con-
centration of 1000 ppm. It was presumed that the presence of an
aromatic ring (phenyl moiety) on the side chain of AD-2 caused
an increase in its toxicity level. AD-1 (LC50: 811.01) displayed low-
er toxicity level than AD-2, and AD-3 (LC50: 3620.41 ppm) indi-
cated the lowest toxicity. Based on these results, AD-3, which
had the lowest potency to cause the toxicity in A. salina and also
showed antibiotic activity, should be considered and developed
as a new synthetic antibiotic that selectively inhibits B. subtilis
and S. aureus growth.
Compounds
Antibiotic activity, MIC (diameter of inhibition)a
E. coli
B. subtilis
S. aureus
C. albicans
AD-1
AD-2
AD-3
Antimycin A3
250 (7.00)
1000 (7.83)
75 (7.00)
250 (7.00)
500 (7.00)
50 (7.00)
250 (7.50)
1000 (7.50)
100 (7.00)
250 (8.00)
500 (7.50)
1000 (7.50)
250 (7.83)
50 (10.00)
50 (7.00)
250 (8.50)
a
MIC, minimum inhibitory concentration in ppm, diameter of inhibition (mm) is
given in parentheses.
Table 2
Brine shrimp assay of AD-1, AD-2 and AD-3 against Artemia salina
Compounds % of mortality in various concentrationa (ppm) Toxicity LC50
(ppm)
In conclusion, we have synthesized novel 2-hydroxynicotinoyl-
serine-butyl esters through three-step reactions afforded AD-1,
AD-2 and AD-3. Among them, AD-3 indicated the lowest potency
to cause the toxicity in A. salina and showed greater activity as
a growth inhibitor of B. subtilis and S. aureus compared to
Antimycin A3.
100
250
500
1000
AD-1
AD-2
AD-3
4.94
9.70
39.62
( 14.42)
76.67
( 5.77)
2.78
( 4.81)
58.66
( 16.21)
100
811.01
266.83
( 4.29)
26.67
( 5.77)
0
( 10.01)
55.58
( 2.41)
0
11.02
( 3.95)
3620.41
a
Values are means of three replications, standard deviation is given in
Acknowledgements
parentheses.
This research was supported partially by Nara Institute of Sci-
ence and Technology (Japan), Department of Chemistry, Faculty
of Mathematics and Science, University of Indonesia, and LIPI Re-
search Center for Chemistry (Indonesia) which is gratefully
appreciated.
(MIC: 250 ppm). Ueki group examined the antibiotic activity of UK-
3A in 1997, and found that UK-3A did not show antibiotic activity
against E. coli, B. subtilis and S. aureus, but indicated antibiotic
activity against C. albicans.3 These results revealed that AD-3
which contains a longer aliphatic chain (octanoyl group), appar-
ently more active as a growth inhibitor of B. subtilis and S. aureus
compare to AD-1, AD-2, Antimycin A3 and the original compound
UK-3A.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.05.104.
Brine Shrimp Lethality Test (BSLT) on Artemia salina provided by
Meyer10 was a convenient probe for preliminary assessment of the

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A. Arsianti et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4018–4020
6. Barrow, J. C.; Oleynek, J. J.; Marinelli, V.; Sun, H. H.; Kaplita, P.; Sedlock, D. M.;
References and notes
Gillum, A. M.; Chadwick, C. C.; Cooper, R. J. Antibiot. 1997, 50, 729.
7. Kurzer, F.; Zadeh, K. D. Chem. Rev. 1967, 67, 107.
8. Sheehan, J. C. J. Am. Chem. Soc. 1955, 77, 1067.
9. DeTar, D. F.; Silverstein, R. J. Am. Chem. Soc. 1966, 88, 1013.
10. Meyer, B. N.; Ferrigni, N. R.; Putnam, J. E.; Jacobsen, L. B.; Nichols, D. E.;
McLaughin, J. L. Planta Med. 1982, 45, 31.
11. Sam, T. W. In Bioactive natural products detection, isolation and structural
determination; Colegate, S. M., Molyneux, R. J., Eds.; CRC Press: Boca Raton,
1993; pp 301–383.
1. Georgopapadakou, N. H.; Walsh, T. J. J. Antimicrob. Agents Chemother. 1996, 40,
279.
2. Ueki, M.; Abe, K.; Hanafi, M.; Shibata, K.; Tanaka, T.; Taniguchi, M. J. Antibiot.
1996, 49, 639.
3. Ueki, M.; Kusumoto, A.; Hanafi, M.; Shibata, K.; Tanaka, T.; Taniguchi, M. J.
Antibiot. 1997, 50, 551.
4. Ueki, M.; Taniguchi, M. J. Antibiot. 1997, 50, 1052.
5. Tamelen, E. E. V.; Dickie, J. P.; Loomans, M. E.; Dewey, R. S.; Strong, F. M. J. Am.
Chem. Soc. 1961, 83, 1639.