The synthesis, antimalarial activity and CoMFA analysis of novel aminoalkylated quercetin analogs

Article abstract of DOI:10.1016/j.bmcl.2014.11.039

A series of novel aminoalkylated quercetin analogs, prepared via the Mannich reaction of various primary and secondary amines with formaldehyde, were tested for antimalarial activity. The compounds were screened against three drug resistant malarial strains (D6, C235 and W2) and were found to exhibit sub-micromolar activity across all three strains (0.065-13.0 μM). The structure-activity relationship determined from the antimalarial activity data suggests the inclusion of phenethyl amine sidechains on the quercetin scaffolding is necessary for potent activity. Additionally, the most active compounds ((5) and (6)) were tested for both early and late stage anti-gametocytocidal activity. Finally, the antimalarial activity data were utilized to construct comparative molecular field analysis (CoMFA) models to be used for further compound refinement.

Full text of DOI:10.1016/j.bmcl.2014.11.039

Accepted Manuscript
The synthesis, Antimalarial Activity and CoMFA Analysis of Novel Aminoal-
kylated Quercetin Analogs
Travis R. Helgren, Richard J. Sciotti, Patricia Lee, Sandra Duffy, Vicky M.
Avery, Osayawemwen Igbinoba, Matthew Akoto, Timothy J. Hagen
PII:
S0960-894X(14)01223-2
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.11.039
BMCL 22194
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 September 2014
11 November 2014
13 November 2014
Please cite this article as: Helgren, T.R., Sciotti, R.J., Lee, P., Duffy, S., Avery, V.M., Igbinoba, O., Akoto, M.,
Hagen, T.J., The synthesis, Antimalarial Activity and CoMFA Analysis of Novel Aminoalkylated Quercetin
Analogs, Bioorganic & Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.11.039
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The Synthesis, Antimalarial Activity and CoMFA Analysis of Novel Aminoalkylated
Quercetin Analogs
Travis R. Helgrena , Richard J. Sciottib, Patricia Leeb, Sandra Duffyc, Vicky M. Averyc,
Osayawemwen Igbinobaa, Matthew Akotoa and Timothy J. Hagena*
a Department of Chemistry and Biochemistry, Northern Illinois University, 300 Normal Road,
Dekalb, Illinois 60115, USA
b Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 2460 Linden
Lane ,Silver Spring, Maryland 20910, USA
c Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, 170 Kessels Road,
Nathan, Queensland 4111, Australia
According to the World Health Organization, there were an estimated 660,000 worldwide
deaths caused by malaria in 20101. Of these, it is estimated that 86% were children under the age
of 5, the vast majority (79%) residing in Africa. The same report indicates that some 90% of
reported malarial cases worldwide are attributed to Plasmodium falciparum, the most deadly of
the four Plasmodium species infecting humans. Additional reports suggest malarial infection and
mortality are more widespread than previously estimated, with Murray et. al. suggesting up to
200 million clinical cases and 1.2 million deaths in 2010 alone2. Efforts to reduce the spread of
P. falciparum have been hindered by the increasing emergence of drug resistant strains.
Flavonoids, a class of naturally occurring polyphenolic compounds found universally
within the Plantae kingdom, have been shown to inhibit numerous enzymatic pathways
necessary for sustained P. falciparum growth throughout the erythrocytic life cycle stages.
Flavonoids have been shown to inhibit amyloid fibril formation of P. falciparum merozoite
surface protein 2, which suggests a significant decrease in erythrocyte intercalation in vivo3.
Additionally, Dormeyer et. al. report that flavonoids, specifically (-)-epigallocatechin gallate ((-)-
ECGC, (1)), inhibit P. falciparum infected erythrocyte cytoadhesion to host small-vessel
endothelial cells via intercellular adhesion molecule 1 (ICAM 1) binding (85-90% inhibition at
50 µM)4 (Figure 1). Khalid et. al. provided an early report of P. falciparum abatement by
flavonoids both extracted from plant material as well as synthetically prepared natural
flavonoids5. More recently, flavonoids have been demonstrated to inhibit the type-II fatty acid
biosynthesis pathway (FAS-II) necessary for the development of cellular walls. For example,
various flavonoids extracted from natural sources have been shown to inhibit β-ketoacyl-ACP-
reductase (FabG), β-hydroxacyl-ACP-dehydratase (FabZ), and enoyl-ACP-reductase (FabI)6-9.
Among these, (-)-EGCG (1) was again shown to strongly inhibit both the various enzymes
involved in the FAS-II pathway (FabG IC50 = 0.3 µM, FabZ IC50 = 0.4 µM and FabI IC50 = 0.2
µM) as well as exhibit P. falciparum anti-plasmodial activity (PfNF54 IC50 = 25.5 µM, PfK1
IC50 = 9.9 µM)9. Tasdemir et. al. suggest the source of the activity is the relative planar
conformation of (-)-EGCG in comparison to other flavonoids, specifically flavan-3-ols9.

The drawback to the potential of these compounds as antimalarial agents is twofold: the
compounds are promiscuous enzyme inhibitors, presumably due to catechol chelation of
metalloenzymes, and the compounds are relatively insoluble in aqueous media. Specifically, the
flavonol quercetin (2) has been shown to exhibit activity not only against P. falciparum, but also
acts as an antiviral10, anticancer11 and anti-inflammatory12 agent (Figure 1). Although this
compound clearly has therapeutic potential for various ailments, it is currently limited mainly by
solubility. To address this, it was determined that introduction of amine moieties could increase
solubility due to the higher degree of solvation by hydrogen bonding in aqueous media.
Solubility could be increased further by converting the free amine bases to the corresponding
hydrochloride or trifluoroacetate salts.
<Figure 1>
Caption: Figure 1. Structures of: Left: (-)-EGCG (1) and Right: Quercetin (2)
Additionally, the activity data can be used to develop Comparative Molecular Field
Analysis (CoMFA) models to predict the activity of novel, structurally similar compounds. We
report herein the synthesis, characterization, solubility, antimalarial activity and CoMFA analysis
of 19 novel aminoalkylated quercetin analogs.
Based upon the emergence of deadly drug resist strains of P. falciparum, it is now
imperative that novel classes of antimalarial agents be developed and the mechanisms of action
be determined. Quercetin (2), a naturally occurring flavonoid found in a wide range of plant life,
has been previously reported as exhibiting antimalarial activity and may provide a natural
scaffold for the synthesis of novel antimalarial agents5. Additionally, (-)-EGCG (1) and (+)-
catechin (3) have been shown to exhibit antimalarial activity and have been included in this
study as commercially available flavonoid P. falciparum inhibitors9. Although quercetin inhibits
the parasitic growth, its clinical application may be limited due to minimal aqueous solubility.
We have therefore integrated basic nitrogen moieties into quercetin via the Mannich reaction of
formaldehyde and various primary and secondary amines. The products (4-21) were transformed
into salts via the addition of hydrochloric or trifluoroacetic acid to a suspension of each
compound in methanol followed by removal of the alcohol. The solubility of the free bases was
determined via UV-spectroscopic solubility assay13.
With the exception of compounds (20) and (21), all compounds were synthesized via the
Mannich reaction of quercetin with formaldehyde and primary amines (Scheme 1). Compounds
(20) and (21) were synthesized by employing secondary instead of primary amines and
compound (21) utilized two rather than one equivalent of both formaldehyde and the amine
(Scheme 2). Due to the minimal solubility of quercetin in ethanol, the reaction is thought to have
progressed slowly with the precipitation of the desired product providing a driving force. The
products were collected by filtration, negating the need for any further chromatographic
purification. Yields ranged from 21 to 85% for the primary aminoalkylated quercetin analogs
(Table 1) and were 65 and 56% for compounds (20) and (21) respectively (Table 2).

Compound solubility in aqueous media was determined based upon a modified version of
the UV-spectroscopic assay developed by Hoelkeet. et. al13. A 1mM stock solution of each
compound as a free base was prepared in DMSO. Calibration curves were generated by
sequentially diluting the stock solution to various concentrations (4, 8, 12, 16 and 20 µM, 2%
DMSO in water) with a final volume of 250µL in a 96-well plate. Concentrated solutions were
prepared by suspending each compound in the media to the saturation point. The suspensions
were centrifuged at 8000 rpm for 10 minutes and filtered. Solution absorbance was measured on
o
a 96-well microplate reader at 25 C and at 280 nm. Concentrations were calculated by
extrapolating the best fit line of the calibration curves for each compound.
A major pitfall in the discovery of novel therapeutic agents is the lack of compound
solubility in aqueous media. To address this, the solubility of the synthetic compounds, as well as
quercetin, was determined. As expected, all synthesized compounds were determined to exhibit
solubility greater than or comparable to that of the parent compound quercetin (2). If solubility
were the sole factor contributing to activity, it would be expected that the most soluble
compounds would be the most active. However, compound activity is clearly structurally based
as demonstrated by the comparison of the activity and solubility data, providing further evidence
of the structure activity relationship discussed in Section 3.
<Scheme 1>
Caption: Synthesis of benzyl and phenethyl aminoalkylated quercetin derivatives
<Scheme 2>
Caption: Synthetic scheme for furfuryl and secondary aminoalkylated quercetin derivatives
<Table 1>
Caption: Synthetic yields and solubility data of phenethyl and benzyl Mannich analogues
There has been some discussion in recent years concerning the site of alkylation when
performing Mannich reactions upon flavonoids. Specifically, the 6 and 8 positions on the A-ring
of quercetin are both nucleophilic and thus susceptible to electrophilic aromatic substitution
(Figure 2, left). A study published by Nguyen et. al. reports moderate to excellent
regioselectivity for the Mannich reaction of chrysin, a flavone, with various cyclic imines is
achieved by varying the reaction solvent. Up to 99:1 selectivity of positions 6:8 was achieved
with the use of ether as the solvent14. Zhang et. al. report selective alkylation at position 8 with
the use of DMSO15. Additionally, Kukharevaet.al. report selective alkylation at position 6 with
the use of isopropanol as the solvent and dihydroquercetin as the nucleophile16.
<Figure 2>
Caption: Left: General numbering scheme for flavonols; Right: Correlation observed in HMBC
NMR
For the system presented herein, proton, carbon and 2D NMR were employed for
structural elucidation. Substitution at the 8 position on the A ring of quercetin was suspected
based upon proton NMR. Quercetin exhibits specific proton NMR peaks at 6.18 and 6.40 ppm

corresponding to the 6 and 8 positions respectively. All of the products exhibited peaks around
5.9 ppm with a notable absence of any peaks within the range of 6.1 to 6.8 ppm suggesting
substitution at the 8 position with a slight shift in the proton peak corresponding to the 6 position.
This observation is corroborated by heteronuclear multiple-bond correlation spectroscopy
(HMBC) NMR. Proton and carbon peaks were first assigned by proton, carbon and HSQC NMR.
Correlation was observed within the HMBC spectrum between protons at the 1 position and
carbon atoms at the 2 and 5 positions (Figure 2, right). Additionally, correlation was observed
between the proton at the 4 position and the carbon atom at the 3 position, strongly suggesting
alkylation at the 8 position.
Antimalarial activity of the compounds against three strains of the P. falciparum parasite,
W2 (Chloroquine (CQ) resistant,mefloquine (MFQ) sensitive), D6 (CQ sensitive, MFQ resistant)
and C235 (CQ, MFQ, and pyrimethamine resistant), is shown in Table 3. Extensive research has
been conducted concerning the relationship between various naturally occurring flavonoids and
P. falciparum abatement6-8. To date, the most potent class of natural flavonoids has been found
to be catechingallate esters6-8. For reference, three flavonoids have been tested for P. falciparum
inhibitory activity (1 – 3). Of these, only (-)-epigallocatechingallate (1), a catechingallate ester,
was found to exhibit potent activity (D6 IC50 = 0.073 µM). Three compounds (5 – 7, IC50 = 0.065
– 0.13µM), exhibited similar activity across all three strains, including the drug resistant strains
against which compound (1) demonstrated reduced activity. All of the aminoalkylated quercetin
analogs exhibit activity superior (up to 160 fold increase) to that of quercetin (2) and (+)-
catechin (3). Phenethyl and benzyl amine derivatives (4 – 17) were found to have activity within
the nanomolar to low micromolar range (IC50 = 0.065 -2.18 µM across all strains) while the
secondary amine and furfurylamine derivatives (18-21) were found to have low micromolar
activity (IC50 = 1.2 – 5.3 µM across all strains). None of the compounds tested were as active as
MFQ or arteminisinin (ART) against any strain; however, many were more potent than CQ
against the W2 and C235 strains (4 – 11, 14). Because the W2 and C235 strains are CQ resistant,
the observed activity of these compounds may be the result of a differing mechanism of action
than that of CQ.
<Table 2>
Caption: Synthetic yields and solubility data of furfuryl and secondary amine Mannich products
Among the potent aminoalkylated quercetin analogs, the phenethyl amine derivatives (4 –
12) exhibited greater activity than the benzyl amine derivatives (13 – 17) suggesting that the
increase in chain length leads to favorable interactions within the mechanism of action. The
relationship between the halogen substitution pattern and inhibitory activity of these compounds
was also explored. For the benzyl amine derivatives (13 – 17), chloro substitution exhibits
stronger inhibitory activity than fluoro substitution as evidenced by the inhibition of W2 by
compounds (14) and (17) (W2 IC50 = 0.26 and 0.69 µM, respectively). For the phenethyl amine
derivatives, the difference between chloro and fluoro substitution is generally minimal, with
chloro substitution exhibiting slightly better activity in the case of compounds (6) and (7) (W2
IC50 = 0.079 and 0.13 µM respectively) and fluoro substitution exhibiting better activity in the
case of compounds (8) and (11) (W2 IC50 = 0.24 and 0.29 µM, respectively). However, fluoro

substitution exhibited a 6 fold increase in activity for compounds (9) and (12) (D6 IC50 = 0.14
and 0.83 µM, respectively).
<Table 3>
Caption: Antimalarial activity of aminoalkylated quercetin analogs against P. falciparum strains
The relationship between substitution positions was also explored. Substitution at the
meta position results in the highest inhibitory activity ((7), D6 IC50 = 0.069 µM), while
substitution at the ortho (8) and para (9) positions generally results in similar inhibitory activity,
with the ortho position being slightly more active (D6 IC50 = 0.11 and 0.14 µM, respectively).
This relationship between ortho and para substitution and activity varies slightly with P.
falciparum strain and compound chain length, however, the activity is generally comparable,
except in the case of para-chloro-phenethylamine (12) where the ortho position (11) exihibits
much greater activity(D6 IC50 = 0.25 and 0.83 µM, respectively). 2,4-Dichlorinated
phenethylamine derivative (5) exhibited the highest inhibitory activity across all strains
suggesting increased halogenation positively contributes to activity. This observation is also
supported by 2,6-dichlorinated phenethyl amine derivative (10), which as higher activity across
all strains than the 2-chloro derivative (11).
Additionally, the most active aminoalkylated quercetin analogs, compounds (5) and (6),
were tested for both early and late stage anti-gametocytocidal activity to ascertain their potential
to impact on transmission (Table 3). It was determined that the compounds were weakly active
against the early gametocyte stages, with inhibition (IC50) values of 9.67 and 6.79 µM for
compounds (5) and (6), respectively for early stage (I-III) gametocytes. Both compounds were
considerably less effective against the late (IV-V) stage gametocytes exhibiting 100% inhibition
at 40 µM. The reference drugs CQ, Puromycin and Artesunate were demonstrated to be effective
at concentrations routinely illustrated17. Neither compound (5) nor (6) exhibited activity
comparable to the reference compounds for early stage (I-III) gametocytes, or more importantly
the late stage (IV-V) gametocytes, indicating the need for further compound optimization if this
quercetin scaffolding is to be explored further as a possible antimalarial effective against not
only the clinical disease but also transmission to the vector.
The antimalarial activity data obtained for the compounds described herein was used to
perform a CoMFA analysis of the compound test set to produce models capable of predicting the
activity of novel compounds. The test compounds were input into a SYBYL X 1.3 database and
aligned by substructure overlap based upon the quercetin scaffold. The CoMFA steric (Lennard-
Jones) and electronic (Coulombic) fields were generated by first assigning atomic charges based
upon the Gasteiger-Huckel method. The CoMFA models were generated by calculating the
energy at lattice points of the compounds placed in a 3D lattice. The energetic cutoff was set at
30Kcal/mol to minimize the effects of highly energetic steric or electronic regions. The models
use a partial least squares (PLS) method to correlate the energy of the lattice points to activity
and model effectiveness was quantified by examining the cross-validated q2 values, which are
calculated from the following equation (1) where Yactual, Ypredicted and Ymean are the experimental,
predicted and average values of the antimalarial activity respectively. Models demonstrating a
cross-validated q2 value of 0.5 or greater are considered acceptable.

ꢎ
ꢂ
(ꢃꢄꢅꢆꢇꢈꢃꢉꢊꢋꢌꢉꢍ)
ꢏ
qꢀ = 1 −ꢁꢂ
(1)
ꢎ
(ꢃꢉꢊꢋꢌꢉꢍꢈꢃꢐꢆꢉꢑ)
ꢏ
CoMFA models were made for each of the three P. falciparum strains with all of the
models utilizing the activity data for the entire compound test set ((2) and (4 – 21). The best
model developed, model 1, includes the test compound set based upon the C235 P. falciparum
strain data (Table 4). The model exhibits a cross-validated (CV) q2 value of 0.520 and is based
upon 2 components. Not surprisingly, the models are dominated by the steric contribution, with
electrostatic interaction accounting for only 2.03% of each model (Table 4). Linear plots of
predicted vs. experimental pIC50 values for each model were constructed (Figure 3). These plots
were constructed to demonstrate the validity of the models and clearly demonstrate that activity
predictions of novel aminoalkylated quercetin analogs should be based upon models 1 or 3.
Additionally, predicted and experimental pIC50 values for each P. falciparum strain can be found
in Table 5. It should be noted that the CoMFA model corresponding to the PfW2 inhibitory data
(Model 2) is weak. With a cross-validated q2 value of 0.306, this model should not be utilized to
predict the activity of structurally similar, novel compounds.
<Table 4>
Caption: Parameters for CoMFA models generated
<Figure 3>
Caption: Predicted pIC50 vs. Experimental pIC50 for all compounds against PfC235, top, PfW2,
middle, and PfD6, bottom. The predicted values were generated from CoMFA models of each
data set.
CoMFA analysis generates 3D contour plots demonstrating regions of favorable (green)
and unfavorable (red) steric effects as well as areas of favorable positive (blue) and negative
(red) electrostatic interaction. Figure 4 depicts both quercetin (top) and the entire set oftest
compounds overlaid (bottom) on the contour plot for model 1 (PfC235). The positive steric
contribution (green) relates to region of space occupied by the Mannich addition products;
specifically, the phenethylamine Mannich derivatives fit within this region better than the
benzylamine, secondary amine and furfuryl amine Mannich derivatives (Figure 4, bottom).
Additionally, the unfavorable steric region (yellow) residing adjacent to the 6 position of the A
ring (Figure 4, top) is occupied by the secondary addition product for compound (21), suggesting
that diaminoalkylation will result in decreased activity, even if phenethylamines were utilized.
Concerning electrostatic interactions, a favorable negatively charged region (red) is shown to
reside over the substituted phenethyl rings, suggesting the incorporation of strongly electron-
withdrawing groups (halogens) leads to increased activity. Finally, a region of favorable positive
electrostatic interaction (blue) is observed to reside adjacent to the 7 position of the A ring.
<Figure 4>
Caption: Top: Contour plot of Model 1 (PfC235) displaying quercetin. The image depicts steric
(left) and electrostatic (right) contributions generated by the CoMFA model. Favorable and
unfavorable steric interactions are shown as green and yellow regions respectively. Additionally,
positive and negative favorable electrostatic contributions are also shown as blue and red regions
respectively. All regions are shown at 95% of the total contribution. Hydrogen atoms have been
removed for clarity.

Bottom: Contour plot of Model 1 with all test compounds, (2), (4-21), included. The color
scheme and percent contribution displayed are the same as those described for the top image.
Hydrogen atoms have been removed for clarity.
To our knowledge, this is the first report of synthetically modified quercetin being tested
against P. falciparum. Quercetin was subject to Mannich conditions in the presence of
formaldehyde and various amines resulting in regioselective aminoalkylation via electrophilic
aromatic substitution. The reaction resulted in fair yields (21 – 98%) and the products were
subject to a solubility assay and tested against three drug resistant strains of the malaria parasite,
P. falciparum. Among the compounds, phenethyl amine derivatives were found to exhibit the
most potent activity against the asexual life cycle stages. Aromatic halo-substitution of the
phenethyl and benzyl moieties results in greater efficacy, specifically when concerning
chlorination. Substitution at the meta-position was determined to produce the most potent
interactions across all three strains of drug resistant P. falciparum. Additionally, multi-
halogenation of the phenethyl derivatives resulted even more effective compounds, the most
active being 2,4-dichlorinated phenethyl amine derivative (5).
<Table 5>
Caption: CoMFA analysis for each P. falciparum strain
Additionally, the compounds were subject to CoMFA analysis for each of the three
strains of P. falciparum. The best model generated (Model 1) includes the data for PfC235
inhibitory activity, with the entire set of test compounds considered. The model exhibits a cross-
validated q2 value of 0.520 and involves total steric and electrostatic contributions of 97.97 and
2.03% respectively. The generated contour maps for the model demonstrate regions of favorable
and unfavorable steric and electrostatic contributions, providing structural insight into the
activity observed for these compounds.
While these results are promising, the mechanism of action is, at this time, unknown.
More research is necessary to determine which pathways, if any, are interacting with the
compounds resulting in microbial abatement. In order to address the second downside of this
class of compounds (enzymatic inhibition promiscuity), the drug-host interactions must be
discovered to produce a more selective inhibitor.
Acknowledments
We would like to thank Northern Illinois University for funding this research and Medicines
for Malaria Ventures for running the anti-gametocytocidal assays.
Supplimental data
Supplementary data associated with this article can be found, in the online version, at URL
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Table 1. Synthetic yields and solubility data of phenethyl
and benzyl Mannich analogs
Yield
(%)
Solubility
(µM)
Compound
n
R1
R2
R3
R4
-
-
-
-
-
-
44
41
2
4
2
2
2
2
2
2
2
2
2
1
1
1
1
1
H
Cl
H
H
F
H
H
Cl
F
H
Cl
H
H
H
F
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
85
47
59
65
72
49
60
21
70
69
24
39
30
42
168
199
275
95
5
6
7
H
H
H
H
H
H
Cl
H
H
F
8
H
Cl
Cl
H
H
H
H
H
H
136
199
85
9
H
H
Cl
H
H
Cl
F
10
11
12
13
14
15
16
17
99
49
107
110
212
123
H

Table 2. Synthetic yields and solubility data of furfuryl and secondary amine Mannich products
Compound
R1
R2
Yield (%)
Solubility (µM)
H
H
H
38
98
65
40
39
18
19
20
131
56
247
21

Table 3. Antimalarial activity of aminoalkylated quercetin analogs against P. falciparum strains
NF54-pfs16-GPF
NF54-pfs16-GPF
Compound W2 IC50 (µM) D6 IC50 (µM) C235 IC50 (µM)
Early (I-III) gama IC50 (µM) Late (VI-V) gama IC50 (µM)
1.4
2.9
0.073
9.0
0.61
13
-
-
-
-
-
-
-
-
1
2
3
4
6.0
6.7
5.9
>2.12
2.11
>2.12
100% at
40 µM
100% at
40 µM
0.071
0.079
0.065
0.069
0.079
0.080
9.67
6.79
5
6
0.13
0.24
0.29
0.23
0.29
1.9
0.069
0.11
0.14
0.16
0.25
0.83
>2.18
0.19
0.37
0.41
0.51
>2.23
>2.21
2.9
0.088
0.18
0.15
0.15
0.26
1.2
-
-
7
-
-
8
-
-
9
-
-
10
-
-
11
-
-
12
>2.18
0.26
0.59
0.72
0.69
>2.23
>2.21
2.4
>2.18
0.22
0.43
0.70
0.62
>2.23
>2.21
5.3
-
-
13
-
-
14
-
-
15
16
-
-
-
-
17
-
-
18
-
-
19
-
-
20
1.2
1.7
3.1
-
-
21
ARTb
CQb
0.007
0.63
0.007
-
0.009
0.014
0.020
-
0.013
0.23
0.077
-
-
-
0.126
-
100% at 120 µM
MFQb
Puromycin
Artesunate
-
0.175
0.003
0.194
0.012
-
-
-
a. Gam = gametocyte, b. From Ref. 18

Table 4. Parameters for CoMFA models generated
Steric
Input
(%)
Standard
Error
# of
Components
Electrostatic
Input (%)
Model
q2
r2
(1)
C235
(2)
W2
(3)
0.520 0.723
0.306 0.491
0.502 0.772
0.375
0.393
0.338
2
1
3
97.97
97.97
97.97
2.03
2.03
2.03
D6

Table 5. CoMFA analysis for each P. falciparum strain
Predicted
C235 pIC50
(Model 1)
Predicted
W2 pIC50
(Model 2)
Predicted
D6 pIC50
(Model 3)
Experimental
C235 pIC50
Experimental
W2 pIC50
Experiment
al D6 pIC50
Compound
4.884
5.674
7.098
7.096
7.054
6.736
6.820
6.815
6.588
5.928
5.662
6.665
6.362
6.156
6.208
5.652
5.656
5.273
5.504
4.7041
6.5379
6.6557
6.7214
6.7543
6.5693
6.6931
6.4995
6.5556
6.6258
5.9967
6.2110
6.1424
6.1369
6.1810
5.6586
5.6422
5.4136
5.2628
5.535
5.674
7.146
7.103
6.888
6.619
6.533
6.643
6.534
5.733
5.662
6.587
6.227
6.144
6.159
5.652
5.656
5.622
5.923
5.6620
6.5065
6.6485
6.6391
6.6636
6.5533
6.6112
6.4445
6.5332
6.6141
5.9530
6.0729
5.9323
5.9199
6.0516
5.7830
5.7885
5.7587
5.6786
5.048
5.676
7.182
7.163
7.159
6.975
6.865
6.791
6.599
6.081
5.662
6.730
6.430
6.392
6.289
5.652
5.656
5.531
5.761
4.9459
6.5266
6.7363
6.9272
7.0629
6.7600
6.7199
6.5066
6.6590
6.5963
5.8906
6.1194
6.1731
6.1519
6.1063
5.3422
5.3372
5.4583
5.9477
2
4
5
6
7
8
9
10
11
12
14
15
16
17
18
19
20
21
22

Figure 1

Scheme 1

Scheme 2

Figure 2

Figure 3 Top

Figure 3 Middle

Figure 3 Bottom

Figure 4 Top

Figure 4 Bottom

The Synthesis, Antimalarial Activity and CoMFA Analysis of Novel Aminoalkylated Quercetin
Analogs
Travis R. Helgrena , Richard J. Sciottib, Patricia Leeb, Sandra Duffyc, Vicky M. Averyc,
Osayawemwen Igbinobaa, Matthew Akotoa and Timothy J. Hagena*
a Department of Chemistry and Biochemistry, Northern Illinois University, 300 Normal Road,
Dekalb, Illinois 60115, USA
b Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 2460 Linden
Lane ,Silver Spring, Maryland 20910, USA
c Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, 170 Kessels Road,
Nathan, Queensland 4111, Australia