Design, synthesis and antimalarial evaluation of novel thiazole derivatives

Article abstract of DOI:10.1016/j.bmcl.2016.07.010

As part of our medicinal chemistry program's ongoing search for compounds with antimalarial activity, we prepared a series of thiazole analogs and conducted a SAR study analyzing their in vitro activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. The results indicate that modifications of the N-aryl amide group linked to the thiazole ring are the most significant in terms of in vitro antimalarial activity, leading to compounds with high antimalarial potency and low cytotoxicity in HepG2 cell lines. Furthermore, the observed SAR implies that non-bulky, electron-withdrawing groups are preferred at ortho position on the phenyl ring, whereas small atoms such as H or F are preferred at para position. Finally, replacement of the phenyl ring by a pyridine affords a compound with similar potency, but with potentially better physicochemical properties which could constitute a new line of research for further studies.

Full text of DOI:10.1016/j.bmcl.2016.07.010

Accepted Manuscript
Design, synthesis and antimalarial evaluation of novel thiazole derivatives
José María Bueno, Miguel Carda, Benigno Crespo, Ana Carmen Cuñat, Cristina
de Cozar, María Luisa León, J. Alberto Marco, Nuria Roda, Juan F. Sanz-
Cervera
PII:
S0960-894X(16)30712-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.07.010
BMCL 24054
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 April 2016
1 July 2016
4 July 2016
Please cite this article as: Bueno, J.M., Carda, M., Crespo, B., Cuñat, A.C., Cozar, C.d., León, M.L., Alberto Marco,
J., Roda, N., Sanz-Cervera, J.F., Design, synthesis and antimalarial evaluation of novel thiazole derivatives,
Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.07.010
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Graphical Abstract
Leave this area blank for abstract info.
Design, synthesis and antimalarial evaluation
of novel thiazole derivatives
José María Bueno, Miguel Carda, Benigno Crespo, Ana Carmen Cuñat, Cristina de Cozar, María Luisa León, J.
Alberto Marco, Nuria Roda and Juan F. Sanz-Cervera

Design, synthesis and antimalarial evaluation of novel thiazole
derivatives
José María Bueno,a Miguel Carda,b Benigno Crespo,a Ana Carmen Cuñat,c,* Cristina de
Cozar,a María Luisa León,a,* J. Alberto Marco,c Nuria Rodac and Juan F. Sanz-Cerverac
aTres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2,
28760 Tres Cantos, Spain
bDepartamento de Química Inorgánica y Orgánica, Univ. Jaume I, 12071 Castellón, Spain
cDepartamento de Química Orgánica, Facultad de Química, Univ. de València, Calle Dr.
Moliner 50, 46100 Burjassot, Spain
Keywords: malaria; antimalarials; synthesis; thiazoles; structure-activity relationship.
Abstract
As part of our medicinal chemistry program’s ongoing search for compounds with antimalarial
activity, we prepared a series of thiazole analogs and conducted a SAR study analyzing their in
vitro activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. The results
indicate that modifications of the N-aryl amide group linked to the thiazole ring are the most
significant in terms of in vitro antimalarial activity, leading to compounds with high
antimalarial potency and low cytotoxicity in HepG2 cell lines. Furthermore, the observed SAR
implies that non-bulky, electron-withdrawing groups are preferred at ortho position on the
phenyl ring, whereas small atoms such as H or F are preferred at para position. Finally,
replacement of the phenyl ring by a pyridine affords a compound with similar potency, but with
potentially better physicochemical properties which could constitute a new line of research for
further studies.
* A. C. C: Tel.: +34-963543038; fax: +34-963544328; e-mail. M. L. L.: Tel: +34-638482694; e-mail:
maria-luisa.d.leon@gsk.com.

Malaria, the most lethal human parasitic infection,1,2 is transmitted by female mosquitos
of the genus Anopheles infected with parasites of the genus Plasmodium.3 Of the latter, P. vivax
and P. falciparum are the most relevant.4,5 Although several drugs can be used to treat this
disease, the rise of drug-resistant strains of Plasmodium is a growing cause for concern.6-8 For
this reason, the need for new drugs for those already infected with malaria has acquired a new
urgency,9,10 especially considering that in the last 10 years, no effective new candidates have
been found to treat this disease. Recently, a significant contribution to the eventual solution of
this problem has been made by GlaxoSmithKline (GSK). Using its corporate collection of over
two million compounds as a starting point, GSK carried out a High–Throughput Screening
(HTS) against the P. falciparum 3D7 strain, which is chloroquine sensitive, to reduce the
original number to around 13,000 confirmed hits; these are known as the Tres Cantos
Antimalarial Set (TCAMS).11,12 More than 8,000 of these compounds show activity against the
Dd2 strain, which is multi-drug resistant.11-12 GSK has published these results in the form of a
data base with free public access through the European Bioinformatics Institute,13 thus offering
academic institutions the opportunity to join the effort in the hit to lead development of
antimalarials. To this end, a collaboration was established between GSK and our two
universities with the aim of selecting a hit from the TCAMS with a thiazole scaffold to conduct
SAR studies based on its antimalarial activity.14
The thiazole ring is a well-known component of many biologically active compounds
with demonstrated antimicrobial, antifungal and anti-inflammatory properties,15 as well as
potential antitumoral activity.16-21 Numerous synthetic approaches have been used in their
preparation, but the classic methods of Hantzsch22-27 and Cook-Heilbron28 still constitute valid
strategies for the introduction of chemical diversity around the thiazole scaffold.
In order to identify a suitable hit from the TCAMS Dataset
(https://www.ebi.ac.uk/chemblntd/compound/activity_home),13 we focused our search on
thiazoles that showed a high percentage of inhibition of P. falciparum at a concentration of 2µM
(>98% for both 3D7 and D2d strains), high potency (XC50 3D7 < 0.3 µM), low cytotoxicity on
HepG2 human liver cells (<15% at 10µM) and a low inhibition frequency index (< 10). As a
result, a cluster of nine structurally related thiazole derivatives with promising antimalarial
activity was selected. The main structural features of these nine compounds are shown in Figure
1.29

Figure 1. Significant common structural features of the nine thiazoles included in the TCAMS chemical cluster
# 300
From the selected compounds, thiazole 1 was chosen as the starting point for a SAR
study on the basis of its potency against both sensitive P. falciparum 3D7 (XC50 3D7 = 190 nM)
and resistant Dd2 strains to the commercially available antimalarial drugs chloroquine and
pyrimethamine (Figure 2).30 At a concentration of 2 µM, 1 was found to inhibit both the 3D7
and Dd2 strains by 100% and 99%, respectively. Additionally, compound 1 displays low
toxicity against the HepG2 cell line (3% inhibition at 10 µM). Finally, the amenable chemistry
involved in its synthesis allows for the introduction of a number of substituents not only at the
thiazole ring, but also around the B and C rings (Figures 2 and 3).
Figure 2: Structure and properties of the hit (1)

Once compound 1 had been selected as a hit, the next step involved the selection of a
series of analogs with suitable structural diversity (Figure 3). Several different R1 groups were
chosen to explore the importance of the B ring. As for R2 groups, we chose to examine
halogenated, electron-rich and electron-withdrawing groups in several positions on the benzene
C ring. Finally, the substitution of benzene with a pyridine as C ring was also considered.
Figure 3: Proposed thiazole analogs of compound 1
Brominated thiazole 2 was identified as a key intermediate for the preparation of the
desired analogs of hit 1. After building the thiazole core, two different synthetic routes can be
used to obtain these analogs. As a first option, reaction of 2 with suitable amines would yield
amino-thiazole derivatives A, which could be then transformed into the corresponding amides
C. Alternatively, 2 could be transformed into amides B, whose subsequent reaction with
suitable amines would lead to a set of analogs C (Scheme 1). Indeed, an initial synthetic trial
showed that both A and B pathways yielded the same compound C in comparable yields. We
thus concluded that both synthetic routes would be suitable for the preparation of a small library
of thiazole derivatives with appropriate chemical diversity, based on the hit compound.

Scheme 1: Two possible approaches for the synthesis of novel antimalarial thiazoles C.
Compound 2 was prepared by means of a Hantzsch synthesis22 in which α-bromoketone
5 (Scheme 2) was an intermediate for the preparation of the thiazole moiety. We were able to
prepare 5 in three steps and with good yield from the Grignard reagent 3. Thus, reaction of 3
with diethyl oxalate afforded α-oxoester 4 (Scheme 2).31 In turn, compound 4 reacted with
CuBr2 to yield the brominated derivative 5,32-35 which then reacted with thiourea in EtOH to
afford thiazole 6 in high yield.36 Compound 2 was then obtained in one step by means of a
Sandmeyer reaction, which involved the formation of an intermediate diazonium salt, followed
by reaction with CuBr2 (Scheme 2).37

Scheme 2: Preparation of intermediate 2. Conditions: (a) Mg, I2, 30 Min. reflux. (b) Diethyl oxalate, Et2O,
-78°C to rt, 1h. (c) CuBr2, EtOAc-DCM 2:1, 18h. reflux. (d) Thiourea, EtOH, 5 h. reflux. (e) CuBr2, t-BuONO,
CH3CN
With compound 2 in hand, we started our SAR study by introducing diversity in the B
ring. Thus, several different cyclic and open secondary amines were introduced in position 2 of
the thiazole ring while retaining the amide moiety of the hit (route B, shown in Scheme 1). To
that end, ester hydrolysis of 2 to the corresponding carboxylic acid followed by reaction with
thionyl chloride provided an acyl chloride which, upon reaction with 4-fluoro-2-
trifluoromethylaniline, yielded amide 7. This amide then reacted with several secondary amines
to afford compounds 1 and 8-11 (Scheme 3 and Table 1).
Scheme 3: Preparation of compounds 1 and 8-11 from intermediate 2
Table 1.
Modifications in the B ring of the hit.a
Entry
Compound
Yield (%)
99%
IC50 (µM) after 48 h
1
2
3
0.024
3.150
3.260
1 (hit)
95%
8
9
96%

4
5
99%
93%
0.102
0.590
10
11
a IC50 values for the commercially available drugs Atovaquone and Artesunate were 0.0005 µM and 0.014 µM,
respectively.
Our initial results (Table 1) showed that open chain compounds 8, 9 and 11 have a
markedly lower potency than 1, especially in the case of the first two compounds. Furthermore,
substitution of an N-methyl group by an O atom in the B ring (as in 1 vs. 10) only causes a
slight decrease in activity. Moreover, similar compounds in the initial thiazole cluster, which
include piperidine, 4-methylpiperidine and N-methylpiperazine B rings also display similar
potency values.38 We therefore concluded that the presence of an additional basic nitrogen in the
B ring is not essential for activity as long as a six-membered ring attached through a N atom is
present at position 2 of the thiazole. This seems to point to the need for steric hindrance in this
part of the molecule.
After having determined that changes to the B ring of 1 do not significantly alter its
activity, we focused our attention on modifications to the C ring while keeping the B ring of the
hit unchanged. This allowed us to study the influence of the aryl group with a range of
substituents. Diversity in the C ring was introduced in position 2 of the thiazole through reaction
of 2 with N-methylpiperazine in refluxing dioxane (Scheme 4). The resulting ester 12 was then
hydrolyzed to the corresponding carboxylate which, upon reaction with thionyl chloride,
provided an acyl chloride. Finally, reaction of the latter with several different anilines yielded
amides 13-36 as analogs of 1 (Schemes 1 and 4 and Table 2, entries 1-25).
Scheme 4: Preparation of compounds 1 and 13-36 from intermediate 2
Table 2.
Modifications on the amide N-phenyl ring substitution in 1 with several different groups.a

Yield
(%)
IC50 (µM)
after 48 h
Entry
1
Compound
Ar
80%
80%
0.024
1.194
1 (hit)
2
13
3
4
79%
90%
>5
14
15
0.058
5
99%
>5
16
6
7
88%
73%
>5
17
18
3.270
8
9
19
20
21
77%
80%
68%
>5
0.72
>5
10

11
12
13
75%
83%
42%
0.058
0.031
0.260
22
23
24
14
46%
>5
25
15
16
17
18
84%
76%
57%
87%
0.350
0.098
0.034
>5
26
27
28
29
O
H2N
19
20
82%
65%
>5
>5
30
31

21
76%
0.08
32
22
23
24
82%
63%
75%
1.7
>5
>5
33
34
35
25
82%
0.35
36
a See footnote to Table 1.
Since 1 has two halogenated groups in the C ring (o-CF3 and p-F), the first round of
compounds explored the effect of the presence of halogen atoms or CF3 groups in several
positions on the phenyl ring. Our initial results showed highly significant changes in the
potency of these analogs (Table 2, entries 1-6). For example, the substitution of a CF3 group
(compound 1 (hit)) by a fluorine atom (compound 13, entry 2) caused a marked loss of activity
(IC50 from 0.024 µM to 1.194 µM). Similarly, when two F atoms were introduced in meta
position (compound 16, entry 5) or when the ortho position was not substituted (compound 14,
entry 3), a complete loss of activity was observed (>5 µM for each compound). Only compound
15 (o-Cl, p-F, entry 4) had a potency similar to that of 1. As these results all seemed to indicate
the importance of substitution in the ortho position, we prepared additional analogs 17-25, all of
which have at least one ortho substituent (Table 2, entries 7-25). The activity of 23 (o-CF3,
entry 12) (IC50 = 0.031 µM), which has a free para position, is similar to that of 1 (o-CF3, p-F,
entry 1) (IC50 = 0.024 µM). At the same time, while the activities of 15 (o-Cl, p-F, entry 4) and
22 (o-Cl, entry 11) are the same (IC50 = 0.058 µM for both compounds), 17 (o-Cl, p-CF3, entry
6) is inactive. These findings not only confirm that substitution in the ortho position is essential
for activity, but also that the para position should preferably be kept free or occupied by a
fluorine atom. Indeed, the presence of a bulkier group such as CF3 in compound 17 (entry 6) or
CH3 in 18 (o-Cl, p-CH3, entry 7) rendered these compounds practically inactive. Additionally,

CF3 and Cl groups in ortho position are almost interchangeable in terms of their effects on
potency, as shown by the data for 1 (entry 1) vs. 15 (entry 4) and 22 (entry 11) vs. 23 (entry 12).
Taken together, our findings point to Ring C as the most important component of these
compounds in their interaction with possible biological targets; we therefore focused most of
our later synthetic efforts here.
In a second round of experiments we decided to prepare several analogs with two
substituted ortho positions. In all cases, the antimalarial activity was completely lost (IC50 > 5
µM), as in 19 (o-Cl, o-Cl, p-CF3, entry 8), 21 (o-Cl, o-Cl, p-F, entry 10) and 25 (o-F, o-F, entry
14).
In a third round, several additional monosubstituted analogs with the ortho position
occupied by either an electron-rich or an electron-withdrawing group were prepared and
assayed (entries 15-20, Table 2). The results showed that when the substituent position is
electron-rich, as in 26 (o-OCH3), the activity is lower (IC50 = 0.350 µM) in comparison to
analogs in which electron-withdrawing groups are present, such as 27 (o-CN) and 28 (o-OCF3),
with IC50 activities of 0.098 µM and 0.034 µM, respectively. Additionally, in ortho
monosubstituted compounds 29 (o-CH2OH), 30 (o-CONH2) and 31 (o-SO2NH2), all of which
display stronger steric and lower lipophilic effects, the antimalarial activity is likewise lost.
Finally, compounds 32-36 include a pyridine instead of a benzene ring (Table 2, entries
21-25). Although compounds 22 (o-Cl, entry 11) and 32 (with a 2-chloropyridin-3-yl group,
entry 21) have similar substitution patterns and potencies, the introduction of pyridyl C rings as
in 33-36 did not generally improve the potency of these analogs. This might, however, have an
effect on other important properties. In fact, a significant decrease in lipophilicity was observed
in compound 32 (chlogD=7.8) compared to the hit 1 (chlogD=9.06).
The toxicity of the most active compounds in our series against HepG2 human cells was
also determined (Figure 4). Preliminary results seem to indicate that toxicity might not be an
issue of concern in this series of compounds.

Figure 4: In vitro antimalarial activity (IC50 for P. falciparum 3D7 strain) and toxicity (IC50 for HepG2 human
liver cells) of the hit and the most active analogs prepared in this study.
In conclusion, starting from the Tres Cantos Antimalarial Set (TCAMS), a previously
published antimalarial data base with free public access, we were able to find a cluster of
thiazoles from which we identified a suitable hit 1. From this compound, we prepared a series of
analogs which allowed us to build a SAR study, analyzing their in vitro activities against the
3D7 strain of P. falciparum. The results led to several conclusions. First, modifications to the B
ring of the molecule do not significantly affect its activity as long as position 2 of the thiazole is
directly bound by a nitrogen atom from a piperidine, piperazine, or N-methylpiperazine moiety.
However, opening the B ring significantly lowers the potency of the corresponding analogs.
Secondly, position 5 of the thiazole must be occupied by an ethyl or isopropyl group, as a
methyl group makes it lose most of its activity.24 Third, and most importantly, ring C is the most
significant in this series, greatly affecting antimalarial activity. The most potent compounds
have one electron attractor group in ortho position and a free para position, with only two
exceptions: compounds 1 and 15, in which the para substituent is a fluorine atom. Furthermore,
when both ortho positions are simultaneously substituted, the analogs are inactive. These
findings indicate that ortho monosubstitution is required for activity, with non-bulky electron-
withdrawing groups being preferred. When the para position is occupied, the substituent must
be a small atom, such as F. Moreover, preliminary assays against HepG2 human liver cells
indicate that toxicity does not seem to be a problem in this series of analogs. Finally,
replacement of the aryl ring by a pyridine affords a compound with similar potency to 1, but

with potentially better physicochemical properties which could constitute a new line of work for
further studies.
Acknowledgements
M. C., A. C. C., J. A. M., N. R. and J. F. S.-C. thank the Spanish Government (Ministerio de
Ciencia e Innovación, research grant CTQ2011-27560) and the Consellería d’Educació,
Investigació, Cultura i Esport de la Generalitat Valenciana (research grant
PROMETEO/2013/027) for financial support.
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Supplementary material
The supplementary material contains experimental procedures used in the biological work as
well as chemical procedures and data.