Design of novel camphane-based derivatives with antimycobacterial activity

Article abstract of DOI:10.1016/j.jmgm.2014.04.008

Although tuberculosis (TB) continues to be one of the leading infectious disease killers globally, it is curable and preventable. Despite the existence of safe, well tolerated and effective drugs used in the TB treatment, the interest in new entities, combinations and regimens increases during the last 10 years. Recently, we reported for a new class of anti-TB agents - camphane-based derivatives with nanomolar activity against Mycobacterium tuberculosis strains. The quantitative structure-activity relationship (QSAR) study on 12 compounds revealed several structural requirements for antimycobacterial activity: two hydrogen bond donors, two or three rings and no large branched substituents. Here, we describe the design of a set of nine novel camphane-based derivatives following these requirements. The compounds were synthesized and tested against M. tuberculosis strain H37Rv. Four of them showed activities in the nanomolar range, significantly higher than the activities in the initial set. The QSAR study based on all 21 derivatives pointed to two main structural requirements for anti-TB activity: two hydrogen bond donors and a side chain with aromatic ring.

Full text of DOI:10.1016/j.jmgm.2014.04.008

Accepted Manuscript
Title: Design of novel camphane-based derivatives with
antimycobacterial activity
Author: Georgi Stavrakov Violeta Valcheva Irena Philipova
Irini Doytchinova
PII:
S1093-3263(14)00053-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jmgm.2014.04.008
JMG 6399
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Journal of Molecular Graphics and Modelling
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Revised date:
Accepted date:
25-10-2013
2-4-2014
21-4-2014
Please cite this article as: G. Stavrakov, V. Valcheva, I. Philipova,
I. Doytchinova, Design of novel camphane-based derivatives with
antimycobacterial activity, Journal of Molecular Graphics and Modelling (2014),
http://dx.doi.org/10.1016/j.jmgm.2014.04.008
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Design of novel camphane-based derivatives with antimycobacterial activity
Georgi Stavrakova, Violeta Valchevab, Irena Philipovac, Irini Doytchinovaa*
aFaculty of Pharmacy, Medical University of Sofia, 2 Dunav st., Sofia 1000, Bulgaria
bInstitute of Microbiology, Bulgarian Academy of Sciences, 26 Akad. Bonchev st., Sofia
1113, Bulgaria
cInstitute of Organic Chemistry, Bulgarian Academy of Sciences, 9 Acad. Bonchev st., Sofia
1113, Bulgaria
*Corresponding author. Faculty of Pharmacy, 2 Dunav st., Sofia 1000, Bulgaria; tel
+3599236506
E-mail address: idoytchinova@pharmfac.net
Abstract
Although tuberculosis (TB) continues to be one of the leading infectious disease killers
globally, it is curable and preventable. Despite the existence of safe, well tolerated and
effective drugs used in the TB treatment, the interest in new entities, combinations and
regimens increases during the last 10 years. Recently, we reported for a new class of anti-TB
agents – camphane-based derivatives with nanomolar activity against M. tuberculosis strains.
The quantitative structure – activity relationship (QSAR) study on 12 compounds revealed
several structural requirements for antimycobacterial activity: two hydrogen bond donors, two
or three rings and no large branched substituents. Here, we describe the design of a set of 9
novel camphane-based derivatives following these requirements. The compounds were
synthesized and tested against M. tuberculosis strain H37Rv. Four of them showed activities
in the nanomolar range, significantly higher than the activities in the initial set. The QSAR
study based on all 21 derivatives pointed to two main structural requirements for anti-TB
activity: two hydrogen bond donors and a side chain with aromatic ring.
Key words: tuberculosis, antimycobacterial activity, camphane-based derivatives, QSAR,
drug design
1. Introduction
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Tuberculosis (TB) remains a leading infectious disease killer globally. In Africa, TB is
the biggest killer of people with HIV/AIDS [1]. One third of the world's population is thought
to have been infected with M. tuberculosis [2] but about 90% of them have asymptomatic,
latent TB infections. TB is curable and preventable. Bacille Calmette Guerin (BCG) is the
only vaccine available today for protection against tuberculosis [3]. It is most effective in
protecting children from the disease. Many strains of tuberculosis resist the drugs mostly used
to treat the disease. People with active tuberculosis must take several types of medications for
many months to eradicate the infection and to prevent the development of antibiotic resistance
[4].
After 40 years of neglect, encouraging advances have been made in TB drug research
and development during the last 10 years, resulting in nine compounds currently under
clinical development and more than 20 new chemical entities in preclinical research [5]. New
drugs and drug combinations are needed that have strong, bactericidal activity against various
strains of M. tuberculosis.
When the target is known, structure-based methods as docking, molecular dynamics
simulations, virtual screening, de novo design, are effective in lead identification and lead
optimization [6]. When the initial information comes from a whole-cell experiment, ligand-
based methods as pharmacophore search, 2D and 3D QSAR studies, fingerprints and
similarity search, are helpful in the design of new ligands [6]. The advances in the chase of
new anti-TB drugs have been recently reviewed [7]. The ligand-based methods are involved
actively [8-18] but the structure-based methods targeting specific M. tuberculosis enzymes
also take place [19-22].
Recently, we synthesized a series of novel camphane-based derivatives and tested
them against two M. tuberculosis strains: strain H37Rv and multi-drug resistant strain 43 [23].
All of them were active against strain H37Rv with MIC values in the micro- and nanomolar
range. Three derivatives showed also activity against MDR strain 43 with MIC values in the
micromolar range. A detailed QSAR study was conducted and the following 2D-QSAR model
was derived:
pMIC = 0.592 knotp – 0.445 SHHBd – 0.683 nrings + 12.992
n = 12 r2 = 0.875 SEE = 0.290 F = 18.58 q2 = 0.675
The structures of the compounds, their experimental MIC and pMIC (-logMIC) are
given in Table 1. In Table 1 also are given the values of the descriptors presented in the model
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and the calculated pMIC and MIC. The descriptor knotp relates to intermolecular accessibility
[24]. Negative knotp values correspond to large molecules with high degree of branching,
distal substituents, or adjacent (conjugated) rings. Such substituents are unfavorable for
antimycobacterial activity. The descriptor SHHBd represents the sum of atom-type hydrogen
E-state indices for hydrogen bond donors. There are two common hydrogen bond donors in
the side chain of the studied structures: the OH and NH groups. Any additional H-bond donor
decreases the activity. The descriptor nrings accounts for the number of rings in the molecular
graph. It has a negative contribution; therefore, the presence of many rings in the structure
decreases the activity. The camphene moiety itself brings two rings. One additional ring in the
side chain is well tolerated. However, four rings in the structure (compound 6) drastically
decrease the activity.
Table 1. Structure, experimental MICs, molecular descriptors and calculated MICs of the training set.
Cmpd.*
Structure
MIC(exp) pMIC(exp) knotp SHHBd nrings pMIC(calc) residual
μM
H
N
1(3a)
0.33
0.33
0.38
6.481 -4.109
6.481 -4.109
6.420 -4.385
4.327
4.382
4.432
3
3
3
6.584
6.559
6.373
-0.103
-0.078
0.047
Ph
Ph
O
OH
H
N
2(3b)
3(3c)
O
OH
H
N
O
O
OH
4(3d)
5(3e)
6(4)
0.30
0.36
6.523 -4.475
6.444 -4.385
4.868 -5.506
4.523
4.416
4.553
3
3
4
6.280
6.381
4.941
0.243
0.063
-0.073
H
N
O
OAc
N
OH
H
N
O
OH
O
H
N
13.55
Ph
Ph
P
OH
3
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H
N
H
7(5)
0.41
6.387 -3.880
4.783 -4.810
6.026
7.105
2
3
6.646
4.932
-0.259
-0.149
N
Et
O
OH
OH
Ph
8(9a)
16.50
H
N
O
OH
OH
9(9b)
10(9c)
11(9d)
12(9e)
6.30
0.74
7.06
0.66
5.201 -4.606
6.131 -4.784
5.151 -4.907
6.180 -4.434
7.049
6.899
6.915
6.939
3
2
2
2
5.078
5.722
5.643
5.912
0.124
0.409
-0.492
0.268
H
N
Ph
O
OH
OH
H
N
O
OH
OH
H
N
O
OH
OH
H
N
S
O
OH
*the compounds ID according to ref. 23 are given in parenthesis.
In the present study, we designed a series of novel camphane-based derivatives
following the structural requirements for antimycobacterial activity derived in the previous
study. The compounds were synthesized and tested against M. tuberculosis strain H37Rv.
Four of them showed MICs in the nanomolar range, two times lower than the lowest MIC in
the initial set. New QSAR studies provide clear directions for further lead optimization of the
camphanes as antimycobacterial agents.
2. Results
2.1. Design of novel camphane-based derivatives and prediction of their antimycobacterial
activity
Based on the structural requirements derived in the previous study, we designed six
new camphane-based derivatives carrying two hydrogen bond donors, two or three rings and
no large branched substituents (Table 2). The side chain was attached equatorially (exo) at
position 3 in the camphane ring. Additionally, three axial (endo) analogues were designed to
test the effect of equatorial/axial position of the side chain on the activity. The
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antimycobacterial activity of the newly designed compounds was predicted by the QSAR
model derived in the previous study. In Table 2 are listed the predicted values for pMIC and
MIC. The predicted activities were in the nanomolar range.
Table 2. Structure, molecular descriptors, predicted and experimental MICs of the designed compounds.
Cmpd.
Structure
knotp SHHBd nrings pMIC(pred) pMIC(exp) residual
MIC(exp) μM
13
-4.417
-4.212
-3.837
-4.513
-4.390
-4.041
4.472
4.420
4.301
4.308
4.294
4.327
3
3
2
2
2
2
6.337
6.481
7.439
7.036
7.115
7.307
6.770
6.796
5.126
5.126
5.103
6.770
0.433
0.17
O
Ph
Ph
N
H
OH
14
15
16
17
18
0.315
0.16
7.48
7.48
7.89
0.17
O
N
H
OH
-2.313
-1.910
-2.012
-0.537
O
N
H
OH
OH
O
O
O
N
H
N
H
OH
OH
N
H
S
19
20
21
-4.417
-4.513
-4.390
4.472
4.308
4.294
3
2
2
6.337
7.036
7.115
5.008
4.728
6.699
-1.329
-2.308
-0.416
9.96
18.70
0.20
O
O
O
Ph
N
H
OH
OH
OH
N
H
N
H
2.2. Synthesis and antimycobacterial activity of the novel camphanes
The newly designed nine camphane-based derivatives were synthesized and tested
against M. tuberculosis strain H37Rv as described in the Methods section. The experimental
MIC values are given in Table 2. Four of the compounds have activities in the nanomolar
range (compounds 13, 14, 18 and 21) and five of them (compounds 15, 16, 17, 19 and 20) – in
5
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the micromolar range. The highly active derivatives are well predicted with residuals below or
around a half log unit. The less active compounds have poor prediction with residuals around
or above 2 log units. In order to investigate the reason for the poor prediction, a new QSAR
study was performed based on the dataset of all 21 camphanes synthesized in our laboratory.
2.3. Quantitative structure – activity relationships on the whole set
The chemical structure of all studied compounds was described by 178 molecular
descriptors computed using the software package MDL QSAR version 2.2 [25]. The
descriptors relevant to the antimycobacterial activity of the studied compounds were selected
by genetic algorithm (GA) and stepwise regression as described in the Methods section. The
best performed model in terms of r2 and q2 is given below:
pMIC = 1.178 knotpv – 1.271 SsssCH_acnt + 14.215
n = 17 r2 = 0.841 SEE = 0.342 F = 36.88 q2 = 0.692
No intercorrelation between the descriptors in the model was observed (R < 0.7). The
descriptors relevant to the anti-TB activity and the calculated by the model MICs are given in
Table 3.
The descriptor knotpv is calculated as a difference between χ valence cluster-3 and χ
valence path/cluster-4. It correlates with the descriptor knotp appeared in our previous QSAR
model and has a similar interpretation. The replacement of knotpv with knotp decreases both
r2 and q2 of the model. Compounds with branched aliphatic side chains have highly negative
values for knotpv and low antimycobacterial activities.
The descriptor SsssCH_acnt counts the >CH– groups in the molecule, i.e. the number
of tertiary carbon atoms. Although it does not correlate with knotpv, this descriptor also
reflects the degree of branching in the molecules. The camphane moiety itself contains 3
tertiary carbons. Additionally, compounds with aliphatic side chains have 1 or 2 tertiary
carbons. The negative coefficient of SsssCH_acnt in the model points to the disfavored
contribution of this atom to the activity of compounds.
The calculated pMIC versus observed pMIC are plotted in Figure 1. The model has
four outliers – compounds with residuals higher than 1 log unit. These are compounds 10 and
11 from the training set and compounds 19 and 21 from the newly designed set. Compounds
10, 11 and 21 are underestimated by the new QSAR model, compound 19 is overestimated.
As 19 and 21 are both endo-analogues, we included in the model an indicator variable
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describing the exo/endo position of the side chain. No improvement of the model was
observed.
Table 3. Experimental MICs, molecular descriptors and calculated MICs of the whole set.
Cmpd.
pMIC(exp) knotpv SsssCH_acnt pMIC(calc) residual
MIC(exp) μM
0.33
1
2
6.481 -3.250
6.481 -3.207
6.420 -3.219
6.523 -3.294
6.444 -3.243
4.868 -4.604
6.387 -3.142
4.783 -3.333
5.201 -3.294
6.131 -3.288
5.151 -3.507
6.180 -3.227
6.770 -3.303
6.796 -3.370
5.126 -3.118
5.126 -3.583
5.103 -3.364
6.770 -3.409
5.008 -3.409
4.728 -3.583
6.699 -3.364
3
3
3
3
3
3
3
4
4
5
5
4
3
3
4
4
4
3
3
4
4
6.576
6.626
6.612
6.524
6.584
4.981
6.702
5.207
5.252
3.989
3.731
5.332
6.388
6.434
5.460
4.913
5.171
6.513
6.388
4.913
5.171
-0.095
-0.145
-0.192
-0.001
-0.140
-0.113
-0.315
-0.424
-0.051
2.142
1.420
-0.848
0.382
0.362
-0.334
0.213
-0.068
0.257
-1.380
-0.185
1.528
0.33
3
0.38
4
0.30
5
0.36
6
13.55
0.41
7
8
16.50
6.30
9
10
11
12
13
14
15
16
17
18
19
20
21
0.74
7.06
0.66
0.17
0.16
7.48
7.48
7.89
0.17
9.96
18.70
0.20
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7
6
5
4
3
4
5
6
7
pMIC(exp)
Figure 1. Calculated vs. observed antimycobacterial activity of the studied compounds.
Outliers are given by blank squares.
3. Discussion
In the present study, a QSAR-guided design of nine novel camphane-based derivatives
was performed. The compounds were design to include two hydrogen bond donors, two or
three rings and no large branched substituents. Additionally, three axial (endo) analogues
were designed to test the effect of equatorial/axial position of the side chain on the activity.
The compounds were synthesized and tested for antimycobacterial activity. Four of them
showed MIC values in the nanomolar range. All of these four MICs were higher than the
highest activity in the training set.
The less active compounds have poor prediction with residuals around or above 2 log
units. In order to investigate further the structure – activity relationship, a new QSAR study
was performed based on the dataset of all 21 camphanes. The newly derived QSAR model
confirmed the negative contribution of large branched substituents. Additionally, the negative
contribution of the tertiary carbon atoms on the anti-TB activity was revealed.
Two well defined clusters are formed in the graph presented in Figure 1. The left
cluster comprises the low active compounds with pMIC values below and around 5. It
contains seven structures carrying three hydrogen bond donors or large branched side chains.
The ten highly active compounds are clustered on the right side of the plot and have pMIC
values above 6. Seven of them have aromatic rings and two contain sulfur in the side chain.
The addition of an indicator variable accounting for the presence of sulfur does not improve
the model.
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The model has four outliers. Compounds 10 and 11 are underestimated (pMIC(exp) =
6.131 and pMIC(calc) = 3.989 for compound 10 and pMIC(exp) = 5.151 and pMIC(calc) =
3.731 for compound 11). Both compounds contain three hydrogen bond donors, no aromatic
ring and one tertiary carbon atom in the side chain. Additionally, compound 11 carries a large
branched substituent.
Compound 19 is overestimated by the model – it has pMIC(pred) = 6.337, pMIC(exp)
= 5.008 and pMIC(calc) = 6.388. It is an endo-analog of compound 13. It contains two
hydrogen bond donors, one aromatic ring and no large branched substituents. Compound 21
also is endo-analog but it is underestimated by the model: pMIC(pred) = 7.115, pMIC(exp) =
6.699 and pMIC(calc) = 5.171. It contains two hydrogen bond donors, no aromatic ring and
one tertiary carbon atom. There are three endo-analogs in the set: compound 19 is low active
in contrast to its high-active exo-analog compound 13 (pMIC(exp) = 6.770); compound 20 is
low-active (pMIC(exp) = 4.728) as its exo-analog compound 16 (pMIC(exp) = 5.126), while
compound 21 is highly active (pMIC(exp) = 6.699) in contrast to its low-active exo-analog
compound 17 (pMIC(exp) = 5.103). These ambiguous contributions of the endo substituents
explain the insignificance of the indicator variable describing the exo/endo position of the side
chain.
Summarizing the QSAR studies performed on the two sets of camphane derivatives,
one might conclude that a side chain containing aromatic ring is preferred for anti-TB activity
instead of aliphatic one even with low branching. Two hydrogen bond donors are optimal for
high affinity. Additionally, two of the highly active compounds carry sulfur-containing side
chains.
4. Methods
4.1. Synthesis of novel camphane-based derivatives
The detailed synthesis of the newly designed camphane derivatives was described
elsewhere [26]. Readily available isobornylamine and bornylamine were selected as the key
(+)-camphor-derived starting compounds [27,28]. These amines were attached to a set of α-
hydroxy acids, derived from the corresponding α-amino-acids. The amide linkage was
accomplished by procedures developed for peptide synthesis (Scheme 1). The reaction was
optimized for the commercially available mandelic acid applying N-(3-
Dimethylaminopropyl)-N′-ethylcarbodiimide
hydrochloride
(EDCI),
and
1-
Hydroxybenzotriazole hydrate (HOBT) as coupling reagents. Following the optimized
9
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protocol we synthesized amido-alcohols 13-21 (Scheme 1) in good yields and excellent purity
after flash column chromatography.
HO2C
R
OH
O
EDCI / HOBT
R
N
H
NH2
CH2Cl2
12 h, r.t.
OH
R = Ph, Bu, iBu, sBu, iPr, (CH2)2SMe
Scheme 1. Synthesis of the newly designed structures.
General procedure for the preparation of amides 13-21: 1-Hydroxybenzotriazole
(HOBt) (1.1 equiv) and the respective α-hydroxy acid (1 equiv) were suspended in
dichloromethane, and the mixture was stirred for 5 min. Then, N-[3-(dimethylamino)propyl]-
N -ethylcarbodiimide (EDC) (1.1 equiv) was added, followed by isobornylamine or
bornylamine (1 equiv). Stirring was continued at room temperature until the starting material
was completely consumed (TLC). The mixture was quenched with water, extracted with
CH2Cl2, washed with 2M HCl, sat. aq. NaHCO3 and brine. The organic phase was dried over
Na2SO4, and concentrated under vacuum. The residue was purified by flash column
chromatography on silica gel.
4.2. Antimycobacterial activity
The antimycobacterial activity was determined through the proportional method of
Canetti towards reference strain M. Tuberculosis H37Rv [29]. A sterile suspension/solution of
each tested compound was added to Löwenstein-Jensen egg based medium before its
coagulation (30 min at 85 °C). Each compound was tested at four concentrations – 5 mg/ml, 2
mg/ml, 0.2 mg/ml and 0.1 mg/ml (in DMSO). Tubes with Löwenstein-Jensen medium (5 ml)
containing tested compounds and those without them (controls) were inoculated with a
suspension of M. tuberculosis H37Rv (105 cells/ml) and incubated for 45 days at 37 °C. The
ratio between the number of colonies of M. Tuberculosis grown in medium containing
compounds and the number of colonies in control medium were calculated and expressed as
percentage of inhibition. The MIC is defined as the minimum concentration of compound
required to inhibit bacterial growth completely (0% growth). The MIC values are calculated
and given as μM.
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4.3. Molecular descriptors
The chemical structure of the studied compounds was described by 178 molecular
descriptors computed using the software package MDL QSAR version 2.2 [25]. The
descriptors were grouped into five types: molecular connectivity χ (chi) indices [30], which
represent molecular structure by encoding significant topological features of whole molecule;
κ shape indices – a family of graph-based structure descriptors that represent shape [31];
electrotopological state (E-state) indices, which represent the electron density at each atom
and the ability of those electrons to participate in intermolecular interactions [31]; molecular
properties – weight, logP, log D7.4, number of rings, number of hydrogen bond donors and
acceptors, etc.; and 3D molecular properties such as polarizability, surface area, volume, etc.
4.4. Variable selection
A genetic algorithm (GA) [32], as implemented in the MDL QSAR package, was used
as a variable selection procedure in the present study. GA allows one to select a subset of the
most significant predictors using two evolutionary operations: random mutation and genetic
recombination (crossover). The algorithm was used in the study with default values for the
size of initial population (32), choice of parents (tournament selection), types of crossover
(uniform crossover) and mutation (one-point mutation), and fitness function (Friedman‟s
lack-of-fit scoring function with 2 parameters) [33]. The selected variables entered a stepwise
linear regression, as implemented in the MDL QSAR package. It was used in a forward mode
with default value for F-to-enter (4.00) and F-to-remove (3.99).
4.5. Models assessment
Final models were assessed by explained variance (r2), standard error of estimate
(SEE), Fisher statistics (F) and leave-one-out cross-validated q2.
Acknowledgements
Financial support of National Science Fund, Bulgaria (DMU 02/3 – 2009) is gratefully
acknowledged.
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Design of novel camphane-based derivatives with antimycobacterial activity
Georgi Stavrakova, Violeta Valchevab, Irena Philipovac, Irini Doytchinovaa*
Research highlights
•
We designed 9 new camphene-based derivatives following the guidelines derived in a
previous QSAR study.
•
•
•
The compounds were synthesized and tested against M. tuberculosis strain H37Rv.
Four compounds showed activities in the nanomolar range.
New QSAR study was performed to guide further lead optimization.
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Graphical Abstract (for review)
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