Synthesis and antiplasmodial activity of novel 2,4-diaminopyrimidines

Article abstract of DOI:10.1016/j.bmcl.2009.10.133

Two sets of diaminopyrimidines, totalling 45 compounds, were synthesized and assayed against Plasmodium falciparum. The SAR was relatively shallow, with only the presence of a 2-(pyrrolidin-1-yl)ethyl group at R² significantly affecting activity. A subsequent series addressed high Log D values by introducing more polar side groups, with the most active compounds possessing diazepine and N-benzyl-4-aminopiperidyl groups at R¹/R². A final series attempted to address high in vitro microsomal clearance by replacing the C6-Me group with CF₃, however antiplasmodial activity decreased without any improvement in clearance. The C6-CF₃ group decreased hERG inhibition, probably as a result of decreased amine basicity at C2/C4.

Full text of DOI:10.1016/j.bmcl.2009.10.133

Bioorganic & Medicinal Chemistry Letters 20 (2010) 228–231
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antiplasmodial activity of novel 2,4-diaminopyrimidines
Derek C. Martyn a, Amarjit Nijjar b, Cassandra A. Celatka b, Ralph Mazitschek a,c, Joseph F. Cortese a,
Erin Tyndall a, Hanlan Liu b, Maria M. Fitzgerald b, Thomas J. O’Shea b, Sanjay Danthi b, Jon Clardy a,d,
*
a Broad Institute Infectious Diseases Initiative, 7 Cambridge Center, Cambridge, MA 02142, USA
b Drug and Biomaterial R&D, Genzyme Corporation, Waltham, MA 02451, USA
c Center for Systems Biology, Massachusetts General Hospital, MA 02142, USA
d Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Two sets of diaminopyrimidines, totalling 45 compounds, were synthesized and assayed against Plasmo-
dium falciparum. The SAR was relatively shallow, with only the presence of a 2-(pyrrolidin-1-yl)ethyl
group at R2 significantly affecting activity. A subsequent series addressed high Log D values by introduc-
ing more polar side groups, with the most active compounds possessing diazepine and N-benzyl-4-
aminopiperidyl groups at R1/R2. A final series attempted to address high in vitro microsomal clearance
by replacing the C6-Me group with CF3, however antiplasmodial activity decreased without any improve-
ment in clearance. The C6-CF3 group decreased hERG inhibition, probably as a result of decreased amine
basicity at C2/C4.
Received 11 August 2009
Revised 26 October 2009
Accepted 29 October 2009
Available online 31 October 2009
Keywords:
Malaria
Antiplasmodials
Diaminopyrimidines
Log D
Ó 2009 Elsevier Ltd. All rights reserved.
Microsomal clearance
hERG Inhibition
Malaria is a major parasitic disease in many areas of Africa, Asia
and South America. The majority of cases are caused by Plasmo-
dium falciparum, and its resistance to many contemporary antimal-
arials has compounded the problem of disease control.1 Resistance
to most available antimalarial drugs has been reported throughout
Africa and parts of Asia, prompting the need to discover novel che-
motherapeutic strategies.2 To address this issue, the Broad Insti-
tute’s Infectious Diseases Initiative, Genzyme and the Medicines
for Malaria Venture have formed the Malaria Drug Discovery Initia-
tive to create a pipeline capable of delivering new candidate ther-
apeutics. Our primary means of identifying small molecule
candidates utilizes a high-throughput screen to uncover scaffolds
amenable to the development of novel antimalarials.3 The struc-
ture of one of our screening positives is displayed below (1a,
Fig. 1). This 2,4-diaminopyrimidine-based compound displayed
excellent antiplasmodial activity, moderate solubility, high lipo-
philicity as measured by Log D at pH 7.4, high permeability as mea-
revealed moderate antiplasmodial activity (P0.9 lM) for a limited
number of compounds analogous in structure to 1a.5 This report
outlines a systematic approach towards the development of 2,4-
diaminopyrimidines, alkylated at both exocyclic nitrogens, in an
effort to discover a lead for our fully integrated drug development
program. Novel analogs could be easily synthesized in only two
steps to enable rapid SAR exploration of this compound class.
Synthesis of the initial DAP series is outlined in Scheme 1. Reac-
tion of commercially available pyrimidine 2 with cyclohexylamine,
benzylamine or N-methylcyclohexylamine gave 3a–c in 71%, 63%
and 68% yields respectively.6 Intermediates 3a–c were then re-
acted with the appropriate amines in dioxane under microwave
irradiation7 to afford 1b–i (yields shown in Table 1).
The antiplasmodial activity of DAPs 1b–i was measured by a
DAPI staining-based method for determining P. falciparum cell
sured by
a parallel artificial membrane permeability assay
(PAMPA), low to moderate human CYP450 inhibition, and >20-fold
selectivity for P. falciparum versus human cell lines.
The antiplasmodial activity of diaminopyrimidine-based com-
pounds has been described on multiple occasions,4 with pyrimeth-
amine the most well-known example.
A recent publication
* Corresponding author. Tel.: +1 617 432 2845; fax: +1 617 738 3702.
E-mail address: jon_clardy@hms.harvard.edu (J. Clardy).
Figure 1. Structure and in vitro assay data for screening positive 1a.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.133

D. C. Martyn et al. / Bioorg. Med. Chem. Lett. 20 (2010) 228–231
229
Scheme 2. Reagents and conditions: (a) EtOH, rt, 24 h and either iPrNH2 (3c, 50%) or
Scheme 1. Reagents and conditions: (a) EtOH, rt, 24 h and either cHexylNH2 (3a,
71%), BnNH2 (3b, 63%) or N-Me cHexylNH (3c, 68%). (b) 3a, 3b or 3c, amine, dioxane,
i
PhNH2 (3d, 58%); (b) 3a, 3b, 3c or 3d, amine, PrOH,
lwave.
lwave.
Table 2
Table 1
Yields and in vitro antiplasmodial activity for 1j–3as
Yields and in vitro antiplasmodial activity for 1b–i
No.
R1
R2
Yield (%)
Pf EC50 (lM)
No.
R1
R2
R3
R4
Yield (%)
Pf EC50 (lM)
3D7
Dd2
3D7
Dd2
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
1u
1v
1w
1x
1y
cHexyl
cHexyl
cHexyl
cHexyl
cHexyl
cHexyl
cHexyl
cHexyl
cHexyl
cHexyl
cHexyl
Bn
iPr
cHexyl
Heptyl
2-(Pyrrolidin-1-yl)ethyl
1-(Adamantyl)methyl
N-Benzylpiperidin-4-yl
Ph
95
69
86
45
45
30
73
55
84
18
5
77
91
60
96
84
96
80
45
82
99
28
93
86
67
97
93
72
37
85
50
80
84
72
83
16
NDa
ND
ND
ND
ND
ND
ND
ND
ND
0.74
0.21
0.21
2.75
0.37
0.25
0.23
0.26
0.20
0.24
>2
1.05
0.46
1.45
0.40
0.16
1.02
0.93
4.27
0.39
0.31
>5
0.27
0.35
0.81
1.50
1.92
0.84
1.22
0.75
0.09
1.24
0.09
2.14
0.36
0.59
1b
1c
1d
1e
1f
1g
1h
1i
cHexyl
cHexyl
cHexyl
Bn
cHexyl
cHexyl
cHexyl
cHexyl
(S)-1-Ph-ethyl
(R)-1-Ph-ethyl
Bn
cHexyl
Bn
H
H
H
H
Me
Me
Me
Me
H
H
Me
H
H
Me
H
H
17
62
72
63
95
25
95
84
0.12
0.09
>10
0.43
0.68
>10
0.50
0.42
>10
1.26
1.02
>10
Bn
(S)-1-Ph-ethyl
(R)-1-Ph-ethyl
0.59
0.63
0.69
0.94
3,4,5-Trimethoxybenzyl
(Piperon-5-yl)methyl
(N-Methylindol-5-yl)methyl
Pyridin-2-yl
ND
>1
iPr
cHexyl
1.43
0.47
1.08
0.41
0.16
0.85
0.78
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
viability after exposure to the compound for 72 h (see Table 1).3
Compounds were tested against the common laboratory strain
3D7 and the multidrug resistant southeast Asian isolate Dd2.8
The most active compounds were 1b–c (R1 = cyclohexyl, R3 = H).
The presence of a methyl group at R4 completely abrogated activity
(1d and 1g), and when R3 = Me (1f, 1h–i), activity also decreased
significantly compared to 1a–c. These results demonstrated that
only primary amines should be reacted at both steps in the synthe-
sis, resulting in R3 and R4 = H.
A second generation library was synthesized to deepen our
understanding of the SAR revealed by the first series of DAPs. In
addition to using intermediates 3a–b, pyrimidine 2 was reacted
with isopropylamine and aniline to afford 3c–d in 50% and 58%
yields respectively (see Scheme 2). Intermediates 3a–d were then
reacted with selected amines to yield 1j–ar, resulting in a range
of sizes, lipophilicities and hydrogen bond acceptors at R2. In con-
trast to Scheme 1, step (b) utilized iPrOH as the reaction solvent,9 as
this forced the reaction to completion more rapidly than dioxane.
Table 2 displays the reaction yield and antiplasmodial activity
for DAPs 1j–1as. The most noteworthy point is the significant num-
ber of compounds (18 out of 36) that were moderately potent, with
Bn
Bn
Bn
Bn
2-(Pyrrolidin-1-yl)ethyl
1-(Adamantyl)methyl
N-Benzylpiperidin-4-yl
Ph
1z
Bn
1aa
1ab
1ac
1ad
1ae
1af
1ag
1ah
1ai
1aj
1ak
1al
1am
1an
1ao
1ap
1aq
1ar
1as
Bn
3,4,5-Trimethoxybenzyl
iPr
iPr
iPr
cHexyl
Heptyl
iPr
iPr
2-(Pyrrolidin-1-yl)ethyl
1-(Adamantyl)methyl
Bn
N-Benzylpiperidin-4-yl
Ph
3,4,5-Trimethoxybenzyl
(Piperon-5-yl)methyl
(N-Methylindol-5-yl)methyl
iPr
Heptyl
2-(Pyrrolidin-1-yl)ethyl
Bn
(Pyridin-2-yl)methyl
(Piperon-5-yl)methyl
(N-Methylindol-5-yl)methyl
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
0.28
0.09
1.46
0.12
ND
0.11
0.35
a
ND = not determined.
EC50s in the 0.20–0.75 lM range. The only SAR that could be teased
out was restricted to the observation that a slight decrease in activ-
ity was seen for compounds with R1 = iPr (1ab–al), and that a 2-
(pyrrolidin-1-yl)ethyl group at R2 led to significantly less active
compounds (1m, 1w, 1ae and 1ao).
The majority of compounds in Table 2 suffered from Log D val-
ues >3 and rapid metabolism in an in vitro rat and human liver
microsome clearance assay (data not shown). To address the high
Log D values, three analogs were synthesized that possessed a dia-
zepine moiety at the C2 position of the pyrimidine ring to decrease
lipophilicity. Intermediate 3d was reacted with N-Me and N-Boc
diazepine to afford 4a and 4b in 87% and 80% yields respectively
(Scheme 3). The latter compound was converted to the unpro-
tected diazepine 4c upon exposure to HCl/dioxane, and isolated
as the free amine in 87% yield. These and subsequent compounds
were tested only against the Dd2 strain, as 1j–t, 1am–ap and
1ar–as did not display consistent selectivity for either 3D7 or Dd2.
i
Scheme 3. Reagents and conditions: (a) PrOH,
lwave and either N-Me diazepine
(4a, 87%) or N-Boc diazepine (4b, 80%); (b) 4 M HCl/dioxane (87%).
Table 3
In vitro antiplasmodial activity and Log D values for 4a–c
No.
Pf EC50 Dd2 (
lM)
Log D
4a
4b
4c
3.52
1.87
1.96
1.70
3.95
0.51
A limited number of these analogs have been described in the literature—1k and
1ab displayed herbicidal/fungicidal activity,10 and 1z showed antimicrobial activity.11

230
D. C. Martyn et al. / Bioorg. Med. Chem. Lett. 20 (2010) 228–231
Table 4
DAPs 4a–c displayed relatively poor antiplasmodial activity (Ta-
In vitro antiplasmodial activity and Log D values for 6a–c and 7a–c
ble 3), in agreement with the lack of activity displayed by 1d and
1g, both of which had a dialkylated nitrogen attached at the C2 po-
sition of the pyrimidine ring. However, both 4a and 4c had lower
Log D values compared to the majority of compounds in Table 2,
and 4a was in our preferred range for compound development (be-
tween 1 and 3). This finding validated the use of heteroatom-con-
taining auxiliary groups as a strategy to lower Log D values.
Further exploration of the Log D properties of this compound
class was undertaken by incorporating heteroatoms in both groups
attached to the pyrimidine core. To this end, 2 was reacted with N-
benzyl-4-aminopiperidine to give regioisomers 5a and 5b in 46%
and 23% yields respectively after chromatographic separation
(Scheme 4). Analogous to Scheme 3, both regioisomers were re-
acted with N-Me and N-Boc diazepine to yield 6a–b and 7a–b.
The N-Boc analogs 6b and 7b were deprotected to afford 6c and
7c as the free amines in 32% and 53% yields respectively.
Pyrimidines 6a–c and 7a–c displayed greater antiplasmodial
activity than 4a–c, especially 7a–c, which all had a monoalkylated
nitrogen at the C2 position (Table 4). The strategy of incorporating
heteroatoms and C2 and C4 brought the Log D values for 6a–b and
7a–b into our preferred range, however 6c and 7c displayed a pref-
erence for partitioning into the aqueous layer in the Log D assay.
To address the high microsomal clearance, we initially wanted
to prevent metabolism occurring at the C6-Me group (cf metabo-
lism of toluene to benzyl alcohol by CYP450 enzymes12) by
replacement with CF3, and by introducing a heteroatom into the
aromatic group at C2. The CF3 group was introduced by reaction
of 8 with aniline to yield 9 in 40% yield (Scheme 5). Intermediate
9 was then reacted with four aromatic methylamines to afford
10a–d, with 10b–c possessing pyridyl groups.
No.
Pf EC50 Dd2 (lM)
Log D
6a
6b
6c
7a
7b
7c
0.30
0.57
0.30
0.16
0.20
0.16
1.00
2.77
À0.17
1.00
2.70
À0.15
Scheme 5. Reagents and conditions: (a) Aniline, EtOH, rt, 24 h (40%); (b) iPrOH,
wave and either BnNH2 (10a, 79%), 2-(pyridyl)CH2NH2 (10b, 92%), 4-(pyri-
l
dyl)CH2NH2 (10c, 37%) or 5-(piperonyl)CH2NH2 (10d, 96%).
Table 5
In vitro antiplasmodial activity and microsomal clearance of 10a–d (live–dead EC50
and microsomal clearance values for the C6-Me analogs 1ap, 1aq and 1ar are also
displayed)
No.
R1
R2
Pf EC50 Dd2 (
l
M)
Clint
Rat
(lL/min/mg prot.)
Human
Table 5 reveals that the C6-CF3 group led to a significant de-
crease in antiplasmodial activity compared to the C6-Me analogs.
Additionally, it decreased solubility to the extent that microsomal
clearance could not be determined (10a, 10d), or increased clear-
ance compared to the C6-Me analog (10b). The pyridyl groups
had no effect on clearance (10b–c).
We also utilized the CF3 group to address the potential inhibi-
tion of hERG, a cardiac ion channel that plays an important role
in ventricular repolarization. hERG inhibition is an undesirable
property in many drug development programs due to the potential
10a
1ap
10b
1aq
10c
10d
1ar
CF3
Me
CF3
Me
CF3
CF3
Me
Ph
Ph
5.00
0.09
7.09
2.14
7.19
10.1
0.36
NDa
>119
>119
114
NDa
55.2
>99
70.0
56.2
NDa
31.3
Pyridin-2-yl
Pyridin-2-yl
Pyridin-4-yl
Piperon-5-yl
Piperon-5-yl
>119
NDa
>119
a
ND = not determined because of low solubility (<0.1 lg/mL).
for heart arrhythmias in patients.13 Inhibition of hERG has been
widely described for pyrimidine-based compounds,14 and the scaf-
fold used in this study fits the model for hERG inhibitors as it fea-
tures
a basic nitrogen flanked by aromatic or hydrophobic
groups.15 Introduction of an electron-withdrawing CF3 group at
C6 would reduce the pKa of the nitrogens at C2/C4, an approach
that has been used to lower hERG inhibition.16 Two pairs of com-
pounds were tested in an in vitro hERG inhibition assay, with the
compounds in a pair differentiated by either Me or CF3 at C6 (Ta-
ble 6). In both cases, the CF3 compound displayed less inhibitory
Table 6
hERG channel inhibitory activity of 1aq, 1ar, 10a and 10da
No.
R1
R2
hERG IC50 (lM)
1aq
1ar
10b
10d
Me
Me
CF3
CF3
Pyridin-2-yl
Piperon-5-yl
Pyridin-2-yl
Piperon-5-yl
15.8
9.50
40.1
135
Scheme 4. Reagents and conditions: (a) N-Benzyl-4-aminopiperidine, EtOH, rt, 24 h
lwave and either N-Me diazepine (6a, 75%), (7a,
40%), or N-Boc diazepine (6b, 73%), (7b, 69%); (c) 4 M HCl/dioxane (6c, 32%), (7c,
(5a, 46%), (5b, 23%); (b) iPrOH,
a
Cisapride was used as a positive control (IC50 = 35 nM).
53%).

D. C. Martyn et al. / Bioorg. Med. Chem. Lett. 20 (2010) 228–231
231
(d) Hynes, J. B.; Gratz, R. F.; Ashton, W. T. J. Med. Chem. 1972, 15, 1332; (e)
Stogryn, E. L. J. Med. Chem. 1973, 16, 1399.
activity, with a 2.5-fold difference between 1ap and 10b, and a 14-
fold difference between 1aq and 10d.
5. Morgan, J.; Haritakul, R.; Keller, P. A. Lett. Drug Des. Disc. 2008, 5, 277.
6. A stirred solution of 2,4-dichloro-6-methylpyrimidine (1, ꢀ1 g) in dry EtOH
(6 mL) under an inert atmosphere was cooled to 0 °C, after which the amine
(2 equiv) was added dropwise. The reaction mixture was warmed to rt over
24 h, then evaporated to dryness. CH2Cl2 (20 mL) was added, washed with
water (2 Â 20 mL), dried (MgSO4), evaporated to dryness, and the crude
material was purified by flash chromatography.
In summary, two sets of 2,4-diaminopyrimidines (DAPs) total-
ling 45 compounds were synthesized and assayed against P. falci-
parum. The SAR revealed relatively few major changes in activity
that could be attributed to the presence or absence of specific
group(s) at R1 or R2. The two major observations were a slight de-
crease in activity when R1 = iPr, and a significant decrease in activ-
ity when R2 = 2-(pyrrolidin-1-yl)ethyl. A subsequent series of nine
compounds addressed high Log D values by the introduction of
more polar side groups at R1/R2. The most active compounds in this
series (7a–c), while 2–2.5-fold less active than 1an, had more
favorable Log D values. A final series attempted to address high
in vitro microsomal clearance by replacing the C6-Me group with
CF3, however antiplasmodial activity decreased without any
improvement in clearance. The C6-CF3 group decreased hERG inhi-
bition, probably as a result of the lower basicity of the nitrogens at
C2/C4.
7. Thomas, A. P.; Nowak, T. PCT. Int. Appl. WO2006106307, 2006. NB: In contrast
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D. A., Jr.; Daily, J. P.; Sarr, O.; Ndiaye, D.; Ndir, O.; Mboup, S.; Duraisingh, M. T.;
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microwaved in a sealed tube at 180–190 °C for 1 h. After cooling to rt, the
solvent was removed by rotary evaporation, and the crude material was
purified by flash chromatography.
10. (a) Eck, H.; Kinzel, P.; Mueller, F. Kemia-Kemi 1974, 1, 611; b Eck, H.; Fischer, G.;
Mueller, F.; Wihrheim, S. E. Ger. Offen. DE2256289, 1974.; c Eck, H.; Kinzel, P.;
Mueller, F. Ger. Offen. DE 2403165, 1975.
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The authors received funding from the Medicines for Malaria
Venture, Broad Institute of MIT and Harvard SPARC, and Genzyme
Corporation. Genzyme Corporation funded these studies on a not-
for-profit basis.
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Fernandes, C.; Gibbs, J. B.; Koester, T. J.; Kohl, N.; Lynch, J. J.; Mao, X.;
McLoughlin, D.; Miller-Stein, C. M.; Rodman, L. D.; Rickert, K. W.; Sepp-
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Gaul, S. L.; Libby, B. E.; Lyle, E. A.; Lynch, J. J.; McCauley, J. A.; Mosser, S. D.;
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.10.133.
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