Parallel synthesis of a library of symmetrically- and dissymmetrically- disubstituted imidazole-4,5-dicarboxamides bearing amino acid esters

Article abstract of DOI:10.3390/molecules14010352

The imidazole-4,5-dicarboxylic acid scaffold is readily derivatized with amino acid esters to afford symmetrically- and dissymmetrically-disubstituted imidazole-4,5-dicarboxamides with intramolecularly hydrogen bonded conformations that predispose the pre

Full text of DOI:10.3390/molecules14010352

Molecules 2009, 14, 352-363; doi:10.3390/molecules14010352
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Parallel Synthesis of a Library of Symmetrically- and
Dissymmetrically-disubstituted Imidazole-4,5-dicarboxamides
Bearing Amino Acid Esters
Rosanna Solinas, John C. DiCesare and Paul W. Baures *
Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, Tulsa,
OK 74104; E-mails: rosannasolinas@yahoo.it (R. S.), john-dicesare@utulsa.edu (J-C. D.)
* Author to whom correspondence should be addressed; E-mail: paul-baures@utulsa.edu (P-W. B.).
Received: 20 November 2008; in revised form: 7 January 2009/ Accepted: 12 January 2009/
Published: 13 January 2009
Abstract: The imidazole-4,5-dicarboxylic acid scaffold is readily derivatized with amino
acid esters to afford symmetrically- and dissymmetrically-disubstituted imidazole-4,5-
dicarboxamides with intramolecularly hydrogen bonded conformations that predispose the
presentation of amino acid pharmacophores. In this work, a total of 45 imidazole-4,5-
dicarboxamides bearing amino acid esters were prepared by parallel synthesis. The library
members were purified by column chromatography on silica gel and the purified
compounds characterized by LC-MS with LC detection at 214 nm. A selection of the final
1
compounds was also analyzed by H-NMR spectroscopy. The analytically pure final
products have been submitted to the Molecular Library Small Molecule Repository
(MLSMR) for screening in the Molecular Library Screening Center Network (MLSCN) as
part of the NIH Roadmap.
Keywords: Imidazole; NIH Roadmap; Heterocyclic scaffold; Drug discovery.
Introduction
Small molecule biological probes that influence protein function are useful tools for studying the
cell and can also serve as lead structures in the development of new therapeutic agents [1-5]. The NIH
Roadmap [6] project has created opportunities for the development of new chemical libraries for

Molecules 2009, 14
353
subsequent screening by the Molecular Libraries Screening Center Network (MLSCN) in a combined
effort to identify unique and useful biological probes.
Selecting compounds for screening is an important, albeit challenging, task [7-8]. Ideally, the
compounds are pure and of known structure, contain only non-reactive functional groups, have a
possibility of some level of selectivity towards a given protein target or at least toward a protein class,
and have the physical properties suitable for use in biological assays, including aqueous solubility and
cellular permeability. Compounds that meet part or all of these parameters are generally described as
“drug-like,” even if their chemical structures can be quite divergent—from marine natural products
with multiple stereocenters and many polar functional groups to small molecule achiral synthetic
compounds that are quite hydrophobic [9-10].
This paper describes the synthesis and characterization of an imidazole-4,5-dicarboxamide (I45DC)
library substituted with two α-amino acid esters. We have been using the imidazole-4,5-dicarboxylic
acid (I45DA) scaffold to design compounds that inhibit specific biological targets [11-13], as well as
for the synthesis of chemical libraries to be used in the MLSCN screening effort. Nevertheless, no
dissymmerically-disubstituted I45DCs bearing only α-amino acid esters and only two symmetrically-
disubstituted I45DCs bearing α-amino acids esters have been previously reported in the literature.
There are related bis-I45DCs bearing one α-amino acid ester per I45DC that we used to target a
protein-protein interaction [12], as well as dissymmetrically-disubstituted I45DCs bearing one α-
amino acid ester along with either a primary or secondary alkanamine that we are concurrently
reporting [14].
Amino acid side chains are natural recognition elements in substrate-enzyme, ligand-receptor, and
protein-protein interactions, and we have shown that I45DCs form a strong intramolecular hydrogen
bond that remains stable even in water at pH 7 [15]. Moreover, the strong intramolecular hydrogen
bond anticipated in each of these I45DCs accomplishes three important tasks: it predisposes the amino
acid ester substituents to be separated by a distance comparable with side chain separations found
adjacent on one side in an α-helix or on one side in a β-strand secondary structure [12,16], yields a
quasi ring that combines with the imidazole to yield mimics of substituted purines [13,16], and offers
added low-energy conformational flexibility for the compound to adapt to the binding site, which is an
advantage over an all covalently bonded scaffold.
Our design of this library incorporated two amino acid ester pharmacophores in each I45DC,
reasoning that α-amino acids are natural recognition elements in substrate-enzyme, ligand-receptor,
and protein-protein interactions. All of the final compounds are of analytical purity and have been
submitted to the Molecular Library Small Molecule Repository (MLSMR) for use by the Molecular
Library Screening Center Network (MLSCN).
Results and Discussion
A library for high-throughput screening and hit identification in the discovery phase of identifying
small molecule probes and drugs must strike a balance between sufficient numbers of compounds in
class to sample pharmacophoric space without a significant redundancy. This balance saves time and
energy in both delivering the compounds and performing the bioassay, as well as in the overall costs of
the effort.

Molecules 2009, 14
354
The α-amino acid esters used in the synthesis of this library were of the S-configuration and are
given in Table 1. We opted for a set of mostly hydrophobic side chains in this work, since a less-than-
perfect burial of a hydrophobic side chain in a binding cleft would still be expected to show some
bioactivity in a screening effort, in contrast with a polar α-amino acid where electrostatic interactions,
such as hydrogen bonding, form quite specific interactions geometrically and may not bind at all if
those conditions are not met. This stated, the amino acids in this library include Ala, Leu, and Phe,
along with Gly. Lysine was also included, but the side chain left protected by a Boc group in this
initial library. The carboxylic acid was protected with either a tert-butyl or benzyl ester to provide a
hydrophobic group for binding interactions, while also providing a convenient deprotection and
modification strategy for derivitizing bioactive compounds.
Table 1. Amino acid ester salts, 2{1-9}, used in library synthesis.
R1
O
X H3N
R2
O
2{1-9}
Membe
r
R1
R2
X
2{1}
2{2}
2{3}
2{4}
2{5}
2{6}
2{7}
2{8}
2{9}
H
H
C(CH3)3
CH2Ph
Cl
Cl
Cl
Cl
Cl
CH3
CH3
C(CH3)3
CH2Ph
CH2CH(CH3)2 C(CH3)3
CH2CH(CH3)2 CH2Ph OSO2C6H4CH3
CH2Ph
CH2Ph
C(CH3)3
CH2Ph
Cl
Cl
Cl
(CH2)4NH2
C(CH3)3
The resulting I45DC library members have reasonable drug-like properties, as illustrated by their
molecular weights that range from 382−724 g/mol with an average value of 522 g/mol, cLogP values
that range from 0.35−4.83 with an average value of 2.95, and relatively few rotatable bonds [17-19].
The synthetic strategy to the pyrazine intermediates and final dI45DCs is shown in Scheme 1. The
starting pyrazine diacid chloride, 1, was prepared as previously described [8], as were the amino acid
ester substituted pyrazines, 3 [14]. Reaction of the appropriate pyrazine, 3, with two equivalents of a
second amino acid ester hydrochloride or tosylate salt, 2{1-9}, and two equivalents of N,N-
diisopropyl-ethylamine as a scavenger for the acid produced a good average yield (73%) of the final
I45DC products, 4, following purification by column chromatography. All of the compounds were
analyzed by using LC-MS with LC detection at 214 nm, while selected compounds were analyzed by
1H-NMR spectroscopy. The yields to the 9 sI45DCs and 36 dI45DCs are given in Tables 2 and 3,
respectively. A comparative analysis of the low, high, average, and median yields as a function of

Molecules 2009, 14
355
an α-amino acid ester is given in Table 4 and indicates there is no consequence on reaction yield based
on structure. We have included tables of data (formula, molecular weight, cLogP values, physical form
of the compound, Rf values, and retention times in the LC-MS) for library members 5{1-45}, LC-MS
spectra for all library members, LC-MS data for 10 reactions to crude library members, as well as 1H-
NMR spectra for the crude reactions and purified library members for 15 representative compounds in
a supporting file. The same information is also available for each compound at the project website
[20].
Scheme 1. Synthesis of library members.
N
Cl
R1
N
N
1
O
O
O
O
X H3N
R2
+
O
Cl
O
N
H
2{1-9}
diethylaniline
CH2Cl2
-78 °C
rt
O
R2
N
N
O
N
N
O
N
R1
O
R1
O
O
O
N
R2
H
O
3{1-9}
2{1-9}
CH2Cl2
[ EtN(iPr)2 ]
rt, 72 h
R1
R1
O
O
H
O
N
H
N
R2
N
R2
O
O
O
N
H
4{1-45}

Molecules 2009, 14
Table 2. Symmetrically-disubstituted Amino Acid Ester I45DCs, 4{1-9}.
356
Yield
(%)
Cmpd.
Reactants
4{1}
4{2}
4{3}
4{4}
4{5}
4{6}
4{7}
4{8}
4{9}
2{1} 2{1}
2{2} 2{2}
2{3} 2{3}
2{4} 2{4}
2{5} 2{5}
2{6} 2{6}
2{7} 2{7}
2{8} 2{8}
2{9} 2{9}
79
22
69
12
83
97
62
73
86
Table 3. Dissymmetrically-disubstituted Amino Acid Ester I45DCs, 4{10-45}.
Yield
(%)
Yield
(%)
Cmpd.
Reactants
Cmpd.
Reactants
4{10} 2{1} 2{2}
4{11} 2{1} 2{3}
4{12} 2{1} 2{4}
4{13} 2{1} 2{5}
4{14} 2{1} 2{6}
4{15} 2{1} 2{7}
4{16} 2{1} 2{8}
4{17} 2{1} 2{9}
4{18} 2{2} 2{3}
4{19} 2{2} 2{4}
4{20} 2{2} 2{5}
4{21} 2{2} 2{6}
4{22} 2{2} 2{7}
4{23} 2{2} 2{8}
4{24} 2{2} 2{9}
4{25} 2{3} 2{4}
4{26} 2{3} 2{5}
4{27} 2{3} 2{6}
83
86
85
91
83
78
84
61
56
70
69
55
67
64
62
57
76
94
4{28} 2{3} 2{7}
4{29} 2{3} 2{8}
4{30} 2{3} 2{9}
4{31} 2{4} 2{5}
4{32} 2{4} 2{6}
4{33} 2{4} 2{7}
4{34} 2{4} 2{8}
4{35} 2{4} 2{9}
4{36} 2{5} 2{6}
4{37} 2{5} 2{7}
4{38} 2{5} 2{8}
4{39} 2{5} 2{9}
4{40} 2{6} 2{7}
4{41} 2{6} 2{8}
4{42} 2{6} 2{9}
4{43} 2{7} 2{8}
4{44} 2{7} 2{9}
4{45} 2{8} 2{9}
54
56
77
86
97
59
90
63
94
87
85
75
88
96
95
48
59
56

Molecules 2009, 14
Table 4. Percent yields of purified library members based on amino acid esters, 2{1-9}.
357
Membe
r
Low
High Average Median
2{1}
2{2}
2{3}
2{4}
2{5}
2{6}
2{7}
2{8}
2{9}
61
22
54
12
69
55
48
48
56
91
83
94
97
94
97
88
96
95
81
61
69
69
83
89
67
72
70
83
64
69
70
85
94
62
73
63
A total of 10 reactions were run and the individual crude reactions compared to the corresponding
pure compounds in order to estimate the level of purity in the crude library and to provide some
indication of the major impurities present. As with the dI45DC libraries bearing amino acid esters and
alkanamines [14], the major impurity in this library results from hydrolysis of the pyrazine
intermediate, 3, to give an imidazole-4-substituted carboxamide-5-carboxylic acid. We observed
evidence of this impurity by LC-MS in 8 out of 10 of the crude reactions, although the level of its
presence appears low compared to the desired product based on the UV trace at 214 nm. There was
evidence by LC-MS for this impurity in the other 2 crude reactions, but this ion gave a relatively low
number of counts in the MS spectrum and, more significantly, the signal was also under the product
peak, so we think the presence of this ion is likely an ionization pathway of the product in these two
instances and does not mean there was significant hydrolysis in the reaction. Indeed, one of these
reactions provided a 97% purified yield and the other a 79% purified yield, supporting this hypothesis.
There is no evidence in the LC-MS traces of any other substantial impurities in the crude reactions,
.
although we know that the diisopropylethylamine hydrochloride (DIEA HCl) is still present.
1
The H-NMR spectra of the crude reactions are similar to those of their purified products, aside
.
from the extra DIEA HCl signals and variations in the amide and imidazole NH signals in the crude
reactions as compared with their purified products (see supporting information). The amide and
imidazole NH chemical shifts are known to be sensitive to both acidity and solvent [15], and it is
.
hypothesized that the presence of the DIEA HCl is the cause for the difference in the chemical shifts
between the crude and purified compounds.
These compounds have two intramolecularly hydrogen bonded conformations as illustrated in
Figure 1. The percentage of each conformation for these compounds has not been determined,
although we have noted in the past that the structure can bias one conformation over another by as
much as 80% to 20% [13, 21]. One advantage of this intramolecular hydrogen bond is that it yields
two conformations of every compound in this library and that either conformation or both may be
bioactive. We reason that a compound with significant bioactivity would be discovered in preliminary
biological screens even when tested at half of the initial screening concentration, as would be in the
case when there are two equivalent hydrogen bonded conformations. Thus, this library provides two

Molecules 2009, 14
358
possible bioactive structures for each compound.
Subsequent structure-activity relationship
development can include the synthesis of imidazole-4-ester-5-amide derivatives with chiral α-
hydroxyacid esters, incorporating one N-methylamino acid ester in the dI45DC, or N-alkylating the
imidazole ring in order to control the hydrogen bond donor and acceptor and thereby gain insight on
the bioactive conformation [16].
Figure 1. Two intramolecularly hydrogen bonded conformations of the dI45DCs.
R1
R3
R3
R1
N
O R4
R2 O
O
O
H
H
O
O
R2
N
N
R4
N
O
O
O
O
O
O
H
H
N
N
N
N
H
H
The library members have all been submitted to and accepted into the MLSMR for screening by the
MLSCN. At the time of this writing, two of the compounds in this library, 4{9} and 4{39}, showed
bioactivity in initial screens towards calpain II, but each just missed the activity cutoff in the follow up
investigation which was greater than 50% inhibition when tested at 0.225 mM [22]. The current
biological data for all of these compounds is best accessed through the PubChem database through a
structure search [23]. Table 5 provides the compound number in this report with the corresponding
PubChem SID numbers that can also be used to find information in PubChem. There is also recently
reported software, PubChemSR, that operates in a Windows environment and may be useful in helping
researchers mine the data found in PubChem [24].
Table 5. Cross reference guide for library members with the PubChem database (SID
identification number).
PubChem
SID‡
PubChem
SID‡
Cmpd.
Cmpd.
4{1}
4{2}
4{3}
4{4}
4{5}
4{6}
4{7}
4{8}
4{9}
4{10}
4{11}
4{12}
4{13}
26732547
49713852
26732537
49733436
26732515
49734139
26732535
49733439
26732539
49713854
26732541
49713857
26732520
4{24}
4{25}
4{26}
4{27}
4{28}
4{29}
4{30}
4{31}
4{32}
4{33}
4{34}
4{35}
4{36}
49733438
49713850
26732546
26732531
26732516
49713848
26732538
49713847
50096426
49734319
49714451
49713851
49713845

Molecules 2009, 14
359
Table 5. Cont.
4{37}
4{14}
4{15}
4{16}
4{17}
4{18}
4{19}
4{20}
4{21}
4{22}
4{23}
26732540
26732542
49713858
26732514
49713855
49731975
49713856
49713853
49731976
49733857
26732533
49731974
26732534
49713844
49713843
49713846
49713849
26732536
50096427
4{38}
4{39}
4{40}
4{41}
4{42}
4{43}
4{44}
4{45}
‡The PubChem information for each library member, along with the current bioassay results, can be
found by inserting the appropriate SID number into the spaces indicated by ######### in the
following
link:
[http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=########&loc
=ec_rcs]. Since each submission of a compound results in a unique PubChem SID number, it is
useful to search for other samples of the same compound under the link “Related Structures”.
Biological data may be listed for one sample of a compound and not for other samples of the same
compound.
Experimental
General
All apparatus was oven-dried and cooled in a desiccator. All reagents were purchased from
commercial suppliers and used without further purification. Reagent grade CH2Cl2 was distilled from
CaH2 before use. Thin layer chromatography (TLC) was performed on 250 µm glass-backed silica gel
plates and visualized using UV. Column chromatography was performed on silica gel (Merck, grade
9385, 230-400 mesh, 60 Å). The columns were prepared in plastic 20 or 30 mL syringe bodies and
filled to approximately 2/3 of their capacity with silica gel. This column volume was sufficient for
purification of most reaction products because the most substantial impurity is the imidazole-4,5-
dicarboxylic acid substituted with a carboxamide and carboxylic acid that absorbs strongly to silica
gel. In select cases, a second column was necessary in order to achieve analytically pure material. 1H-
NMR spectra were recorded at 10 mM at 400 MHz in CDCl3 with CHCl3 as the internal reference (δ
7.24). The names of the final compounds are provided in Table 6 at the end of the experimental
section.
LC-MS Analysis
Characterization of the purity and identity of the library members was carried out by liquid
chromatography-mass spectrometry (LC-MS) using a Varian 500-MS LC Ion Trap mass spectrometer.
Solutions of the compounds were prepared at an approximate concentration of 1 mg/mL by first
adding <10% by volume of CH2Cl2 to dissolve the sample and then diluting to the final volume with

Molecules 2009, 14
360
HPLC grade methanol. Five microliters of the sample was injected onto a Polaris 5 mm C18-A
(50×2.0 mm) HPLC column and eluted with a gradient of CH3CN/H2O containing 0.1% CH3CO2H at a
0.2 mL/min flow rate. Compounds were detected at 214 nm. The gradient was as follows: 0 min., 4:6
CH3CN/H2O → 1 min., 4:6 CH3CN/H2O → 6 min., 9:1 CH3CN/H2O → 8 min., 9:1 CH3CN/H2O → 9
min., 4:6 CH3CN/H2O → 10 min., 4:6 CH3CN/H2O. The mass spectrum was recorded for the entire
elution time by using ESI detection from 50-800 (m/z) with the following parameters: capillary
voltage at 60.0, Rf loading at 100%, drying gas at 250 °C, spray chamber at 50 °C, nebulizer gas at
50.0 psi, drying gas at 25 psi, and damping gas at 0.8 mL/min.
Synthesis
Symmetrically- and Dissymmetrically-disubstituted Imidazole-4,5-dicarboxamides [4{1-45}].
Screw capped culture tubes were dried overnight in a drying oven. Each tube was filled with a unique
combination of one amino acid ester substituted pyrazine 3{1-9} (0.100 mmol) and one α-amino acid
ester hydrochloride or tosylate salt 2{1-9} (0.200 mmol) (for a total of 45 tubes). Dry CH2Cl2 (3 mL)
was added to each tube. The tubes were then cooled to 0 °C and N,N-diisopropylethylamine (25.8 mg,
34.8 μL, 0.200 mmol) was added. The tubes were purged with argon and sealed. The resulting
solutions were shaken for 3 days at room temperature. The progress of each reaction was followed
with TLC by using a mixture of EtOAc/hexanes (1:1) as the eluant. The solvent was evaporated and
the residues were purified by column chromatography on silica gel using EtOAc/hexanes (1:1) and
then just EtOAc as the eluants. The desired fractions were combined and concentrated to give the final
products 4{1-45}. The purity and identity of the final products was determined by LC-MS as well as
1H NMR spectroscopy for selected examples.
Table 6. Final Product Numbers and Nomenclature.
cmpd
Name
4{1}
4{2}
4,5-bis[(tert-butoxyglycyl)carbonyl]-1H-imidazole
4,5-bis[(benzyloxyglycyl)carbonyl]-1H-imidazole
4{3}
4,5-bis[(tert-butoxy-S-alanyl)carbonyl]-1H-imidazole
4{4}
4{5}
4,5-bis[(benzyloxy-S-alanyl)carbonyl]-1H-imidazole
4,5-bis[(tert-butoxy-S-leucyl)carbonyl]-1H-imidazole
4{6}
4,5-bis[(benzyloxy-S-leucyl)carbonyl]-1H-imidazole
4{7}
4,5-bis[(tert-butoxy-S-phenylalanyl)carbonyl]-1H-imidazole
4{8}
4,5-bis[(benzyloxy-S-phenylalanyl)carbonyl]-1H-imidazole
4{9}
4,5-bis[(tert-butoxy-S-[Nε-(tert-butoxy)carbonyl]lysyl)carbonyl]-1H-imidazole
4-[(benzyloxyglycyl)carbonyl]-5-[(tert-butoxyglycyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-alanyl)carbonyl]-5-[(tert-butoxyglycyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-alanyl)carbonyl]-5-[(tert-butoxyglycyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-leucyl)carbonyl]-5-[(tert-butoxyglycyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-leucyl)carbonyl]-5-[(tert-butoxyglycyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-phenylalanyl)carbonyl]-5-[(benzyloxyglycyl)carbonyl]-1H-imidazole
4{10}
4{11}
4{12}
4{13}
4{14}
4{15}

Molecules 2009, 14
361
Table 3. Cont.
4{16}
4{17}
4-[(benzyloxy-S-phenylalanyl)carbonyl]-5-[(benzyloxyglycyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-[Nε-(tert-butoxy)carbonyl]lysyl)carbonyl]-5-[(benzyloxyglycyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-alanyl)carbonyl]-5-[(benzyloxyglycyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-alanyl)carbonyl]-5-[(benzyloxyglycyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-leucyl)carbonyl]-5-[(benzyloxyglycyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-leucyl)carbonyl]-5-[(benzyloxyglycyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-phenylalanyl)carbonyl]-5-[(benzyloxyglycyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-phenylalanyl)carbonyl]-5-[(benzyloxyglycyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-[Nε-(tert-butoxy)carbonyl]lysyl)carbonyl]-5-[(benzyloxyglycyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-alanyl)carbonyl]-5-[(tert-butoxy-S-alanyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-leucyl)carbonyl]-5-[(tert-butoxy-S-alanyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-leucyl)carbonyl]-5-[(tert-butoxy-S-alanyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-phenylalanyl)carbonyl]-5-[(tert-butoxy-S-alanyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-phenylalanyl)carbonyl]-5-[(tert-butoxy-S-alanyl)carbonyl]-1H-imidazole
4{18}
4{19}
4{20}
4{21}
4{22}
4{23}
4{24}
4{25}
4{26}
4{27}
4{28}
4{29}
4-[(tert-butoxy-S-[Nε-(tert-butoxy)carbonyl]lysyl)carbonyl]-5-[(tert-butoxy-S-alanyl)carbonyl]-1H-imidazole
4{30}
4{31}
4{32}
4{33}
4{34}
4{35}
4{36}
4{37}
4{38}
4{39}
4{40}
4{41}
4{42}
4{43}
4{44}
4{45}
4-[(tert-butoxy-S-leucyl)carbonyl]-5-[(benzyloxy-S-alanyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-leucyl)carbonyl]-5-[(benzyloxy-S-alanyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-phenylalanyl)carbonyl]-5-[(benzyloxy-S-alanyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-phenylalanyl)carbonyl]-5-[(benzyloxy-S-alanyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-[Nε-(tert-butoxy)carbonyl]lysyl)carbonyl]-5-[(benzyloxy-S-alanyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-leucyl)carbonyl]-5-[(tert-butoxy-S-leucyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-phenylalanyl)carbonyl]-5-[(tert-butoxy-S-leucyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-phenylalanyl)carbonyl]-5-[(tert-butoxy-S-leucyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-[Nε-(tert-butoxy)carbonyl]lysyl)carbonyl]-5-[(tert-butoxy-S-leucyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-phenylalanyl)carbonyl]-5-[(benzyloxy-S-leucyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-phenylalanyl)carbonyl]-5-[(benzyloxy-S-leucyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-[Nε-(tert-butoxy)carbonyl]lysyl)carbonyl]-5-[(benzyloxy-S-leucyl)carbonyl]-1H-imidazole
4-[(benzyloxy-S-phenylalanyl)carbonyl]-5-[(tert-butoxy-S-phenylalanyl)carbonyl]-1H-imidazole
4-[(tert-butoxy-S-[Nε-(tert-butoxy)carbonyl]lysyl)carbonyl]-5-[(tert-butoxy-S-phenylalanyl)carbonyl]-1H-
imidazole
4-[(tert-butoxy-S-[Nε-(tert-butoxy)carbonyl]lysyl)carbonyl]-5-[(benzyloxy-S-phenylalanyl)carbonyl]-1H-imidazole

Molecules 2009, 14
362
Acknowledgements
The authors thank Jennifer Parker for assistance with the submission of these compounds to the
MLSMR, The University of Tulsa for the purchase of a 400 MHz NMR spectrometer, and The
National Institutes of General Medical Sciences for funding this research (5 P41 GM79589).
References and Notes
1. Nielsen, T.E.; Schreiber, S. L. Towards the optimal screening collection: a synthesis strategy.
Angew. Chem. Int. Ed. 2008, 47, 48-56.
2. Kaiser, M.; Wetzel, S.; Kumar, K.; Waldmann, H. Biology-inspired synthesis of compound
libraries. Cell. Mol. Life Sci. 2008, 65, 1186-1201.
3. Huryn, D. M.; Cosford, N. D. P. The Molecular Libraries Screening Center Network (MLSCN):
Identifying chemical probes of biological systems. Ann. Rep. Med. Chem. 2007, 42, 401-406.
4. Winssinger, N.; Pianowski, Z.; Debaene, F. Probing biology with Small Molecule Microarrays
(SMM). Top. Curr. Chem. 2007, 278, 311-342.
5. Haggarty, S. J.; Schreiber, S. L. Forward chemical genetics. In Chemical Biology From Small
Molecules to Systems Biology and Drug Design; Schreiber, S. L., Kapoor, T.M., Günther, W.,
Eds.; Wiley-VCH Verlag GmbH & Co: KGaA, Weinheim, 2007; 299-354.
6. Zerhouni, E: Medicine. The NIH Roadmap. Science 2003, 302, 63-72.
7. Schnur, D. M. Recent trends in library design: 'rational design' revisited. Curr. Opin. Drug
Discov. Devel. 2008, 11, 375-380.
8. Olah, M. M.; Bologa, C. G.; Oprea, T. I. Strategies for compound selection. Curr. Drug Discov.
Technol. 2004, 1, 211-220.
9. Vistoli, G.; Pedretti, A.; Testa, B. Assessing drug-likeness-what are we missing? Drug Discov.
Today 2008, 13, 285-294.
10. Muegge, I. Selection criteria for drug-like compounds. Med. Res. Rev. 2003, 23, 302-321.
11. Baures, P. W. Heterocyclic HIV-1 protease inhibitors. Org. Lett. 1999, 1, 249-252.
12. Van Compernolle, S.; Wiznycia, A. V.; Rush, J. R.; Dhanasekaran, M.; Baures, P. W.; Todd, S. C.
Small molecule inhibition of Hepatitis C virus E2 binding to CD81. Virology 2003, 314, 371-380.
13. Perchellet, E. M.; Perchellet, J. P.; Baures, P. W. Imidazole-4,5-dicarboxamides with
antiproliferative activity against HL-60 cells. J. Med. Chem. 2005, 48, 5955-5965.
14. Solinas, R.; DiCesare, J. C.; Baures, P. W. Parallel synthesis of an imidazole-4,5-dicarboxylic
acid library bearing amino acid esters and alkanamines. Molecules 2008, 13, 3149-3170.
15. Rush, J. R.; Sandstrom, S. L.; Yang, J.; Davis, R.; Prakash, O.; Baures, P. W. Intramolecular
hydrogen bond strength and pKa determination of N,N’-disubstituted imidazole-4,5-
dicarboxamides. Org. Lett. 2005, 7, 135-138.
16. Baures, P. W. Imidazole-4,5-dicarboxylic acid: A versatile scaffold for drug discovery and
materials research. Trends Heterocy. Chem. 2006, 11, 1-22.
17. Lipinski, C. A. Drug-like properties and the causes of poor solubility and poor permeability. J.
Pharmacol. Toxicol. Methods 2000, 44, 235-249.

Molecules 2009, 14
363
18. Veber, D. F.; Johnson, S. R.; Cheng, H. Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. Molecular
properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002, 45,
2615-2623.
19. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational
approaches to estimate solubility and permeability in drug discovery and development settings.
Adv. Drug Deliv. Rev. 2001, 46, 3-26.
20. A website with data for these compounds and background information for the overall project is
found at the following link: http://www.imidazole.utulsa.edu.
21. Wiznycia, A. V.; Helfrich, B. A.; Baures, P. W. An improved method for the synthesis of
dissymmetric N,N’-disubstituted imidazole-4,5-dicarboxamides. J. Org. Chem. 2002, 67, 7151-
7154.
22. The
details
of
this
bioassay
can
be
accessed
at:
http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?q=&pagefrom=BioAssaySrvice&aid=1236
23. The PubChem database can be accessed at http://www.ncbi.nlm.nih.gov/PubMed.
24. Hur, J.; Wild, D. J. PubChemSR: A search and retrieval tool for PubChem. Chem. Cent. J. 2008,
2, 11.
Sample Availability: Please contact the corresponding author.
© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).