Synthesis and antimicrobial activity of symmetrical two-tailed dendritic tricarboxylato amphiphiles

Article abstract of DOI:10.1016/j.bmc.2007.03.017

Two series of water-soluble, symmetrical two-tailed homologous dendritic amphiphiles-R₂NCONHC((CH₂)₂COOH)₃, 2(n,n), and R₂CHNHCONHC((CH₂)₂COOH)₃, 3(n,n), where R = n-C_nH_2n+1-were synthesized and compared to R″NHCONHC((CH₂)₂COOH)₃, 1(n), R″ = n-C_nH_2n+1, to determine whether antimicrobial activity was influenced by total or individual alkyl chain lengths, and whether antimicrobial activity depends on hydrophobicity or tail topology (one or two). In a broad screen of 11 microorganisms, 2(n,n) and 3(n,n) generally displayed higher minimal inhibitory concentrations (MICs) than 1(n) against growth as measured by broth microdilution assays. Chain-length specificity was observed against Candida albicans as 1(16), 2(8,8), and 3(8,8) showed the lowest MIC in their respective series. The one case where two-tailed compounds displayed the lowest MICs-3(10,10), 15 μM; 3(11,11), 7.2 μM; and 3(12,12), 6.9 μM-was against Cryptococcus neoformans.

Full text of DOI:10.1016/j.bmc.2007.03.017

Bioorganic & Medicinal Chemistry 15 (2007) 3842–3853
Synthesis and antimicrobial activity of symmetrical
two-tailed dendritic tricarboxylato amphiphiles
Eko W. Sugandhi,a Joseph O. Falkinham, IIIb and Richard D. Gandoura,*
aDepartment of Chemistry MC 0212, Virginia Tech, Blacksburg, VA 24061, USA
bDepartment of Biological Sciences MC 0406, Virginia Tech, Blacksburg, VA 24061, USA
Received 4 December 2006; revised 2 March 2007; accepted 8 March 2007
Available online 12 March 2007
Abstract—Two series of water-soluble, symmetrical two-tailed homologous dendritic amphiphiles—R2NCONHC((CH2)2COOH)3,
2(n,n), and R2CHNHCONHC((CH2)2COOH)3, 3(n,n), where R = n-CnH2n+1—were synthesized and compared to
R00NHCONHC((CH2)2COOH)3, 1(n), R00 = n-CnH2n+1, to determine whether antimicrobial activity was influenced by total or indi-
vidual alkyl chain lengths, and whether antimicrobial activity depends on hydrophobicity or tail topology (one or two). In a broad
screen of 11 microorganisms, 2(n,n) and 3(n,n) generally displayed higher minimal inhibitory concentrations (MICs) than 1(n)
against growth as measured by broth microdilution assays. Chain-length specificity was observed against Candida albicans as
1(16), 2(8,8), and 3(8,8) showed the lowest MIC in their respective series. The one case where two-tailed compounds displayed
the lowest MICs—3(10,10), 15 lM; 3(11,11), 7.2 lM; and 3(12,12), 6.9 lM—was against Cryptococcus neoformans.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
carboxyl groups, Am = amido linker, Ur = ureido lin-
ker, Cb = carbamato linker, and n = the number of car-
bons in the fatty chain. These amphiphiles with the
Newkome-type first-generation dendron5 as a head-
group have >20,000 lM solubility in aqueous trietha-
nolamine for the longest chains.4 As a result of the
relatively high solubility of these amphiphiles with very
hydrophobic chains, one can probe the inherent chain-
length specificities of antimicrobial activities without
resorting to organic solvents, suspensions, or emulsions
to deliver the agent.
Studies1,2 of homologous fatty acid carboxylates as ger-
micides date back to the 1920s and 1930s. Over the
years, measuring microbial susceptibility to long-chain
fatty acids has involved dissolving the fatty acid in an
organic solvent, typically alcohols and DMSO, then
diluting it in an aqueous broth. Natural saturated fatty
acids have low solubilities in aqueous solutions.3 As
such, uncertainties in measurements of antimicrobial
activities arise because the precise concentration of fatty
acid available to the microorganism is unknown. To
overcome this uncertainty and to probe the structure–
activity of the hydrocarbon moiety of an amphiphile,
highly hydrophobic headgroups are needed to enable
solubility in water.
O
OH
O
OH
R" = n-CnH2n+1
O
O
H
N
H
N
R"
O
OH
OH
R"
Our recent report4 describes the selective antimicrobial
activity of one-tailed, long-chain, water-soluble, den-
dritic tricarboxylato amphiphiles against a broad spec-
trum of microorganisms. Very long fatty chains, up to
22 carbon atoms, are included in these one-tailed amphi-
philes—3CAmn, 3CCbn, 3CUrn (1(n)), where 3C = three
O
O
3CAmn
3CCbn
OH
O
OH
O
OH
O
O
H
N
H
N
OH
R"
Keywords: Dendritic amphiphiles; Antimicrobial activity; Hydropho-
bicity, Structure–activity study.
O
*
Corresponding author. Tel.: +1 540 231 3731; fax: +1 540 231
3255; e-mail: gandour@vt.edu
3CUrn, 1(n)
O
OH
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.03.017

E. W. Sugandhi et al. / Bioorg. Med. Chem. 15 (2007) 3842–3853
3843
To further understand the characteristics that determine
antimicrobial activity, we examine how hydrophobicity
and tail topology (one or two) affect antimicrobial activ-
ity. The two series, 2(n,n) and 3(n,n), of two-tailed
amphiphiles correspond with the 1(n) series of one-tailed
amphiphiles; the total carbon number (2 · n) equals that
of the 1(n) series. The 2(n,n) series, where ‘n’ represents
the number of carbons in a tail, has two tails attached to
the distal nitrogen (from the headgroup) of the ureido
linker. The 3(n,n) series, where ‘n’ represents the number
of carbons in a tail, has a single carbon separating the
ureido linker and the two symmetrical tails. In other
words, a long tail is connected to the distal nitrogen
on the ureido linker via the middle carbon atom of a
long chain (R2CH–).
and that the pattern of antimicrobial activity will enable
designing more active antimicrobial amphiphiles. Fur-
ther, highly active amphiphiles can then lead to identifi-
cation of novel targets for antimicrobial activity.
2. Chemistry
2.1. Synthesis of 2(n,n)
Based on the reaction of WeNCO and piperidine,7 we
expected acyclic secondary amines to react readily with
WeNCO to form 4(n,n) (Scheme 1). The even-numbered
symmetrical dialkylamines (8b,d) are readily available;
the odd-numbered compounds (8a,c,e) required synthe-
sis. Our procedure followed that of Nagase et al.,8 who
synthesized secondary amines 8 by treating N-alkylal-
kanamides 7 with lithium aluminum hydride. More
O
OH
recently, Djedovic et al.9 reported syntheses of
O
ˇ
R
N
H
N
symmetrical N-alkylalkanamines 8 with a similar proce-
dure. Condensing 5a,c,e and 6a,c,e gave 7a,c,e, which
were isolated by flash column chromatography. Reduc-
tion of 7a,c,e produced 8a,c,e, which were used as iso-
lated along with commercial 8b,d for the reaction with
WeNCO to give 4(n,n). Flash column chromatography
of crude products gave purified homologues, which were
fully characterized. Formolysis of the tri-tert-butyl esters
gave 2(n,n) in high yields of recrystallized products.
OH
R
O
2(n,n)
O
OH
OH
R = n-CnH2n+1
O
O
H
N
H
N
R
OH
2.2. Synthesis of 3(n,n)
O
R
3(n,n)
The synthesis began with Grignard reactions of 1-bro-
moalkanes 9a–f and ethyl formate 10 to form dialkylcar-
binols 11a–f following a recent synthesis10 of 11f
(Scheme 2). After recrystallization, the known products
were identified by comparison with melting points11–14
O
OH
The objective is to understand how the tail topology
(one or two) affects antimicrobial activity and to dis-
cover new leads for affordable anti-infectives. Here, we
describe the synthesis of two homologous series of sym-
metrical two-tailed dendritic amphiphiles. Because of
the similarity of the total number of carbon atoms in
the two tails, the different series have similar hydrophob-
icities (e.g., logD).6 By comparing antimicrobial activi-
ties as the minimal inhibitory concentrations (MICs)
against a broad spectrum of microorganisms, the simi-
larities and differences among 3(n,n), 2(n,n), and 1(n)
can be identified. We anticipate that these series can
serve as probes of membrane structure and function,
1
and the H NMR spectrum10 of 11f with appropriate
adjustment for integration of the methylenes for each
homologue. The rapid reactions of 11a–f with mesyl
1
chloride gave 12a–f as clean products as judged by H
NMR spectra in comparison with the spectrum15 of
the known 12(n = 16) making adjustments for each
homologue. Based on a procedure16 for a smaller
analogue, 12a–f reacted with sodium azide in hot
DMF to produce 13a–f after flash column chromatogra-
phy. As these compounds were unknown and stable, full
characterization ensued. Reductions of 13a–f to 14a–f
O
O
Et3N, THF
LiAlH4, Et2O
+
N
R
H2
R'
N R
H
R'
N R
H
R'
Cl
rt, 15 min
71–85%
reflux, 16 h
80–84%
5a,c,e
6a,c,e
7a,c,e
8a–e
a, R = C7H15, R' = C6H13; c, R = C9H19, R' = C8H17; e, R = C11H23, R' = C10H21
O
O
R
N
R
N
OtBu
8, CH2Cl2
HCO2H
H
N
H
OCN
N
OtBu
OH
R
R
O
rt, 16 h
rt, 9 h
3
O
3
77–90%
O
3
60–85%
WeNCO
4(n,n)
2(n,n)
Scheme 1. Synthesis of 2(n,n).

3844
E. W. Sugandhi et al. / Bioorg. Med. Chem. 15 (2007) 3842–3853
OH
OMs
R
N3
O
Mg, THF
MsCl, Et3N
NaN3, DMF
H2, 10% Pd/C
+
RBr
R
R
R
R
R
H
OEt
60 °C, 3 d
49–56%
THF, rt, 15 min
90–98%
80 °C, 4 h
78–97%
EtOH, rt, 3 h
75–88%
10
9a–f
11a–f
12a–f
13a–f
R = n-CnH2n+1, a, n = 7; b, n = 8; c, n = 9; d, n = 10; e, n = 11; f, n = 12
NH2
R
O
O
R
R
R
R
WeNCO, rt
HCO2H
H
N
H
N
H
N
H
N
OtBu
R
OH
3
CH2Cl2, 16 h
60–87%
rt, 9 h
81–87%
3
O
O
14a–f
Scheme 2. Synthesis of 3(n,n).
by catalytic hydrogenation proceeded to clean product
as judged by H NMR spectra in comparison with the
pneumoniae, and Saccharomyces cerevisiae were distin-
guished from the other microorganisms by their suscep-
tibility to all 5 members of the 1(n) series tested.
(Although the three bacteria have an outer membrane,
S. cerevisiae and the remaining microorganisms lack
an outer membrane, so that is apparently not the com-
mon cellular structure responsible for susceptibility.)
1
spectrum17 of the known 14c making adjustments for
each homologue. The amines 14a–f reacted with WeN-
CO to produce 15(n,n), which were purified by flash col-
umn chromatography and recrystallized. Formolysis of
the tri-tert-butyl esters gave 3(n,n), which were
recrystallized.
Lactobacillus plantarum, Staphylococcus aureus, methi-
cillin-resistant S. aureus (MRSA), Micrococcus luteus,
and Aspergillus niger were simply not inhibited to any
degree by the compounds (Table 1). Lack of antimicro-
bial activity against L. plantarum is advantageous
because lactobacilli, members of the skin microflora
(e.g., vagina), provide some protection to acquisition
of infections (e.g., sexually transmitted pathogens).21
2.3. Aqueous solubility
Following our previous method,4 all members of both
2(n,n) and 3(n,n) dissolved readily in a solution of
triethanolamine/water [ꢀ5% (wt/vol)]; the final solution
contained P9:1 molar equivalents of triethanol-
amine:2(n,n) or 3(n,n). Choosing the counterions for
the ionized carboxyls followed from a study18 of N-lau-
royl-L-glutamate in water; the triethanolammonium salt
dissolved to a much greater concentration than did the
potassium salt. As chain length affects the pKa of fatty
acids because of aggregation,19 we explored several con-
ditions to achieve the maximum solubility in aqueous
solutions while maintaining the minimum equivalents
of triethanolamine (pKa 7.76).20 Stock solutions
(12.5 mg/mL) for all homologues were prepared by sim-
ply vortexing the tricarboxylic acid in the aqueous trieth-
anolamine solution. Final stock concentrations ranged
from 19,500 to 25,700 lM depending on the formula
weight of the homologue. Stock solutions of the amphi-
philes in aqueous triethanolamine had a pH of 8–9.
These results with long chains contrasted with those
studies22,23 that have shown that medium chain free fatty
acids (C8–C12) exhibit the highest antibiotic activity
against a variety of mycobacteria, including M. smegma-
tis. C. neoformans was unique by its susceptibility to all 5
members of the 3(n,n) series (Table 1). With the excep-
tion of C. neoformans (e.g., 2(10,10)), the panel of micro-
organisms, including the other pathogenic yeast Candida
albicans, were resistant to the 2(n,n) series (Table 1).
Amphiphile-series specificity is shown when a particular
series of amphiphiles—1(n), 2(n,n) or 3(n,n)—is specifi-
cally active against
a
tested microorganism.
Amphiphile-series-specific antimicrobial activities were
displayed by the 1(n) series against E. coli, K. pneumo-
niae, M. smegmatis, and S. cerevisiae (Table 1).
Members of the 1(n) series were significantly more active
against those microorganisms than the corresponding
members of the 2(n,n) and 3(n,n) series. The one excep-
tion to that statement was activity against S. cerevisiae
by 2(8,8) (MIC = 380 lM) and 1(16) (MIC = 550 lM);
2(8,8) showed incomplete inhibition but 1(16) showed
complete inhibition.
3. Microbiology
3.1. Antimicrobial results
The three series of dendritic tricarboxylato amphiphiles
did not display a uniform pattern of activity against the
broad spectrum of microorganisms tested, but displayed
amphiphile-series-, species-, or chain-length-specific pat-
terns. Although the MIC values obtained were not in the
range of 1 lM or lower, a few MICs were below 10 lM
(Table 1).
Species specificity was displayed when a particular
microbial species is uniquely susceptible to a particular
amphiphile. The 1(n) homologues were active against
the two Gram-negative bacteria, the mycobacterium
and S. cerevisiae, they were not active against Gram-
positive bacteria, the pathogenic yeast, and the
filamentous fungus (Table 1). Two-tailed amphiphiles
were only active against the yeast, but not the bacteria,
Cryptococcus neoformans was unique among the micro-
organisms tested by virtue of its susceptibility to mem-
bers of both series of two-tailed amphiphiles and the
one-tailed tricarboxylato dendritic amphiphiles (Table 1).
Mycobacterium smegmatis, Escherichia coli, Klebsiella

E. W. Sugandhi et al. / Bioorg. Med. Chem. 15 (2007) 3842–3853
3845
mycobacterium, or filamentous fungus. For the yeasts
tested, some homologues of the 2(n,n) series had antimi-
crobial activity against both C. albicans and C. neofor-
mans, while all but one of the 3(n,n) amphiphile series
had strong antimicrobial activity against C. neoformans.
As only particular members of the homologous series
with specific chain length show distinct activities, these
amphiphiles also displayed another type of specificity,
namely chain-length specificity. Chain-length specific-
ity was displayed when amphiphiles in a homologous
series with a particular chain length are exceptionally
active compared to those with other chain lengths.
Chain-length specificity was displayed by members of
the 1(n) series against M. smegmatis, S. cerevisiae,
C. albicans, and C. neoformans, by those of the 2(n,n)
series against C. albicans and C. neoformans, and
by those of the 3(n,n) series against C. neoformans
(Table 1).
In the 1(n) series, the MIC of 1(16) against both
C. albicans and C. neoformans was 47 lM, the MIC
of 1(18) against M. smegmatis was 33 lM, and the
MIC of 1(22) against S. cerevisiae was 30 lM. This
chain-length specificity was not found in the 1(n) ser-
ies against the rest of the microorganisms tested and
the homologues of 1(n) were not particularly active
against those microorganisms. Among the two-tailed
amphiphiles, the three homologues 3(10,10), 3(11,11),
and 3(12,12) showed unique and promising MICs of
15 lM, 7.2 lM, and 6.9 lM, respectively, against
C. neoformans.
Chain-length specificity was particularly demonstrated
by 2(8,8) against C. albicans (MIC = 190 lM) and
2(10,10) against C. neoformans (MIC = 62 lM) (Table
1). As the strain of C. albicans was grown at 37 ꢁC, it
had low cell surface hydrophobicity,24 which likely con-
tributed to relative resistance of the cells to amphiphiles.
3.2. Comparing hydrophobicity and antimicrobial activity
Partitioning of these amphiphiles into both outer and
cytoplasmic membranes should be a major contributor
to their antimicrobial activity. From simple approxi-
mations of hydrophobicity, the distribution coefficient
increases with increasing alkyl chain length. Calcula-
tions6 of logD at pH 7.4 give values that range from
ꢁ5.1 for 1(14) to ꢁ1.9 for 1(22) in increments of 0.8
for each additional –CH2–CH2– unit, from ꢁ5.2 for
2(7,7) to ꢁ2.0 for 2(11,11) in increments of 0.8 for
each additional –CH2– in each chain, and from ꢁ5.0
for 3(7,7) to ꢁ1.0 for 3(12,12) in increments of 0.8
for an additional –CH2– in each chain. Because of
the multiple ionization states of the headgroup, logD
is the appropriate choice. These calculations suggest
that the triheaded amphiphiles are substantially more
likely to favor being in a hydrophilic phase than in
a hydrophobic phase.
Comparing logD versus MIC for each member of the
three series reveals the similarities with respect to the
antimicrobial activity against C. albicans (Fig. 1).

3846
E. W. Sugandhi et al. / Bioorg. Med. Chem. 15 (2007) 3842–3853
4. Conclusions
-1
-1.5
-2
4.1. Comparison with prior work
Many compounds containing two symmetrical alkyl
chains bonded to a nitrogen atom have been synthesized
and studied for their antibacterial and antifungal activ-
ity. To our knowledge, none of these compounds have
anionic headgroups as reported in this study. In these
previous studies, the compounds are in the neutral25,26
or charged form.27–30 The charged forms involve quater-
nary ammonium with chloride counterions,27–29 or
intercalation complexes30 with montmorillonite or sapo-
nite. In a study27 of antibacterial properties against
S. aureus, several homologous tertiary amines quaternize
cross-linked chloromethyl polystyrenes; antibacterial
efficiency increases as the alkyl chain length increases.
-2.5
-3
-3.5
-4
1(n)
2(n,n)
3(n,n)
-4.5
-5
-6
-4
-2
0
logD
Figure 1. Relationship between MIC and logD for C. albicans. Error
bars (not shown for clarity) are 0.3. Lines connecting the symbols are
eye guides.
Unlike compounds containing a nitrogen atom directly
bonded to two symmetrical fatty chains, there are only
few studies on compounds containing a nitrogen atom
bonded to a swallowtail, a long fatty chain bonded
through the middle carbon atom. These compounds
have been synthesized and investigated for antibacte-
rial31,32 and antifungal31 activity. These compounds
have cationic31,32 and neutral31 headgroups.
-2
-2.5
-3
4.2. Summary and mechanistic speculation
-3.5
-4
In our study, amphiphiles with two tails are less active
than the amphiphiles with one tail. However, two results
worth further investigation emerge from this study. The
first result is the good activity of 3(11,11) and 3(12,12)
against C. neoformans. It will be interesting to measure
the antimicrobial activity of longer homologues of
3(n,n). The second result is the chain-length specificity
for activity against C. albicans by 1(16), 2(8,8), and
3(8,8). For the most part, long one-tailed amphiphiles
were more antimicrobial than two-tailed amphiphiles
with the same total chain length. As two-tailed amphi-
philes had moderate antimicrobial activity, longer chain
two-tailed amphiphiles may have even higher antimicro-
bial activities compared to the long one-tailed amphi-
philes. Accordingly, measurement of the activity of the
odd-numbered chain homologues and those with unsym-
metrical tails is planned. Further, substitutions in the
chain might lead to more active antifungal agents as evi-
denced by recent studies of synthetic fatty acids.33–36
-4.5
1(n)
2(n,n)
3(n,n)
-5
-5.5
-6
-4
-2
0
logD
Figure 2. Relationship between MIC and logD for C. neoformans.
Error bars (not shown for clarity) are 0.3. Lines connecting the
symbols are eye guides.
All series show a similar pattern of activity against
C. albicans, a microorganism that shows chain-length
specificity. In this comparison, one can see that the
logD predicts activity, but it is not the only property
of the amphiphile that contributes to the antimicrobial
activity. As the one-tail amphiphile 1(16) has better
activity than 2(8,8) and 3(8,8), tail topology also
contributes.
Although the mechanism of action of these amphiphiles
remains to be determined, we expect that these amphi-
philes exert their antimicrobial activity by interacting
with the cell membranes or cell walls or both. Excluding
detergency (disrupting cell walls and solubilizing mem-
branes), these amphiphiles can inactivate microorgan-
isms by several mechanisms: (1) as monomers,
changing fluidity and porosity of membranes; (2) as
monomers, altering membrane-associated pathways
(e.g., cell signaling); (3) as monomers, changing the flow
of constituents and nutrients between a cell and a med-
ium; and (4) as monomers, inhibiting membrane-associ-
ated enzymes or enzymes involved in fatty acid
synthesis.
Comparing logD versus MIC for each member of the
three series reveals significant differences with respect
to the antimicrobial activity against C. neoformans
(Fig. 2). For C. neoformans, there is no similarity in
the patterns among the three series; logD does not pre-
dict activity. Amphiphiles 1(16), 2(10,10), and 3(12,12)
are the most active members of the respective series.
Clearly, the 3(n,n) series is the best among these three
series. The trend in the plot of the 3(n,n) series suggests
that longer homologues should be tested to see whether
3(12,12) is the best in the series.

E. W. Sugandhi et al. / Bioorg. Med. Chem. 15 (2007) 3842–3853
3847
As our recent study37 of the antimycobacterial activity
of 1(n) reveals, the MIC (and possibly the mechanism
of action) depends on the number of colonies in the
inoculum. Studies are planned to measure this inoculum
effect with 2(n,n) and 3(n,n) against selected
microorganisms.
5.2.1. N-Heptylheptanamide (7a). The general procedure
described above afforded a white solid (2.50 g, 85%); mp
1
45.0–45.7 ꢁC (lit.9 mp 44–46 ꢁC); H NMR (CDCl3) d
0.88 (t, 6H), 1.20–1.35 (bm, 14H), 1.50 (m, 2H), 1.62
(m, 2H), 2.17 (t, 2H), 3.24 (m, 2H), 5.69 (bs, 1H) (lit.
250 MHz,39 300 MHz9); 13C NMR (CDCl3) d 14.19,
14.20, 22.69, 22.75, 26.0, 27.1, 29.15, 29.17, 29.9, 31.7,
31.9, 37.1, 39.7, 173.3 (lit.9 75 MHz); IR 3287, 2955,
2921, 2851, 1640, 1555, 1467 (lit.39 neat); HRMS: for
C14H30NO [M+H]+ calcd 228.2327, found 228.2328.
5. Experimental
5.1. General chemical procedures
5.2.2. N-Nonylnonanamide (7c). The general procedure
described above afforded a white solid (3.05 g, 83%);
mp 62.7–63.39 ꢁC (lit.40 mp 52–55 ꢁC); 1H NMR
(CDCl3) d 0.88 (t, 3H), 1.20–1.35 (bm, 22H), 1.48 (m,
2H), 1.62 (m, 2H), 2.15 (t, 2H), 3.25 (m, 2H), 5.36 (bs,
1H); 13C NMR (CDCl3) d 14.1, 22.66, 22.68, 25.9,
26.9, 29.18, 29.25, 29.32, 29.35, 29.5, 29.7, 31.84,
31.87, 37.0, 39.5, 173.03; IR 3287, 2955, 2918, 2849,
1638, 1551, 1467; HRMS: for C18H38NO [M+H]+ calcd
284.2953, found 284.2940.
Chemicals were obtained from Aldrich, Acros, Lan-
caster, and TCI; they were used without further puri-
fication. Solvents were reagent grade or HPLC grade;
they were used as received unless otherwise specified.
THF was distilled from sodium/benzophenone ketyl.
WeNCO was prepared as described38 with a shorter
reaction time—15 min. Analytical thin layer chroma-
tography was performed on polyester-coated silica
˚
gel 60 A strips and detected by treating with 10%
ethanolic phosphomolybdic acid reagent (20 wt. %
solution in ethanol) followed by heating. Flash col-
umn chromatography was carried out on silica gel
5.2.3. N-Undecylundecanamide (7e). The general proce-
dure described above afforded a white solid (3.12 g,
71%); mp 73.9–74.7 ꢁC (lit.41 mp 73 ꢁC); 1H NMR
(CDCl3) d 0.88 (t, 6H), 1.20–1.35 (bm, 32H), 1.49 (m,
2H), 1.62 (m, 2H), 2.15 (t, 2H), 3.24 (m, 2H), 5.36 (bs,
1H); 13C NMR (CDCl3) d 14.3, 22.9, 26.1, 27.2, 29.53,
29.54, 29.59, 29.73, 29.77, 29.79, 29.80, 29.9, 32.1,
37.2, 39.7, 173.3; IR 3312, 2953, 2914, 2849, 1634,
1544, 1471 (lit.42 bands); HRMS: for C22H46NO
[M+H]+ calcd 340.3579, found 340.3584.
˚
(60 A); samples were loaded as concentrated solutions
in the solvent system needed; column diame-
ter · height (13/4 · 6 in), eluted samples varied be-
tween ꢀ2.00 and 4.00 g, flow rate (ꢀ1.5–2 in/min)
was controlled by air pressure. Solutions were con-
centrated by rotary evaporation. Melting ranges were
determined in open capillary tubes and are uncor-
rected. NMR spectra were recorded at 400 and
100 MHz for 1H and 13C, respectively, and reported
in ppm relative to the known solvent residual peak.
Resonances were reported in the order of chemical
shift (d), followed by the splitting pattern, and the
number of protons. Abbreviations used in the split-
ting pattern were as follows: s = singlet, d = doublet,
5.3. General procedures for N-alkylalkan-1-amine (8a,c,e)
An N-alkylalkanamide 7 (9.58 mmol) was added slowly
to a stirred suspension of LiAlH4 (574 mg, 14.7 mmol)
in Et2O (50 mL). Addition took place in an ice–salt
bath, while the temperature was maintained at
0.0 1.0 ꢁC. After the addition, the reaction mixture
was warmed to rt and then heated to reflux. After being
refluxed overnight, the resulting reaction mixture was
cooled to rt. Successive addition of water (2 mL), NaOH
(10 M, 2.5 mL), and water (4 mL) yields a sticky white
solid. The organic layer was decanted, and the sticky
white solid was washed once with Et2O (10 mL). The
organic layers were combined, dried with Na2SO4, and
concentrated to give clear liquids (n = 7, 9), and a white
solid (n = 11) in 80–85% yield. Each resulting N-alkylal-
kan-1-amine (8a,c,e) was used for the next step without
further purification.
t = triplet,
quin = quintet,
m = multiplet,
and
b = broad. IR spectra were recorded on neat samples
with an FTIR equipped with a diamond ATR system
and reported in cmꢁ1. HRMS data were obtained on
a dual-sector mass spectrometer in FAB mode with
2-nitrobenzyl alcohol as the proton donor. Elemental
analyses were performed by Atlantic Microlabs, Inc.,
Norcross, GA.
5.2. General procedures for N-alkylalkanamide (7a,c,e)
An alkan-1-amine 5 (13.0 mmol) and Et3N (15.6 mmol)
were combined, dissolved in dry THF (38 mL), and stir-
red in the ice bath. An acid chloride 6 (14.3 mmol) was
added dropwise to the solution, which was maintained
at 2.5 1.0 ꢁC. After the addition, the ice bath was
removed, and the reaction mixture was stirred for
another 15 min at rt. The resulting reaction mixture
was washed successively with HCl (1 M, 7.5 mL),
saturated aqueous NaHCO3 (12 mL), and water
(12 mL). The organic layer was dried with Na2SO4
and concentrated to dryness to give a white solid, which
was purified by flash column chromatography to give a
pure white solid, which gave a single spot on TLC with
2% MeOH in CH2Cl2 (Rf = 0.23–0.31).
5.3.1. N-Heptylheptan-1-amine (8a). The general proce-
dure described above afforded a clear liquid (1.72 g,
1
84%) (lit.9 mp 30–31 ꢁC); H NMR (CDCl3) d 0.88 (t,
6H), 1.20–1.35 (bm, 16H), 1.48 (m, 4H), 2.58 (t, 4H)
(lit. 60 MHz,43 300 MHz9); 13C NMR (CDCl3) d 14.3,
22.8, 27.6, 29.5, 30.4, 32.0, 50.4 (lit.9 75 MHz); IR
2955, 2922, 2853, 1457, 1377, 1129 (lit.43 neat); HRMS:
for C14H32N [M+H]+ calcd 214.2535, found 214.2538.
5.3.2. N-Nonylnonan-1-amine (8c). The general proce-
dure described above afforded a clear liquid (2.14 g,

3848
E. W. Sugandhi et al. / Bioorg. Med. Chem. 15 (2007) 3842–3853
83%) (lit.40 37–39 ꢁC); 1H NMR (CDCl3) d 0.88 (t, 6H),
1.20–1.35 (bm, 24H), 1.47 (m, 4H), 2.58 (t, 4H); 13C
NMR (CDCl3) d 14.3, 22.9, 27.7, 29.5, 29.79, 29.82,
30.5, 32.1, 50.4; IR 2954, 2921, 2852, 1466, 1377, 1130;
HRMS: for C18H40N [M+H]+ calcd 270.3161, found
270.3148.
156.1, 173.15; IR 3377, 2922, 1732, 1725, 1617, 1365,
1144; HRMS: for C41H79N2O7 [M+H]+ calcd
711.5887, found 711.5893. Anal. Calcd for
C41H78N2O7: C, 69.25; H, 11.06; N, 3.94. Found: C,
69.34; H, 11.27; N, 3.96.
5.4.4. Di-tert-butyl 4-(2-tert-butoxycarbonylethyl)-4-(3,3-
didecylureido)heptanedioate, 4(10,10). The general proce-
dure described above afforded a white solid (2.96 g,
85%); mp 49.7–50.4 ꢁC; 1H NMR (CDCl3) d 0.88 (t,
6H), 1.20–1.35 (bs, 28H), 1.43 (s, 27H), 1.50 (m, 4H),
1.96 (m, 6H), 2.21 (m, 6H), 3.11 (m, 4H), 4.55 (s, 1H);
13C NMR (CDCl3) d 14.1, 22.7, 27.0, 28.1, 28.7, 29.3,
29.49, 29.55, 29.63, 29.9, 30.6, 31.9, 47.3, 56.6, 80.4,
156.1, 173.2; IR 3389, 2925, 1729, 1719, 1618, 1365,
1143; HRMS: for C43H83N2O7 [M+H]+ calcd
739.6200, found 739.6213. Anal. Calcd for
C43H82N2O7: C, 69.88; H, 11.18; N, 3.79. Found: C,
70.02; H, 11.41; N, 3.80.
5.3.3. N-Undecylundecan-1-amine (8e). The general pro-
cedure described above afforded a white solid (2.50 g,
1
80%); mp 47.5–48.3 ꢁC (lit.44 51.5–52.5 ꢁC); H NMR
(CDCl3) d 0.88 (t, 6H), 1.20–1.35 (bm, 32H), 1.47 (m,
4H), 2.58 (t, 4H); 13C NMR (CDCl3) d 14.3, 22.9,
27.7, 29.6, 29.8, 30.5, 32.1, 50.4; IR 2955, 2913, 2827,
1469, 1375, 1127; HRMS: for C22H48N [M+H]+ calcd
326.3787, found 326.3775.
5.4. General procedures for two-tailed tri-tert-butyl
esters, 4(n,n)
A dialkylamine 8 (4.95 mmol) was added slowly to a
solution of WeNCO (4.71 mmol) in CH2Cl2 (20 mL).
The resulting transparent solution was stirred at rt.
After stirring overnight, the solution was concentrated
to leave a crude white solid. The crude solid was purified
by flash column chromatography with 5:1 (v/v) hex-
ane:EtOAc to give a white solid (60–85%), which gave
a single spot on TLC (hexane/EtOAc, 5:1, Rf = 0.18–
0.25).
5.4.5. Di-tert-butyl 4-(2-tert-butoxycarbonylethyl)-4-(3,3-
diundecylureido)heptanedioate, 4(11,11). The general
procedure described above afforded a white solid
(2.64 g, 73%); mp 42.9–43.5 ꢁC; 1H NMR (CDCl3) d
0.88 (t, 6H), 1.20–1.35 (bm, 32H), 1.43 (bs, 27H), 1.50
(bm, 4H), 1.96 (m, 6H), 2.21 (m, 6H), 3.11 (m, 4H),
4.56(s, 1H); 13C NMR (CDCl3) d 14.1, 22.65, 27.03,
28.1, 28.7, 29.3, 29.49, 29.59, 29.62, 29.9, 30.6, 31.9,
47.3, 56.6, 80.35, 156.1, 173.1; IR 3372, 2923, 1734,
1725, 1616, 1365, 1143; HRMS: for C45H87N2O7
[M+H]+ calcd 767.6513, found 767.6498. Anal. Calcd
for C45H86N2O7: C, 70.45; H, 11.30; N, 3.65. Found:
C, 70.45; H, 11.46; N, 3.71.
5.4.1. Di-tert-butyl 4-(2-tert-butoxycarbonylethyl)-4-(3,3-
diheptylureido)heptanedioate, 4(7,7). The general proce-
dure described above afforded a white solid (2.44 g,
1
79%); mp 53.5–54.1 ꢁC; H NMR (CDCl3) d 0.88 (t,
6H), 1.20–1.35 (bm, 16H), 1.43 (bs, 27H), 1.51 (m,
4H), 1.96 (m, 6H), 2.22 (m, 6H), 3.12 (m, 4H), 4.56(s,
1H); 13C NMR (CDCl3) d 14.0, 22.5, 27.0, 28.0, 28.7,
29.1, 29.9, 30.6, 31.8, 47.2, 56.6, 80.3, 156.1, 173.1; IR
3368, 2925, 1733, 1725, 1615, 1365, 1143; HRMS: for
C37H71N2O7 [M+H]+ calcd 655.5261, found 655.5242.
Anal. Calcd for C37H70N2O7: C, 67.85; H, 10.77; N,
4.28. Found: C, 67.89; H, 10.84; N, 4.30.
5.5. General procedures for two-tailed triacids, 2(n,n)
A tri-tert-butyl ester 4(n,n) (3.33 mmol) was dissolved in
99% HCOOH so that its concentration was 0.1 M. The
mixture might need to be warmed slightly to get all the
4(n,n) to dissolve. Once dissolved to give a clear colorless
solution, the solution was stirred at rt. After 9 h, the
resulting milky white solution was concentrated. The
white solid was recrystallized from EtOAc to yield a
white solid (77–90%).
5.4.2. Di-tert-butyl 4-(2-tert-butoxycarbonylethyl)-4-(3,3-
dioctylureido)heptanedioate, 4(8,8). The general proce-
dure described above afforded a white solid (1.93 g,
1
60%); mp 56.8–57.5 ꢁC; H NMR (CDCl3) d 0.89 (t,
5.5.1. 4-(2-Carboxyethyl)-4-(3,3-diheptylureido)hepta-
nedioic acid, 2(7,7). The general procedure described
above afforded a white solid (1.46 g, 90%); mp 125.3–
6H), 1.20–1.35 (bm, 20H), 1.43 (s, 27H), 1.50 (m, 4H),
1.96 (m, 6H), 2.21 (m, 6H), 3.11 (m, 4H), 4.55 (s, 1H);
13C NMR (CDCl3) d 14.1, 22.6, 27.0, 28.1, 28.7, 29.27,
29.44, 29.9, 30.6, 31.8, 47.3, 56.6, 80.4, 156.1, 173.2;
IR 3366, 2923, 1732, 1724, 1615, 1365, 1144; HRMS:
for C39H75N2O7 [M+H]+ calcd 638.5574, found
638.5540. Anal. Calcd for C39H74N2O7: C, 68.58; H,
10.92; N, 4.10. Found: C, 68.55; H, 11.07; N, 4.10.
1
125.9 ꢁC; H NMR (DMSO-d6) d 0.83 (t, 6H), 1.10–
1.30 (bm, 16H), 1.38 (m, 4H), 1.81 (m, 6H), 2.09 (m,
6H), 3.09 (m, 4H), 5.07 (s, 1H), 12.00 (bs, 3H); 13C
NMR (DMSO-d6) d 14.4, 22.5, 26.7, 28.5, 28.7, 29.0,
30.2, 31.7, 46.3, 56.4, 156.3, 175.1; IR 2926, 1735,
1701, 1590, 1527, 1285, 1174; HRMS: for C25H47N2O7
[M+H]+ calcd 487.3383 found 487.3391. Anal. Calcd
for C25H46N2O7: C, 61.70; H, 9.53; N, 5.76. Found: C,
61.61; H, 9.50; N, 5.75.
5.4.3. Di-tert-butyl 4-(2-tert-butoxycarbonylethyl)-4-(3,3-
dinonylureido)heptanedioate, 4(9,9). The general proce-
dure described above afforded a white solid (2.34 g,
1
70%); mp 62.6–63.4 ꢁC; H NMR (CDCl3) d 0.88 (t,
5.5.2. 4-(2-Carboxyethyl)-4-(3,3-dioctylureido)hepta-
nedioic acid, 2(8,8). The general procedure described
above afforded a white solid (1.47 g, 86%); mp 120.4–
6H), 1.20–1.35 (bm, 24H), 1.44 (bs, 27H), 1.51 (bm,
4H), 1.97 (m, 6H), 2.22 (m, 6H), 3.12 (m, 4H), 4.57 (s,
1H); 13C NMR (CDCl3) d 14.1, 22.6, 27.0, 28.1, 28.7,
29.2, 29.49, 29.58, 29.9, 30.6, 31.8, 47.3, 56.6, 80.4,
1
120.8 ꢁC; H NMR (DMSO-d6) d 0.80 (t, 6H), 1.10–
1.30 (bm, 20H), 1.38 (m, 4H), 1.81 (m, 6H), 2.08 (m,

E. W. Sugandhi et al. / Bioorg. Med. Chem. 15 (2007) 3842–3853
3849
6H), 3.09 (m, 4H), 5.06 (s, 1H), 12.00 (bs, 3H); 13C
NMR (DMSO-d6) d 13.9, 22.0, 26.2, 28.0, 28.2, 28.7,
28.8, 29.7, 31.2, 45.8, 55.9, 155.9, 174.7; IR 2921,
1713, 1694, 1607, 1533, 1293, 1175; HRMS: for
C27H51N2O7 [M+H]+ calcd 515.3702, found 515.3696.
Anal. Calcd for C27H50N2O7: C, 63.01; H, 9.79; N,
5.40. Found: C, 62.98; H, 9.79; N, 5.40.
MeOH (4 mL) and saturated NH4Cl (30 mL). The
organic layer was separated and washed with saturated
NaCl (65 mL). The organic layer was dried and concen-
trated to give a light yellow solid, which was recrystal-
lized from EtOAc to give a pure white solid (11) in
1
moderate yield (49–56%); H NMR (CDCl3) d 0.88 (t,
6H), 1.20–1.50 (bm, 24–44Hs), 3.58 (bm, 1H) (lit.10
200 MHz, 11f); 11a mp 53.5–54.3 ꢁC (lit.12 52–52.6 ꢁC);
11b 61.7–62.2 ꢁC (lit.12 60.8–61.2 ꢁC); 11c 67.0–67.4 ꢁC
(lit.13 65.9–66.1 ꢁC); 11d 71.1–72.0 ꢁC (lit.14 71.3–
72.5 ꢁC); 11e 76.8–77.6 ꢁC (lit.12 75.5–75.7 ꢁC); 11f
80.2–81.0 ꢁC (lit.11 79.5–80.5 ꢁC).
5.5.3. 4-(2-Carboxyethyl)-4-(3,3-dinonylureido)hepta-
nedioic acid, 2(9,9). The general procedure described
above afforded a white solid (1.59 g, 88%); mp 121.3–
1
121.7 ꢁC; H NMR (DMSO-d6) d 0.83 (t, 6H), 1.10–
1.30 (bm, 24H), 1.38 (m, 4H), 1.82 (m, 6H), 2.09 (m,
6H), 3.09 (m, 4H), 5.07 (s, 1H), 11.98 (bs, 3H); 13C
NMR (DMSO-d6) d 14.6, 22.8, 27.0, 28.7, 29.0, 29.3,
29.58, 29.66, 30.4, 32.0, 46.6, 56.6, 156.6, 175.4; IR
3446, 2919, 1712, 1694, 1608, 1534, 1293, 1175; HRMS:
for C29H55N2O7 [M+H]+ calcd 543.4009, found
543.3997. Anal. Calcd for C29H54N2O7: C, 64.18; H,
10.03; N, 5.16. Found: C, 63.93; H, 10.02; N, 5.15.
5.7. General procedure for the preparation of bis(alk-
yl)methyl mesylates (12a–f)
To a solution of 11 (8.96 mmol) and Et3N (9.86 mmol)
in THF (59 mL) was added MsCl (25.7 mmol) dropwise
through a syringe at rt. In the middle of the addition, the
clear solution became cloudy. After the addition, the
reaction mixture was stirred for another 15 min. The
resulting suspension was filtered; the filtrate was washed
successively with water (8 mL) and saturated aqueous
NaCl (2 mL). The organic layer was dried with Na2SO4,
filtered, and concentrated to give a light yellow liquid
(12) in 90–98% yield. The product was used for the next
5.5.4. 4-(2-Carboxyethyl)-4-(3,3-didecylureido)hepta-
nedioic acid, 2(10,10). The general procedure described
above afforded a white solid (1.63 g, 88%); mp 120.9–
1
121.2 ꢁC. H NMR (DMSO-d6) d 0.83 (t, 6H), 1.10–
1.30 (bm, 28H), 1.37 (m, 4H), 1.81 (m, 6H), 2.08 (m,
6H), 3.09 (m, 4H), 5.08 (s, 1H), 11.99 (bs, 3H); 13C
NMR (DMSO-d6) d 14.4, 22.5, 26.7, 28.5, 28.7, 29.1,
29.32, 29.40, 29.46, 30.2, 31.7, 46.3, 56.4, 156.3, 175.2;
IR 2919, 1712, 1694, 1608, 1534, 1293, 1175; HRMS:
for C31H59N2O7 [M+H]+ calcd 571.4322, found
571.4315. Anal. Calcd for C31H58N2O7: C, 65.23; H,
10.24; N, 4.91. Found: C, 65.33; H, 10.34; N, 4.93.
1
step without further purification; H NMR (CDCl3) d
0.88 (t, 6H), 1.20–1.50 (bm, 24–44Hs), 1.60–1.75 (m,
4H), 3.00 (s, 3H), 4.70 (quin, 1H) (lit.15 200 MHz, 9,
R = n-C16H33).
5.8. General procedures for bis(alkyl)azidomethanes
(13a–f)
5.5.5. 4-(2-Carboxyethyl)-4-(3,3-diundecylureido)hepta-
nedioic acid, 2(11,11). The general procedure described
above afforded a white solid (1.53 g, 77%); mp 121.4–
122.1 ꢁC; H NMR (DMSO-d6) d 0.83 (t, 6H), 1.10–
1.30 (bm, 32H), 1.38 (m, 4H), 1.81 (m, 6H), 2.08 (m,
6H), 3.09 (m, 4H), 5.07 (s, 1H), 12.00 (bs, 3H); 13C
NMR (DMSO-d6) d 14.4, 22.6, 26.7, 28.5, 28.7, 29.17,
29.33, 29.46, 30.2, 31.8, 46.4, 56.4, 156.3, 175.2; IR
2917, 1713, 1694, 1608, 1535, 1295, 1185; HRMS: for
C33H63N2O7 [M+H]+ calcd 599.4635, found 599.4620.
Anal. Calcd for C33H62N2O7: C, 66.19; H, 10.44; N,
4.68. Found: C, 66.17; H, 10.40; N, 4.69.
To a stirred solution of 12 (7.41 mmol) in DMF (49 mL)
at rt was slowly added NaN3 (36.3 mmol). The suspen-
sion was heated to 85 ꢁC for 4 h. After the resulting yel-
low solution was cooled to rt, hexane (98 mL) and water
(16 mL) were added. The organic layer was separated
and washed successively with saturated NaHCO3
(8 mL) and saturated NaCl (8 mL). The organic layer
was dried with Na2SO4 and concentrated to give a col-
orless oil, which was purified by flash column chroma-
tography with hexane to give a pure colorless oil (13a–
e) or a white solid (13f), which gave a single spot on
TLC with hexane (Rf = 0.41), in 78–97% yield.
1
5.6. General procedure for the preparation of dialkylcar-
binols (11a–f)
5.8.1. 8-Azidopentadecane (13a). The general procedure
described above afforded a colorless liquid (1.46 g,
78%); 1H NMR (CDCl3) d 0.89 (m, 6H), 1.20–1.53
(bm, 24H), 3.22 (quin, 1H); 13C NMR (CDCl3) d 14.3,
22.9, 26.4, 29.4, 29.6, 32.0, 34.6, 63.4; IR 2924, 2855,
2093; HRMS: for C15H32N3 [M+H]+ calcd 254.2596,
found 254.2597. Anal. Calcd for C15H31N3: C, 71.09;
H, 12.33; N, 16.58. Found: C, 71.16; H, 12.44; N, 16.44.
To a three-necked round-bottomed flask containing Mg
turnings (2.34 g, 100 mmol) were added several chips of
I2. After the flask was flushed with N2, the mixture was
stirred for a couple of minutes until I2 sublimed. THF
(12 mL) was added, following a solution of bromoal-
kane 9 (48.1 mmol) in THF (36 mL) in a dropwise (1
drop/3 s) manner through a dropping funnel. Then, 10
(1.43 g, 19.0 mmol) in dry THF (24 mL) was added at
the same rate through a dropping funnel. The reaction
mixture was stirred and heated (65–70 ꢁC). Monitoring
the reaction with TLC showed that 3 d were needed to
achieve the best yields. The reaction mixture was diluted
with THF (36 mL), followed by successive addition of
5.8.2. 9-Azidoheptadecane (13b). The general procedure
described above afforded a colorless liquid (1.73 g,
1
83%); H NMR (CDCl3) d 0.88 (t, 6H), 1.20–1.53 (bm,
28H), 3.22 (quin, 1H); 13C NMR (CDCl3) d14.3, 22.9,
26.4, 29.5, 29.68, 29.70, 32.1, 34.6, 63.4; IR 2923,
2854, 2091; HRMS: for C17H36N3 [M+H]+ calcd
254.2848, found 254.2847. Anal. Calcd for C17H35N3:

3850
E. W. Sugandhi et al. / Bioorg. Med. Chem. 15 (2007) 3842–3853
C, 72.54; H, 12.53; N, 14.93. Found: C, 72.83; H, 12.68;
N, 14.86.
1H NMR (CDCl3) d 0.88 (t, 6H), 1.20–1.45 (bm, 30H),
2.67 (bm, 1H); 13C NMR (CDCl3) d 14.3, 22.9, 26.4,
29.5, 29.8, 30.0, 32.1, 38.2, 51.4; R 2955, 2921, 2852,
1464, 800.
5.8.3. 10-Azidononadecane (13c). The general procedure
described above afforded a colorless liquid (2.11 g, 92%);
1H NMR (CDCl3) d 0.88 (t, 6H), 1.20–1.54 (bm, 32H),
3.22 (quin, 1H); 13C NMR (CDCl3) d 14.3, 22.9, 26.4,
29.5, 29.65, 29.72, 32.1, 34.6, 63.3; IR 2922, 2853,
2093; HRMS: for C19H40N3 [M+H]+ calcd 282.3161,
found 282.3149. Anal. Calcd for C19H39N3: C, 73.73;
H, 12.70; N, 13.57. Found: C, 73.91; H, 12.77; N, 13.42.
5.9.3. Nonadecan-10-amine (14c). The general procedure
described above afforded a colorless liquid (1.67 g, 84%);
1H NMR (CDCl3) d 0.88 (t, 6H), 1.20–1.45 (bm, 34H;
2Hs exchange with D2O), 2.68 (bm, 1H) (lit.17
500 MHz); 13C NMR (CDCl3) d 14.3, 22.9, 26.4, 29.5,
29.8, 29.9, 30.0, 32.1, 38.4, 51.4; IR 2955, 2921, 2852,
1464, 797 (lit.17 KBr pellet).
5.8.4. 11-Azidohenicosane (13d). The general procedure
described above afforded a colorless liquid (2.47 g,
5.9.4. Henicosan-11-amine (14d). The general procedure
described above afforded a colorless liquid (1.93 g,
1
97%); H NMR (CDCl3) d 0.89 (t, 6H), 1.24–1.55 (bm,
36H), 3.22 (quin, 1H); 13C NMR (CDCl3) d 14.3, 22.9,
26.3, 29.5, 29.65, 29.71, 29.76, 29.78, 32.1, 34.6, 63.4;
IR 2922, 2853, 2093; HRMS: for C21H44N3 [M+H]+
calcd 310.3474, found 310.3467. Anal. Calcd for
C21H43N3: C, 74.71; H, 12.84; N, 12.45. Found: C,
74.86; H, 12.98; N, 12.44.
88%); H NMR (CDCl3) d 0.88 (t, 6H), 1.20–1.45 (bm,
1
38H; 2Hs exchange with D2O), 2.67 (bm, 1H); 13C
NMR (CDCl3) d 14.3, 22.9, 26.4, 29.5, 29.83, 29.85,
29.87, 30.0, 32.1, 38.3, 51.4; IR 2955, 2920, 2852, 1464,
792.
5.9.5. Tricosan-12-amine (14e). The general procedure
described above afforded a white solid (1.93 g, 81%);
mp 65.5–66.4 ꢁC; 1H NMR (CDCl3) d 0.88 (t, 6H),
1.13 (s, 2H), 1.20–1.45 (bm, 42H; 2Hs exchange with
D2O), 2.67 (bm, 1H); 13C NMR (CDCl3) d 14.3, 22.9,
26.4, 29.6, 29.86, 29.89, 30.1, 32.1, 33.3, 51.4; IR 2953,
2913, 2848, 1468, 720.
5.8.5. 12-Azidotricosane (13e). The general procedure de-
scribed above afforded a colorless liquid (2.28 g, 84%);
1H NMR (CDCl3) d 0.89 (t, 6H), 1.20–1.54 (bm, 40H),
3.23 (quin, 1H); 13C NMR (CDCl3) d 14.3, 22.9, 26.4,
29.6, 29.7, 29.75, 29.78, 29.85, 29.86, 32.1, 34.6, 63.4;
IR 2921, 2852, 2094; HRMS: for C23H48N3 [M+H]+
calcd 338.3787, found 338.3794. Anal. Calcd for
C23H47N3: C, 75.55; H, 12.96; N, 11.49. Found: C,
75.78; H, 13.10; N, 11.49.
5.9.6. Pentacosan-13-amine (14f). The general procedure
described above afforded a white solid (2.15 g, 86%); mp
1
79.7–80.4 ꢁC; H NMR (CDCl3) d 0.88 (t, 6H), 1.20–
5.8.6. 13-Azidopentacosane (13f). The general procedure
described above afforded a white solid (2.63 g, 90%); mp
1.45 (bm, 46H; 2Hs exchange with D2O), 2.67 (bm,
1H); 13C NMR (CDCl3) d 14.3, 22.9, 26.4, 29.6, 29.87,
29.89, 29.91, 30.1, 32.1, 38.4, 51.4; IR 2952, 2914,
2848, 1467, 720.
1
36.8–37.4 ꢁC; H NMR (CDCl3) d 0.88 (t, 6H), 1.26–
1.52 (bm, 44H), 3.22 (quin, 1H); 13C NMR (CDCl3) d
14.3, 22.9, 26.4, 29.6, 29.67, 29.75, 29.8, 29.86, 29.88,
32.1, 34.6, 63.4; IR 2913, 2848, 2085; HRMS: for
C25H52N3 [M+H]+ calcd 366.4100, found 366.4090.
Anal. Calcd for C25H51N3: C, 72.67; H, 13.06; N,
10.67. Found: C, 76.35; H, 13.14; N, 10.63.
5.10. General procedures for swallowtail tri-tert-butyl
esters, 15(n,n)
An amine 14 (4.95 mmol) was added slowly to a solution
of WeNCO (4.71 mmol) in CH2Cl2 (20 mL). The result-
ing transparent solution was stirred at rt. After stirring
overnight, the solution was concentrated to afford a
crude white solid. This crude product was purified by
flash column chromatography to give a white solid,
which gave a single spot on TLC (hexane/EtOAc, 5:1,
Rf = 0.17–0.30). The isolated solid was then recrystal-
lized from CH3CN (60–87%).
5.9. General procedures for bis(alkyl)methanamines (14a–
f)
To a solution of 13 (7.03 mmol) in hexane (35 mL) was
added 10% Pd/C (3% weight of azidoalkane). The result-
ing solution was shaken and hydrogenated under 62 psi
at rt for 3 h. After sitting overnight, the resulting solu-
tion was filtered. The filtrate was concentrated to give
a colorless liquid (14a–d) or a white solid (14e,f) in 75–
88% yield. The product was used in the next step with-
out purification.
5.10.1. Di-tert-butyl 4-(2-tert-butoxycarbonylethyl)-4-[3-
(1-heptyloctyl)ureido]heptanedioate, 15(7,7). The general
procedure described above afforded a white solid
(1.89 g, 60%); mp 109.0–109.8 ꢁC; 1H NMR (CDCl3)
d 0.88 (t, 6H), 1.20–1.35 (bm, 22H), 1.43 (bs, 29H),
1.94 (m, 6H), 2.23 (m, 6H), 3.52 (bm, 1H), 3.76 (d,
1H), 4.41 (s, 1H); 13C NMR (CDCl3) d 14.0, 22.6,
25.8, 28.0, 29.2, 29.6, 29.8, 30.6, 31.8, 35.7, 50.2,
56.4, 80.4, 156.4, 173.0; IR 3329, 2922, 2852, 1726,
1650, 1151; HRMS: for C38H73N2O7 [M+H]+ calcd
669.5418, found 669.5419. Anal. Calcd for
C38H72N2O7: C, 68.22; H, 10.85; N, 4.19. Found: C,
67.96; H, 10.91; N, 4.26.
5.9.1. Pentadecan-8-amine (14a). The general procedure
described above afforded a colorless liquid (1.22 g,
1
76%); H NMR (CDCl3) d 0.88 (t, 6H), 1.20–1.45 (bm,
26H; 2Hs exchange with D2O), 2.67 (bm, 1H); 13C
NMR (CDCl3) d 14.3, 22.8, 26.4, 29.5, 30.0, 32.0, 38.4,
51.40; IR 2955, 2921, 2852, 1464, 767.
5.9.2. Heptadecan-9-amine (14b). The general procedure
described above afforded a colorless liquid (1.35 g, 75%);

E. W. Sugandhi et al. / Bioorg. Med. Chem. 15 (2007) 3842–3853
3851
5.10.2. Di-tert-butyl 4-(2-tert-butoxycarbonylethyl)-4-[3-
(1-octylnonyl)ureido]heptanedioate, 15(8,8). The general
procedure described above afforded a white solid
(2.30 g, 70%); mp 108.5–109.3 ꢁC; H NMR (CDCl3) d
0.88 (t, 6H), 1.20–1.35 (bm, 26H), 1.43 (bs, 29H), 1.94
(m, 6H), 2.23 (m, 6H), 3.51 (bm, 1H), 3.75 (d, 1H),
4.41 (s, 1H); 13C NMR (CDCl3) d 14.0, 22.6, 25.8,
28.0, 29.2, 29.5, 29.7, 29.8, 30.6, 31.8, 35.7, 50.2, 56.4,
80.4, 156.4, 173.0; IR 3317, 2925, 2855, 1730, 1630,
1147; HRMS: for C40H77N2O7 [M+H]+ calcd
697.5731, found 697.5731. Anal. Calcd for
C40H76N2O7: C, 68.92; H, 10.99; N, 4.02. Found: C,
69.06; H, 11.17; N, 4.06.
28.0, 29.3, 29.61, 29.63, 29.66, 29.70, 29.85, 30.6, 31.9,
35.7, 50.2, 56.4, 80.4, 156.4, 173.1; IR 3319, 2917,
2851, 1730, 1654, 1147; HRMS: for C48H93N2O7
[M+H]+ calcd 809.6983, found 809.7014. Anal. Calcd
for C48H92N2O7: C, 71.24; H, 11.46; N, 3.46. Found:
C, 71.43; H, 11.58; N, 3.50.
1
5.11. General procedures for swallowtail triacids, 3(n,n)
A tri-tert-butyl ester 15(n,n) (3.00 mmol) was dissolved
in 99% HCOOH so that the concentration was 0.1 M.
Some mixtures needed warming to completely dissolve
15(n,n). Once dissolved to give a clear colorless solution,
the mixture was stirred at rt. After stirring for 9 h, the
resulting milky white solution was concentrated. The
white solid was recrystallized from EtOAc to yield a
white solid (77–90%).
5.10.3. Di-tert-butyl 4-(2-tert-butoxycarbonylethyl)-4-[3-
(1-nonyldecyl)ureido]heptanedioate, 15(9,9). The general
procedure described above afforded a white solid
(2.90 g, 85%); mp 89.6–90.3 ꢁC; 1H NMR (CDCl3) d
0.88 (t, 6H), 1.20–1.40 (bm, 30H), 1.43 (bs, 29H), 1.93
(m, 6H), 2.23 (m, 6H), 3.51 (bm, 1H), 3.76 (d, 1H),
4.41 (s, 1H); 13C NMR (CDCl3) d 14.0, 22.6, 25.9,
28.0, 29.3, 29.55, 29.56, 29.7, 29.9, 30.7, 31.8, 35.7,
50.2, 56.4, 80.4, 156.4, 173.0; IR 3328, 2922, 2852,
1726, 1651, 1148; HRMS: for C42H81N2O7 [M+H]+
calcd 725.6044, found 725.6028. Anal. Calcd for
C42H80N2O7: C, 69.57; H, 11.12; N, 3.86. Found: C,
69.60; H, 11.22; N, 3.85.
5.11.1. 4-(2-Carboxyethyl)-4-[3-(1-heptyloctyl)ureido]hep-
tanedioic acid, 3(7,7). The general procedure described
above afforded a white solid (1.28 g, 85%); mp 168.5–
1
169.2 ꢁC; H NMR (CD3OD) d 0.89 (t, 6H), 1.20–1.40
(bm, 24H), 1.44 (m, 2H), 1.95 (m, 6H), 2.28 (m, 6H),
3.55 (bm, 1H); 13C NMR (DMSO-d6) d 14.4, 22.5, 25.8,
28.6, 29.2, 29.4, 30.5, 31.7, 35.8, 48.3, 55.4, 157.4, 175.0;
IR 3405, 2924, 2855, 1732, 1700 1585; HRMS: for
C26H49N2O7 [M+H]+ calcd 501.3540, found 501.3562.
Anal. Calcd for C26H48N2O7: C, 62.37; H, 9.66; N, 5.60.
Found: C, 62.28; H, 9.57; N 5.52.
5.10.4. Di-tert-butyl 4-(2-tert-butoxycarbonylethyl)-4-[3-
(1-decylundecyl)ureido]heptandioate, 15(10,10). The gen-
eral procedure described above afforded a white solid
(2.73 g, 77%); mp 87.0–87.6 ꢁC; 1H NMR (CDCl3) d
0.88 (t, 6H), 1.20–1.40 (bm, 34H), 1.44 (bs, 29H), 1.93
(m, 6H), 2.23 (m, 6H), 3.52 (bm, 1H), 3.86 (d, 1H),
4.47 (s, 1H); 13C NMR (CDCl3) d 14.1, 22.6, 25.9,
28.02, 28.04, 29.3, 29.57, 29.61, 29.68, 29.9, 30.6, 31.9,
35.7, 50.2, 56.4, 80.4, 156.4, 173.0; IR 3376, 2919,
2850, 1730, 1675, 1146; HRMS: for C44H85N2O7
[M+H]+ calcd 753.6357, found 753.6376. Anal. Calcd
for C44H84N2O7: C, 70.17; H, 11.24; N, 3.72. Found:
C, 69.89; H, 11.33; N, 3.70.
5.11.2. 4-(2-Carboxyethyl)-4-[3-(1-octylnonyl)ureido]hep-
tanedioic acid, 3(8,8). The general procedure described
above afforded a white solid (1.36 g, 86%); mp 164.3–
1
165.1 ꢁC; H NMR (CD3OD) d 0.89 (t, 6H), 1.20–1.40
(bm, 28H), 1.44 (m, 2H), 1.95 (m, 6H), 2.28 (m, 6H),
3.54 (bm, 1H); 13C NMR (DMSO-d6) d 14.7, 22.8,
26.1, 28.8, 29.4, 29.69, 29.73, 30.8, 31.9, 36.0, 48.5,
55.6, 157.6, 175.2; IR 3404, 2921, 2852, 1730, 1699,
1556; HRMS: for C28H53N2O7 [M+H]+ calcd
529.3853, found 529.3837. Anal. Calcd for
C28H52N2O7: C, 63.61; H, 9.91; N, 5.30. Found: C,
63.65; H, 9.94; N 5.20.
5.10.5. Di-tert-butyl 4-(2-tert-butoxycarbonylethyl)-4-[3-
(1-undecyldodecyl)ureido]heptanedioate, 15(11,11). The
general procedure described above afforded a white solid
(3.16 g, 86%); mp 92.9–93.8 ꢁC; 1H NMR (CDCl3) d
0.88 (t, 6H), 1.20–1.40 (bm, 38H), 1.44 (bs, 29H), 1.94
(m, 6H), 2.24 (m, 6H), 3.52 (bm, 1H), 3.83 (m, 1H),
4.45 (s, 1H); 13C NMR (CDCl3) d 14.0, 22.6, 25.9,
28.0, 29.3, 29.58, 29.60, 29.7, 29.9, 30.7, 31.9, 35.7,
50.2, 56.4, 80.4, 156.4, 173.0; IR 3374, 2920, 2850,
1722, 1676, 1148; HRMS: for C46H89N2O7 [M+H]+
calcd 781.6670, found 781.6657. Anal. Calcd for
C46H88N2O7: C, 70.72; H, 11.35; N, 3.59. Found: C,
70.49; H, 11.37; N, 3.67.
5.11.3. 4-(2-Carboxyethyl)-4-[3-(1-nonyldecyl)ureido]hep-
tanedioic acid, 3(9,9). The general procedure described
above afforded a white solid (1.39 g 83%); mp 165.1–
165.7 ꢁC; H NMR (CD3OD) d 0.86 (t, 6H), 1.20–1.35
(bm, 30H), 1.41 (m, 2H), 1.92 (m, 6H), 2.25 (m, 6H),
3.51 (bm, 1H); 13C NMR (DMSO-d6) d 14.4, 22.5,
25.8, 28.6, 29.1, 29.36, 29.43, 30.5, 31.7, 35.7, 48.3,
55.4, 157.3, 174.9; IR 3405, 2921, 2852, 1730, 1699,
1554; HRMS: for C30H57N2O7 [M+H]+ calcd
557.4166, found 557.4172. Anal. Calcd for
C30H56N2O7: C, 64.72; H, 10.14; N, 5.03. Found: C,
64.73; H, 10.20; N 5.01.
1
5.10.6. Di-tert-butyl 4-(2-tert-butoxycarbonylethyl)-4-[3-
(1-dodecyltridecyl)ureido]heptanedioate, 15(12,12). The
general procedure described above afforded a white solid
(3.49 g, 87%); mp 73.8–74.3 ꢁC; 1H NMR (CDCl3) d
0.89 (t, 6H), 1.20–1.40 (bm, 42H), 1.44 (bs, 29H), 1.94
(m, 6H), 2.24 (m, 6H), 3.51 (bm, 1H), 3.80 (d, 1H),
4.44 (s, 1H); 13C NMR (CDCl3) d 14.1, 22.7, 25.9,
5.11.4. 4-(2-Carboxyethyl)-4-[3-(1-decylundecyl)ure-
ido]heptanedioic acid, 3(10,10). The general procedure
described above afforded a white solid (1.42 g, 81%);
mp 162.8–163.5 ꢁC; H NMR (CD3OD) d 0.86 (t, 6H),
1.20–1.35 (bm, 34H), 1.41 (m, 2H), 1.87 (t, 6H), 2.25
(t, 6H), 3.51 (bm, 1H); 13C NMR (DMSO-d6) d 14.4,
22.5, 25.8, 28.5, 29.1, 29.41, 29.43, 30.5, 31.7, 35.6,
1

3852
E. W. Sugandhi et al. / Bioorg. Med. Chem. 15 (2007) 3842–3853
48.3, 55.4, 157.3, 174.9; IR 3404, 2921, 2852, 1731, 1699,
1557; HRMS: for C32H61N2O7 [M+H]+ calcd 585.4479,
found 585.4501. Anal. Calcd for C32H60N2O7: C, 65.72;
H, 10.34; N, 4.79. Found: C, 65.52; H, 10.31; N 4.78.
broth (S. cerevisiae, C. albicans, and C. neoformans) and
incubated at 37 ꢁC (S. cerevisiae and M. luteus at 30 ꢁC)
for 4–7 days. After growth, the resulting broth cultures
were diluted with buffered saline gelatin [BSG, gelatin
(0.1 g/L), NaCl (8.5 g/L), KH2PO4 (0.3 g/L), Na2HPO4
(0.6 g/L)] to equal the turbidity of a No. 1 McFarland
Standard. To check for viability and contamination,
broth cultures were streaked on Plate Count Agar
(BBL Microbiology Systems, Cockeysville, MD); the
plates were incubated at 37 ꢁC for 3–4 days, except those
for M. luteus and S. cerevisiae which were incubated at
30 ꢁC. Spores of A. niger were scraped from the surface
of PDA and suspended in 5 mL of 1/10-strength
BHIB + S and that suspension transferred to a sterile test
tube. The turbidity was adjusted to a No. 1 McFarland
Standard by dilution with BSG. To check for viability
and contamination, those spore suspensions were
streaked on PDA and incubated at 37 ꢁC for 3–4 days.
5.11.5. 4-(2-Carboxyethyl)-4-[3-(1-undecyldodecyl)ure-
ido]heptanedioic acid, 3(11,11). The general procedure
described above afforded a white solid (1.56 g, 85%);
1
mp 164.6–165.1 ꢁC; H NMR (CD3OD) d 0.86 (t, 6H),
1.20–1.35 (bm, 38H), 1.41 (m, 2H), 1.92 (m, 6H), 2.25
(m, 6H), 3.51 (bm, 1H); 13C NMR (DMSO-d6) d 14.4,
22.5, 25.7, 28.5, 29.1, 29.41, 29.44, 30.5, 31.7, 35.6,
48.2, 55.3, 157.3, 174.9; IR 3404, 2921, 2852, 1732,
1699, 1557; HRMS: for C34H65N2O7 [M+H]+ calcd
613.4792, found 613.4792. Anal. Calcd for
C34H64N2O7: C, 66.63; H, 10.53; N, 4.57. Found: C,
66.77; H, 10.64; N 4.56.
5.11.6. 4-(2-Carboxyethyl)-4-[3-(1-dodecyltridecyl)ure-
ido]heptanedioic acid, 3(12,12). The general procedure
described above afforded a white solid (1.67 g, 87%);
5.13. Quality assurance
1
mp 163.3–163.9 ꢁC; H NMR (CD3OD) d 0.86 (t, 6H),
For the work reported here, all cultures and suspensions
that were used as inocula were uncontaminated and the
colonies had the expected morphologies. All viable,
uncontaminated inocula were stored up to 14 days at
4 ꢁC until used without any differences in susceptibility
to antimicrobial compounds.
1.20–1.35 (bm, 42H), 1.41 (m, 2H), 1.95 (m, 6H), 2.25
(m, 6H), 3.51 (bm, 1H); 13C NMR (DMSO-d6) d 14.6,
22.8, 26.0, 28.8, 29.4, 29.67, 29.71, 29.75, 30.8, 32.0,
35.9, 48.5, 55.6, 157.6, 175.2; IR 3403, 2920, 2851,
1731, 1700, 1559; HRMS: for C36H69N2O7 [M+H]+
calcd 641.5105, found 641.5095. Anal. Calcd for
C36H68N2O7: C, 67.46; H, 10.69; N, 4.37. Found: C,
67.31; H, 10.62, N 4.34.
5.14. Measurement of MIC
Stock solutions (12,500 mg/L) for all homologues were
easily prepared by simply vortexing the tricarboxylic
acid in the aqueous triethanolamine solution. Final
stock concentrations ranged from 19,500 to 25,700 lM
depending on the formula weight of the homologue.
5.12. Microbial strains, culture conditions, and prepara-
tions of inocula for susceptibility testing
Strains of E. coli strain C (ATCC # 13706), K. pneumo-
niae (ATCC # 4352), L. plantarum (ATCC # 14917),
S. aureus (ATCC # 6538), and M. smegmatis (ATCC #
607) were obtained from the American Type Culture
Collection. A methicillin-resistant isolate of S. aureus
(MRSA) was obtained from the Microbiology Labora-
tory, Danville Community Hospital (Virginia), and
S. cerevisiae, C. albicans, C. neoformans, A. niger, and
M. luteus strains were obtained from the Virginia Tech
Microbiology teaching culture collection. Colonies of
E. coli, K. pneumoniae, S. aureus, MRSA, M. luteus,
S. cerevisiae, C. albicans, and C. neoformans were grown
on 1/10-strength Brain Heart Infusion Broth (BBL
Microbiology Systems, Cockeysville, MD) containing
0.2% (wt/vol) sucrose (BHIB + S) and 1.5% (wt/vol)
agar. L. plantarum was grown on 1/4-strength Tryptic
Soy Broth (TSB, BBL Microbiology Systems, Cockeys-
ville, MD) containing 0.2% glucose (TSB + G) and
1.5% (wt/vol) agar. M. smegmatis was grown on Middle-
brook 7H10 agar (BBL Microbiology Systems, Cockeys-
ville, MD) and A. niger on Potato Dextrose Agar (PDA,
BBL Microbiology Systems, Cockeysville, MD).
Streaked plates were incubated at 37 ꢁC for 3–7 days,
except for that of A. niger, which was incubated in the
dark at 30 ꢁC. A single colony for each microbe except
A. niger was used to inoculate 5 mL of 1/10-strength
BHIB + S (E. coli, K. pneumoniae, M. luteus, S. aureus,
and MRSA), TSB (L. plantarum), Middlebrook 7H9
broth (M. smegmatis), or Yeast Extract Peptone Maltose
MICs of compounds dissolved in aqueous triethanol-
amine were measured by broth microdilution in 96-well
microtiter plates.4 Preliminary experiments demon-
strated that 4% (wt/vol) triethanolamine/water did not
inhibit the growth of any microorganism tested. A two-
fold dilution series of the compounds was prepared in
96-well microtiter plates in a 50 lL volume of 1/10-
strength BHIB + S and the dilution series was inoculated
with 50 lL of each cell suspension. For E. coli and
K. pneumoniae, the volumes of the medium and the inoc-
ulum were doubled. The resulting inoculated dilution
series were incubated at 30 ꢁC (37 ꢁC for E. coli and
K. pneumoniae) and growth, as turbidity, scored visually
and recorded on the fourth day (the seventh day for
E. coli and K. pneumoniae). The MIC of each compound
was measured in triplicate and was defined as the lowest
concentration of drug resulting in a prominent visible
decrease in turbidity (incomplete; i.e., P50%) or an
absence of visible turbidity (complete) compared to the
drug-free control. In many cases (identified in Table 1
by superscripta), inhibition was incomplete.
Acknowledgments
The authors acknowledge the guidance and technical
assistance of Ms. Myra D. Williams on growing target

E. W. Sugandhi et al. / Bioorg. Med. Chem. 15 (2007) 3842–3853
3853
17. Wescott, L. D.; Mattern, D. L. J. Org. Chem. 2003, 68,
10058.
18. Kaneko, D.; Olsson, U.; Sakamoto, K. Langmuir 2002, 18,
4699.
19. Kanicky, J. R.; Shah, D. O. Langmuir 2003, 19, 2034.
20. Bates, R. G.; Allen, G. F. J. Res. Natl. Bur. Stand. (US)
1960, 64A, 343.
21. Boris, S.; Barbes, C. Microbes Infect. 2000, 2, 543.
22. Kondo, E.; Kanai, K. Jpn. J. Med. Sci. Biol. 1972, 25, 1.
23. Seidel, V.; Taylor, P. W. Int. J. Antimicrob. Agents 2004,
23, 613.
24. Masuoka, J.; Hazen, K. C. Glycobiology 1999, 9, 1281.
25. Genco, C. A.; Maloy, W. L.; Kari, U. P.; Motley, M. Int.
J. Antimicrob. Agents 2003, 21, 75.
26. Quinn, F. R.; Driscoll, J. S.; Hansch, C. J. Med. Chem.
1975, 18, 332.
microorganisms and measuring MICs, and Ms. Laura
Link, Director, Microbiology Teaching Laboratories,
Virginia Tech, for the gift of these strains. Ms. Williams
was supported by funds provided by Applied Microbio-
logy and Genetics. We also thank the Contraceptive
Research and Development (CONRAD) Program
under a cooperative agreement with the US. Agency
for International Development (USAID) for partially
supporting this work. Our views expressed in this paper
do not necessarily reflect the views of CONRAD or
USAID. We also gratefully acknowledge DOE for
financial support through the Center for Advanced
Separation Technology (DE-FC26-02NT41607) at
Virginia Tech under subproject VA017. We thank the
reviewers of this manuscript for helpful comments.
27. Jiang, S.; Wang, L.; Yu, H.; Chen, Y. React. Funct. Polym.
2005, 62, 209.
28. Langsrud, S.; Sundheim, G.; Borgmann-Strahsen, R.
J. Appl. Microbiol. 2003, 95, 874.
References and notes
29. Walsh, S. E.; Maillard, J.-Y.; Russell, A. D.; Catrenich, C.
E.; Charbonneau, D. L.; Bartolo, R. G. J. Appl. Microbiol.
2003, 94, 240.
30. Oya, A.; Funato, Y.; Sugiyama, K. J. Mater. Sci. 1994, 29,
11.
31. Cox, J. M.; Marsden, J. H. E.; Elmore, N.; Shephard, M.
C.; Burrell, R. A. US Patent 4146716, 1979, 17 pp
32. Grier, N.; Dybas, R. A.; Strelitz, R. A.; Witzel, B. E.;
Dulaney, E. L. J. Pharm. Sci. 1982, 71, 365.
33. Carballeira, N. M.; Ortiz, D.; Parang, K.; Sardari, S.
Arch. Pharm. 2004, 337, 152.
1. Bayliss, M. J. Bacteriol. 1936, 31, 489.
2. Walker, J. E. J. Infect. Dis. 1924, 35, 557.
3. Vorum, H.; Brodersen, R.; Kragh–Hansen, U.; Pedersen,
A. O. Biochim. Biophys. Acta 1992, 1126, 135.
4. Williams, A. A.; Sugandhi, E. W.; Macri, R. V.; Falkin-
ham, J. O., III; Gandour, R. D. J. Antimicrob. Chemother.
2007, 59, 451.
5. Newkome, G. R.; Behera, R. K.; Moorefield, C. N.;
Baker, G. R. J. Org. Chem. 1991, 56, 7162.
6. Csizmadia, F. LogP and logD calculator <http://intro.
bio.umb.edu/111-112/OLLM/111F98/newclogp.html>,
accessed November 15, 2006.
34. Carballeira, N. M.; O’Neill, R.; Parang, K. Chem. Phys.
Lipids 2005, 136, 47.
7. Newkome, G. R.; Weis, C. D.; Moorefield, C. N.;
Fronczek, F. R. Tetrahedron Lett. 1997, 38, 7053.
8. Nagase, A.; Kuwahara, Y.; Tominaga, Y.; Sugawara, R.
Agric. Biol. Chem. 1983, 47, 53.
35. Carballeira, N. M.; Sanabria, D.; Parang, K. Arch. Pharm.
2005, 338, 441.
36. Carballeira, N. M.; Sanabria, D.; Cruz, C.; Parang, K.;
Wan, B. J.; Franzblau, S. Lipids 2006, 41, 507.
37. Sugandhi, E. W.; Macri, R. V.; Kite, B. L.; Williams, A.
A.; Slebodnick, C.; Falkinham, J. O., III; Esker, A. R.;
Gandour, R. D. J. Med. Chem. 2007, 50, doi:10.1021/
jm061240d. Available online 9 March 2007.
38. Newkome, G. R.; Weis, C. D.; Childs, B. J. Des.
Monomers Polym. 1998, 1, 3.
39. Troyanskii, E. I.; Ioffe, V. A.; Mizintsev, V. V.; Nikishin,
G. I. Izv. Akad. Nauk SSSR, Ser. Khim. 1984, 8, 1814.
40. Gall, R.; Bosies, E. Germany Patent DE 3623397 A1,
1988, 12 pp
41. Froger, C.; Parisot, A. Compt. Rend. 1954, 238, 1589.
42. Yoshioka, Y.; Tashiro, K. J. Phys. Chem. B 2003, 107,
11835.
43. Rao, H. S. P.; Bharathi, B. Indian J. Chem. B 2002, 41,
1072.
ˇ
9. Djedovic, N.; Ferdani, R.; Harder, E.; Pajewska, J.;
Pajewski, R.; Weber, M. E.; Schlesinger, P. H.; Gokel, G.
W. New J. Chem. 2005, 29, 291.
10. Boal, A. K.; Das, K.; Gray, M.; Rotello, V. M. Chem.
Mater. 2002, 14, 2628.
11. Baykut, F. Rev. Fac. Sci. Univ. Istanbul. 1954, 19, 121.
12. Breusch, F. L.; Sokullu, S. Chem. Ber. 1953, 86, 678.
13. Meakins, R. J.; Sack, R. A. Aust. J. Sci. Res. 1951, 4A,
213.
14. Overmars, F. J. J.; Engberts, J. B. F. N.; Weringa, W. D.
Recl. Trav. Chim. Pays-Bas 1994, 113, 293.
ˇ
´
15. Meekel, A. A. P.; Wagenaar, A.; Smisterova, J.; Kroeze, J.
E.; Haadsma, P.; Bosgraaf, B.; Stuart, M. C. A.; Brisson,
A.; Ruiters, M. H. J.; Hoekstra, D.; Engberts, J. B. F. N.
Eur. J. Org. Chem. 2000, 2000, 665.
16. Malanga, C.; Mannucci, S.; Lardicci, L. J. Chem. Res.
Synop. 2000, 6, 701.
44. Wright, J. B.; Elderfield, R. C. J. Org. Chem. 1946, 11,
111.