Similarity analysis, synthesis, and bioassay of antibacterial cyclic peptidomimetics

Article abstract of DOI:10.3762/bjoc.8.128

The chemical similarity of antibacterial cyclic peptides and peptidomimetics was studied in order to identify new promising cyclic scaffolds. A large descriptor space coupled with cluster analysis was employed to digitize known antibacterial structures and to gauge the potential of new peptidomimetic macrocycles, which were conveniently synthesized by acylbenzotriazole methodology. Some of the synthesized compounds were tested against an array of microorganisms and showed antibacterial activity against Bordetella bronchistepica, Micrococcus luteus, and Salmonella typhimurium.

Full text of DOI:10.3762/bjoc.8.128

Similarity analysis, synthesis, and bioassay of
antibacterial cyclic peptidomimetics
Workalemahu M. Berhanu1, Mohamed A. Ibrahim1,2,3, Girinath G. Pillai1,
Alexander A. Oliferenko1, Levan Khelashvili1, Farukh Jabeen4,
Bushra Mirza5, Farzana Latif Ansari4, Ihsan ul-Haq5, Said A. El-Feky2
and Alan R. Katritzky*1,6
Full Research Paper
Open Access
Address:
Center for Heterocyclic Compounds, Department of Chemistry,
Beilstein J. Org. Chem. 2012, 8, 1146–1160.
1
doi:10.3762/bjoc.8.128
University of Florida, Gainesville, FL 32611-7200, USA, 2Department
of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig
University, Zagazig-44519, Egypt, 3Department of Organic Chemistry,
College of Pharmacy, Misr University for Science and Technology,
Al-Motamayez District, P.O. Box: 77, Egypt, 4Department of
Received: 24 February 2012
Accepted: 01 June 2012
Published: 24 July 2012
Chemistry, Quaid i Azam University, Islamabad 45320, Pakistan,
This article is part of the Thematic Series "Antibiotic and cytotoxic
peptides".
5Department of Biochemistry, Quaid i Azam University, Islamabad
45320, Pakistan and 6Department of Chemistry, King Abdulaziz
University, Jeddah 21589, Saudi Arabia
Guest Editor: N. Sewald
Email:
© 2012 Berhanu et al; licensee Beilstein-Institut.
License and terms: see end of document.
Alan R. Katritzky* - katritzky@chem.ufl.edu
*
Corresponding author
Keywords:
antibacterial; cluster analysis; N-acylbenzotriazoles; peptidomimetics;
similarity
Abstract
The chemical similarity of antibacterial cyclic peptides and peptidomimetics was studied in order to identify new promising cyclic
scaffolds. A large descriptor space coupled with cluster analysis was employed to digitize known antibacterial structures and to
gauge the potential of new peptidomimetic macrocycles, which were conveniently synthesized by acylbenzotriazole methodology.
Some of the synthesized compounds were tested against an array of microorganisms and showed antibacterial activity against
Bordetella bronchistepica, Micrococcus luteus, and Salmonella typhimurium.
Introduction
Diverse cyclic peptides, both natural and synthesized, are potent antifungal agents: It is believed that cyclic peptides are more
antibiotics [1-3]. Gramicidin S, vancomycine, bacitracin, stable to proteolysis due to the lack of free N- and C-termini, as
polymixin B, colistin, valinomycin, actinomycin, and many well as reduced conformational freedom. Stability can also be
more, have been tested and used clinically as antimicrobial and achieved by modifying peptides into “peptidomimetics” that
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Beilstein J. Org. Chem. 2012, 8, 1146–1160.
mimic and/or stabilize the secondary structure that modifies opens the cell wall, “allowing a small anionic peptide to pene-
associated biological processes, thus affording opportunities for trate”. Topical administration of such anionic peptides is
drug design and development.
possible, for example in the form of nasal or throat sprays but,
at least one anionic peptide, daptomycin, is administered intra-
One strategy to create peptidomimetics couples a small-mole- venously.
cule scaffold with a peptide. Such scaffolds include aromatic
rings or heterocycles, which may be positioned in the interior of The abundance of natural and synthetic antimicrobial peptides
the peptide chain [4,5] or at the C- [6-8] or N-terminus [9]. and peptidomimetics of varying structure and activity reported
Many reports describe the successful use of heterocycles as raises the question of how their similarity or dissimilarity can be
peptide-bond surrogates or as potential protein-recognition quantified and how synthetic efforts can be focused towards
motifs to achieve superior potency in biological assays [10-14]. novel active compounds. It would be beneficial to be able to
draw practical conclusions (even if approximate) based solely
Pyridines are well-established as important heterocycles in on the chemical structures of existing agents. In the case of
medicinally and biologically active compounds and also as cyclic peptides, the complex cyclomatic structure, involving
important structural elements. Pyridine scaffolds possess impor- smaller rings and heteroatoms, as well as a limited con-
tant antiviral [15], anti-inflammatory [16,17], anticonvulsant formational flexibility, makes it difficult to classify or compare
[
18], antibacterial [19], and antitumor pharmacological activi- such compounds by their ring sizes. Fortunately, chemical
ties [20,21].
informatics provides formalized procedures for comparing
chemical compounds based on composition and structure.
Chiral macrocyclic ligands have found wide application in While the principle of molecular similarity is quite simple, that
asymmetric synthesis and enantiomeric recognition [22,23]. is, “similar compounds have similar properties”, the unam-
Incorporation of amino acids in abiotic anion receptors can lead biguous and automated implementation of this principle needed
to systems that mimic the anion coordination properties of to be backed with a solid mathematical background; this has
anion-binding proteins [24]. Introduction of cysteine subunits been accomplished and has made it possible to develop effi-
into a macrocycle facilitates receptor synthesis and allows cient similarity measures [33]. The simplest similarity measure
control of the relative direction of the two chains attached to the of two molecules would be the Euclidian distance between them
cysteine residue. For example, one of the early cysteine- in a descriptor space, which is an abstract n-dimensional space
containing macrocycles was designed to mimic the cation spanned by n molecular descriptors, or parameters. More elabo-
binding ability of valinomycin [24].
rate measures have been developed, such as the Tanimoto coef-
ficient or the Tversky index [34]. Although a well-established
Numerous literature approaches to the synthesis of 17-, 18- and concept, molecular similarity has previously been used almost
4-membered rings utilize: (i) acyl chlorides, (ii) active esters entirely in the design of small-molecule drugs, with very few
2
and (iii) coupling reagents. However, some of the published applications in other chemical disciplines. To the best of our
literature methods involve the utilization of complex pro- knowledge, despite their promise of consistent analysis and
cedures, protection/deprotection strategies, harsh reaction comparison, the principles of molecular similarity have never
conditions, and long reaction times; provide only low yields; been used in the design of peptides.
and are plagued with difficulties associated with product purifi-
cation [25-29]. According to the literature [30,31], most The aim of the present work is thus three-fold: (i) To identify
antimicrobial cyclic peptides are active in their cationic form. promising peptidomimetic scaffolds by using molecular simi-
Cationic peptides are considered advantageous, because they larity; (ii) to design a range of cyclic pyridine-containing
adhere better to the outer anionic parts of phospholipid peptidomimetics capable of facile synthesis; and (iii) to synthe-
membranes.
size and biotest promising candidates. A synthetic route seems
highly relevant, since N-acylbenzotriazoles have been reported
Although anionic peptides are less common in clinical practice, elsewhere [35-37] to be stable, easy-to-handle acylating agents
they are gaining momentum, because natural anionic peptides and have found numerous applications for advantageous N-, O-,
are a part of the innate immune system of living organisms C- and S-acylations.
(
located in human, ovine, and bovine lungs) and also serve as
immunomodulators [32]. The activity of anionic peptides can be
enhanced when associated with zinc cations and/or surfactants Similarity analysis
30-32]. Anionic peptides bind with lysozyme, an important Our literature search identified the thirty three cyclic peptides
cationic hydrolytic enzyme. It is believed that the lysozyme and peptidomimetic structures given in Table 1. All the
Results and Discussion
[
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Beilstein J. Org. Chem. 2012, 8, 1146–1160.
minimum inhibition constants (MIC) are pertinent to Staphylo- through the proper choice of the dicarboxylic starting materials.
coccus aureus. These include (i) one 12-membered ring cyclic While scaffold 37 and the 16-membered ring scaffolds
tetrapeptide, (ii) two 14-membered ring peptidomimetics each described in Table 1 seem to be visually different, we under-
with two peptide links, (iii) two 18-membered ring took analysis of their proximity in a multidimensional
peptidomimetics each with five peptide links, and (iv) twenty descriptor space to afford a more rigorous comparison. Such
seven 16-membered ring pentapeptides. Table 1 demonstrates analysis takes into account not only structural similarity
that compounds of group (iv) show the best antibacterial features, but also electronic, charge-distribution, and hydrogen-
activity, with compounds 24 and 27 being the most active. The bond characteristics. We generated such a multidimensional
side-chain substitution clearly controls the antibacterial activity, descriptor space for all structures in Table 1 as well as for struc-
as the cyclic scaffold is identical. The 18-membered ring scaf- tures 37a–c, using CODESSA-Pro software [38]. Clustering of
fold 37, accessible through the benzotriazole route, provides an the structures in such a multidimensional space is the natural
excellent opportunity for introducing substituents economically, choice for similarity analysis.
Table 1: Structures of cyclic peptides with their MIC values.
Structure
Cluster number
Observed MIC (μg/mL)
Ref.
3
8.0
[39]
1
2
16
[39]
2
3
--
[40]
3
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Beilstein J. Org. Chem. 2012, 8, 1146–1160.
Table 1: Structures of cyclic peptides with their MIC values. (continued)
3
3.12
[41]
4
3
3.12
[42]
5
2
0.50
[43,44]
6
3
1.5
[44]
7
1
12.5
[45]
8
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Beilstein J. Org. Chem. 2012, 8, 1146–1160.
Table 1: Structures of cyclic peptides with their MIC values. (continued)
2
1
2
50
[45]
[45]
[45]
9
12.5
10
1.56
11
1
1.56
[45]
12
2
6.25
[46]
13
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Beilstein J. Org. Chem. 2012, 8, 1146–1160.
Table 1: Structures of cyclic peptides with their MIC values. (continued)
2
1.56
[46]
14
2
3.12
[47]
15
2
12.5
[47]
16
2
12.5
[47]
17
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Beilstein J. Org. Chem. 2012, 8, 1146–1160.
Table 1: Structures of cyclic peptides with their MIC values. (continued)
2
12.5
[47]
18
2
12.5
[47]
19
1
25.0
[47]
20
2
25.0
[47]
21
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Beilstein J. Org. Chem. 2012, 8, 1146–1160.
Table 1: Structures of cyclic peptides with their MIC values. (continued)
2
12.5
[47]
22
2
12.5
[47]
23
2
0.78
[48]
24
2
6.25
[48]
25
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Beilstein J. Org. Chem. 2012, 8, 1146–1160.
Table 1: Structures of cyclic peptides with their MIC values. (continued)
1
1.56
[48]
26
2
0.780
[48]
27
2
3.12
[48]
28
2
1.56
[48]
29
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Beilstein J. Org. Chem. 2012, 8, 1146–1160.
Table 1: Structures of cyclic peptides with their MIC values. (continued)
2
1.56
[48]
30
2
3.12
[48]
31
2
3.12
[48]
32
2
3.12
[48]
33
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Beilstein J. Org. Chem. 2012, 8, 1146–1160.
Clustering
proposed for synthesis are located in cluster 1. Cluster 1 mainly
Clustering is a widely used technique that has found applica- consists of both cyclotetra- and cyclopentapeptides that are
tion in the selection of compounds for screening, analysis of similar in ring size to 37a–c; this cluster also includes those
substructure search output, and the prediction of molecular cyclic peptides that are highly potent as antibacterial agents
properties [49]. The “k-means method” implemented in (smallest MIC values). Clusters 1 and 2 contain structurally
Statistica software is effective in clustering results for many more diverse peptides. Thus, the majority of 12-membered ring-
practical applications, and was used to classify the current data cyclic compounds were assigned to cluster 1, while the more
set. All types of descriptors are calculated by using the branched structures with longer side chains were found in
CODESSA Pro program and the descriptor matrix is generated, cluster 2. These assignments are chemically meaningful and
which served as an input for the cluster-analysis module in thus bear witness to the validity of the clusterization method
STATISTICA software. The use of descriptors in this study can used.
give differing clustering patterns [50]. The first step in the
structure clustering is the generation of a matrix containing The proximity of the cyclic peptidomimetics under study
similarity values of descriptors for all pairs of compounds. (37a–c) and the existing antibacterial cyclic peptides in such a
Further, the matrix is converted to a hierarchical clustering tree rich descriptor space, in which all major structural, electronic,
by using single-linkage amalgamation and Euclidian distance and intermolecular-interaction features are taken into account,
measure. The single-linkage approach assigns sequential cluster attests to the feasibility of using the 17- and 18-membered ring
labels to nearest-neighbor clusters. Then a series of clustering scaffolds 37 as a main building block for designing novel
experiments was carried out with different cutoffs on the antibacterial agents. This, along with the facile and economic
descriptor dependence, to clearly establish whether parameters synthetic route, renders scaffold 37 as a promising platform for
produce realistic improvements in the quality of the results or further rational drug design.
not [51].
Synthesis
Analysis of the membership functions shows that the clusters Treatment of dicarboxylic acids 34a–c by a standard method
are well-defined with each compound typically having one [36] using thionyl chloride and 1H-benzotriazole gave the
membership function, as shown in Figure 1 and Table 1. The corresponding benzotriazole derivatives in 37–54% yield
cluster analysis results demonstrate that most of the studied (Scheme 1, see Supporting Information File 1 for experimental
compounds are clustered clusters. The peptidomimetics 37a–c details).
Figure 1: Molecular-descriptor-based cluster analysis; single-linkage Euclidean distances. Clustering of compounds in the descriptor space; a two-
dimensional representation of chemical space being partitioned into clusters of similar compounds based on descriptors using a top-down (hierar-
chical) clustering method. Structures for compounds 37a–37c are shown in Scheme 2. (Axis X denotes compounds and axis Y denotes linkage dis-
tance); the red oval, blue rectangle, and green oval represent cluster 1, cluster 2, and cluster 3, respectively.
1156

Beilstein J. Org. Chem. 2012, 8, 1146–1160.
treated with 1 equiv of 35a–c to synthesize cyclic enantiopure
peptidomimetic products 37a–c in 81–82% yield (Scheme 2,
see Supporting Information File 1 for experimental details).
In a further application of this synthetic approach 35 was
coupled with 2 equiv of L-Phe-OH in the presence of TEA in
aqueous acetonitrile at room temperature over 3 h giving the bis
N-acylated compound 38 in 88% yield. Compound 38 was
converted to the corresponding benzotriazole derivative 39 and
coupled with bis(S-acylcysteine) 36 forming the
pyridine–cysteine-containing macrocycle 40 in 70% yield
Scheme 1: Preparation of dicarboxylic benzotriazole derivatives.
The methodology used for the regioselective syntheses of S- (Scheme 3, see Supporting Information File 1 for experimental
and N-acylcysteines was developed recently in our group by details).
using N-acylbenzotriazoles under mild reaction conditions [37].
Utilizing this methodology, 35a was coupled with two equiv of Bioassay
free cysteine in aqueous acetonitrile at 20 °C over 12 h to give Screening for antibacterial activity was performed for two
bis(S-acylcysteine) 36 in 64% yield. Compound 36 was then cyclic peptidomimetics belonging to scaffold 37, namely 37a
Scheme 2: Preparation of pyridine-based cysteine-containing macrocycles.
Scheme 3: Preparation of pyridine–cysteine-containing macrocycle 39.
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Beilstein J. Org. Chem. 2012, 8, 1146–1160.
and 37b, with the pyridine- and phenyl-linking fragments, res- which is a fairly promising result for a “bare” cyclic scaffold
pectively. The array of microbial strains assayed in this study with no intentional functionalization. Given the successful scaf-
included six pathogens listed in Table 2 (see Supporting Infor- fold identified, the next step will be to furnish it with appro-
mation File 1, for antibacterial testing protocol).
priate functional groups and substituents by using rational
design principles.
The in vitro data for 37a and 37b are given in Table 2. Refer-
Experimental
ence antibiotics roxithromycin and cefixime were used as posi-
tive controls. It is seen that peptidomimetic 37b exhibits Methodology
moderate activity against Bordetella bronchiseptica, Micro- Molecular similarity
coccus luteus, and Salmonella typhimurium. For a “bare” scaf- The potential of cyclic peptidomimetics, widely acknowledged
fold with no tailor-made substitution, this should be considered as significant, arises because they are less prone to hydrolysis in
as an encouraging result and an indication of the possibility of vivo and can be synthesized rather inexpensively. The synthetic
more interesting results if the scaffold is furnished with appro- methodology that has been developed in our lab affords facile
priate functions.
assembles of cyclic structures from dicarboxylic building
blocks by using a benzotriazole methodology. Seventeen and
Peptidomimetic 37a showed no activity in this test, which can eighteen-membered sulfur-containing rings can be synthesized
be explained by the formation of a zwitter-ionic structure due to readily if cysteine is used as the coupling agent. Such facile
protonation of the pyridine moiety by free carboxylic groups. It access to cyclic peptidomimetics is appropriate for the design of
is reasonable to assume that such a zwitter-ionic structure alters compounds expected to be biologically active as antibacterial
the charge distribution and also eliminates hydrogen bonding in agents. Exploring the molecular similarity of existing antibacte-
which the pyridine nitrogen atom acts as a H-bond acceptor. rial cyclic peptides using the Tanimoto method in the Instant
These factors increase hydrophobicity and thus deteriorate JChem software [52], and the peptidomimetics easily acces-
bioavailability, as reflected in the absence of activity of 37a. sible through the benzotriazole route, should give structural
Absence of data in Table 2 means that the sample is not active insights and design criteria. Guidance for such a similarity-
at the highest concentration tested.
based design should be available by analysis of a reasonably
sized dataset of existing analogues. As abundant data can be
found in the literature for Staphylococcus aureus, this was
Conclusion
Two new cyclic peptidomimetic scaffolds were identified by chosen as a reference for antibacterial activity. SciFinder
using similarity-based rational design. Their chemical simi- Scholar was used to retrieve the structures of 33 cyclic peptides
larity with existing antibacterial cyclic peptidomimetics was with reported antibacterial activity (Table 1). The minimum
established in a huge descriptor space generated by Codessa-Pro growth inhibition constant (MIC) was used as the measure of
software. At least one compound (37b) demonstrated a antibacterial activity, and the data collected were converted
moderate antibacterial activity against three bacterial strains, where necessary to μg/mL. Three structures newly synthesized
Table 2: Antibacterial activity in vitro.
Microbial straina
Inhibition zone (mm) at 200 µg/mL
MICb (µg/mL)
3
7a
37b
0.0
0.0
6.0
6.0
6.0
0.0
Roxc
30
Cfxd
40
37a
–
37b
–
Roxc
Cfxd
6.25
50
Staphylococcus aureus
0.0
0.0
0.0
0.0
0.0
0.0
12.5
100
150
12.5
100
100
(
ATCC 6538)
Escherichia coli
ATCC 8739)
Bordetella bronchiseptica
ATCC 4617)
Micrococcus luteus
ATCC 10240)
Salmonella typhimurium
ATCC 14028)
Enterobacter aerogenes
ATCC 13048)
14.6
8
22.9
33
–
–
(
–
150
150
150
–
12.5
12.5
6.25
12.5
(
30
40
–
(
12
40
–
(
15
34
–
(
aBordetella bronchistepica: Gram negative, relevant to veterinary science; Micrococcus luteus: Gram positive, not dangerous for humans; Salmonella
typhimurium: Gram negative, relevant to veterinary science. bMIC = minimum inhibitory concentration. cRox = roxithromycin. dCfx = cefixime.
1158

Beilstein J. Org. Chem. 2012, 8, 1146–1160.
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