Design, synthesis, and antiplasmodial evaluation of a series of novel sulfoximine analogues of carbohydrate-based thiochromans

Article abstract of DOI:10.1111/cbdd.13408

Sulfone/sulfoxide-containing carbohydrate derived thiochromans were found to be highly active antiplasmodial agents. However, the inability of the sulfone/sulfoxide functional groups for further derivatization and manipulation limited the potential for further exploration. In this study, based on the interesting and important physicochemical properties, as well as amenability of sulfoximines (isosters of sulfones) for further derivatization, a series of novel sulfoximine-type carbohydrate-derived thiochroman derivatives have been successfully synthesized, characterized, and evaluated for their antiplasmodial activity. Although the replacement of the sulfone functional group with a sulfoximine unit improved the antiplasmodial activity of the scaffolds, the activity was highly dependent on the configuration of the stereogenic centre at the sulfur atom. Moreover, analysis of the crystal structures of the sulfoximine analogues revealed that the bond between the sulfur and nitrogen atoms of the sulfoximine functional group is not a true double bond but rather a polarized single bond.

Full text of DOI:10.1111/cbdd.13408

PROFESSOR HENOK KINFE (Orcid ID : 0000-0002-4958-2836)
Article type : Research Article
Design, synthesis and antiplasmodial evaluation of a series of novel sulfoximine analogues of
carbohydrate–based thiochromans
Munashe Chizema,1 Tommy F Mabasa,1 Heinrich C Hoppe2 and Henok H Kinfe1
1Center of Synthesis and Catalysis, Department of Chemistry, University of Johannesburg–Kingsway
Campus, Auckland Park 2006, Johannesburg, South Africa
2Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa
Keywords: thiochroman, sulfoximine, antiplasmodial, antimalarial
Abstract
Sulfone/sulfoxide–containing carbohydrate derived thiochromans were found to be highly active
antiplasmodial agents. However, the inability of the sulfone/sulfoxide functional groups for further
derivatization and manipulation limited the potential for further exploration. In this study, based on
the interesting and important physicochemical properties, as well as amenability of sulfoximines
(isosters of sulfones) for further derivatization, a series of novel sulfoximine–type carbohydrate–
derived thiochroman derivatives have been successfully synthesized, characterised and evaluated
for their antiplasmodial activity. Although the replacement of the sulfone functional group with a
sulfoximine unit improved the antiplasmodial activity of the scaffolds, the activity was highly
dependent on the configuration of the stereogenic centre at the sulfur atom. Moreover, analysis of
the crystal structures of the sulfoximine analogues revealed that the bond between the sulfur and
nitrogen atoms of the sulfoximine functional group is not a true double bond but rather a polarized
single bond.
 Corresponding author. Tel.: +27-011 559 3918; fax: +27-011-559-2819; e-mail: hhkinfe@uj.ac.za
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/cbdd.13408
This article is protected by copyright. All rights reserved.

Introduction
Malaria is one of the leading causes of death globally especially in poor communities and in children
under the age of five.[1–5] Protozoan parasites of the genus Plasmodium are the causative agents of
malaria that are transmitted by the bite of the female Anopheles mosquito.[6] There are six species of
Plasmodium that cause malaria in humans, namely: P. falciparum, P. vivax, P. ovale curtisi, P. ovale
wallikeri, P. malariae and P. knowlesi.[6,7] Among them, P. falciparum and P. vivax are the most
deadly species and responsible for the main burden of malaria in sub–Saharan Africa and the rest of
the world, respectively.[7] According to the 2017 WHO report half of the world’s population was at
risk of malaria and malaria cases and malaria deaths stood at 216 000 000 and 445 000, respectively,
of which sub–Saharan countries accounted for almost 90% of these cases.[7]
Preventative and curative measures for this significant health challenge have been implemented
predominantly using antimalarial drugs. Currently, the use of a combination of two or more drugs
possessing different modes of action, such as ACT (artemisinin–based combination therapy that
involves the use of artemisinin along with companion drugs: lumefantrine, mefloquine, amodiaquine,
sulfadoxine/pyrimethamine, piperaquine and chlorproguanil/dapsone), is the WHO recommended
treatment of malaria.[7–11] However, tolerance, which may lead to resistance against this class of drugs,
has been reported. The emergence of these drug resistant strains of malaria necessitates the discovery
of new drugs, paying particular attention to new chemotypes, cellular targets or pivotal characteristics
that could retard the emergence of resistance.[7,12–14]
Sulfur–containing compounds in the form of sulfides, sulfoxides and sulfones are known to possess
interesting biological activities as exemplified by the famous drug compounds, Penicillin 1,[15,16]
Esomeprazole 2,[17] Dapsone 3a[18] and Prontosil 3b[15,16] (Figure 1).[7]
However, sulfoximine (an isostere of sulfone)–containing compounds are less explored for their
therapeutic use, despite being discovered over six decades ago. It is only in the last ten years that
the synthesis of bioactive sulfoximine derivatives started to pick up momentum due to their
favorable physicochemical properties,[19-21] hydrogen–bond acceptor/donor functionalities,[20,21c]
relatively higher metabolic stability[21a,21b] and solubility[21] than the corresponding analogues. The
presence of a stereogenic centre at the sulfur atom and amenability for further derivatization are
additional attractive features of sulfoximines in medicinal chemistry. For instance, sulfoximine
containing compounds have been reported to exhibit various biological activities such as antiviral
4a,22 anticancer 4b23 and antidepression 4c24 (Figure 1).
In our efforts in the development of new antimalarial agents, we have recently reported the
synthesis and antiplasmodial activity of novel carbohydrate–derived thiochromans.[25,26] Although
compound 5 (Figure 3) from the series of the tested compounds exhibited promising activity against
both chloroquine–sensitive (3D7) and chloroquine–resistant (FCR3) strains with IC50 values of 0.3–
0.4 μM, however, the inability of the sulfone functional group to undergo further diversification and
manipulation limited the potential to explore the possibility of improving the IC50 values of these
scaffolds to nanomolar concentrations.
This article is protected by copyright. All rights reserved.

Derivatization at the α–carbon of the sulfone led to epimerization at the anomeric centre of the sugar
moiety resulting in products which were found to be less potent against the Plasmodium strains.[25]
These limitations, coupled with the special features endowed to sulfoximines, prompted us to
synthesise sulfoximine analogue 6 (Figure 2) of the most active carbohydrate derived thiochroman 5,
in the hope of improving the antiplasmodial activity of these scaffolds. Herein, we report the
synthesis, antiplasmodial activity results and the structural activity relationship (SAR) studies of novel
sulfoximine derivatives of the carbohydrate derived thiochroman scaffolds.
Methods and Materials
Chemistry
The solvents were dried by appropriate techniques reported in the Purification of Laboratory
Chemicals by Perrin and Armarego.[27] All reactions were monitored by thin layer chromatography
(TLC) on aluminum–backed silica gel 60 F254 plates using an ascending technique. The plates were
visualized under UV–light. Gravity column chromatography was done on silica gel 60 (70–230 mesh).
1
Melting points were determined using a hot–stage and are uncorrected. All H and 13C nuclear
magnetic resonance spectra were recorded as deuteriochloroform solutions using tetramethylsilane
as an internal standard. All chemical shifts are reported in ppm. The carbohydrate-based
thiochroman 7 and the corresponding sulfone 5 and sulfoxide derivatives 8a and 8b were
synthesized according to literature methods previously reported and their experimental data were in
agreement with the literature.[25, 28, 32] The experimental procedures, NMR and IR spectroscopic as
well as HRMS data for all new compounds is provided in the Supporting Information.
Antiplasmodial assay
Plasmodium falciparum (strain 3D7) parasites were maintained in culture medium consisting of
RPMI 1640 supplemented with 25 mM HEPES, 0.5% (w/v) Albumax II, 22 mM glucose, 0.65 mM
hypoxanthine and antibiotics (20 µg/ml gentamicin). The cultures contained human erythrocytes (2 –
o
4% haematocrit) and were incubated at 37 C under an atmosphere of 5% CO2, 5% O2, and 90% N2.
To assess compound activity, a parasite culture containing predominantly mature stage parasites
was distributed into 96–well plates, compounds added to a final concentration of 20 µM (from 10
mM stocks in DMSO; final culture parasitemia 2%, haematocrit 1%) and incubation continued for 48
hours. Twenty µl of resuspended culture was removed from each well and used to perform a
parasite lactate dehydrogenase (pLDH) colorimetric enzyme assay.[29] After subtracting background
readings from wells containing uninfected erythrocytes, the absorbance values were converted to %
parasite viability relative to wells containing untreated control parasite cultures. Dose–response IC50
assays were performed as described above, except that parasites were incubated with 3–fold serial
dilutions of the test compounds. Plots of % parasite viability vs. log[compound] were used to
determine IC50 values by non–linear regression analysis using GraphPad Prism software.
This article is protected by copyright. All rights reserved.

Cytotixicity assay
HeLa cells were cultured in DMEM medium containing 10% fetal calf serum and
o
penicillin/streptomycin/amphotericin B at 37 C in a 5% CO2 incubator. Twenty–four hours prior to
compound addition, cells were plated into 96–well plates at a density of 2 x 104 cells per well.
Compounds were added to a final concentration of 20 µM and incubation continued for 48 h. To
assess cell viability, 20 µl resazurin reagent (0.5 mM resazurin in phosphate–buffered saline) was
added to each well, incubation continued for 4 hours and fluorescence (Ex560/Em590) measured in a
plate reader. After subtracting background reading obtained from empty wells, the fluorescence
readings were converted to % cell viability relative to wells containing untreated control HeLa cells.
Result and discussion
Chemistry
Synthesis of sulfoximine analogues of the sulfone–derived thiochroman.
In order to investigate whether replacing the sulfone moiety with a sulfoximine improves the
antiplasmodial activity of the thiochroman scaffolds, sulfoximines 6a and 6b were prepared as shown
in Scheme 1 using the protocol reported by Zenzola et al.[30,31] Accordingly thiochroman 7, prepared
according to our previously reported protocol,[32] was oxidized using 1.2 equiv. of oxone® to afford
sulfoxides 8a and 8b as a separable mixture in 1:3 diastereoisomeric ratio, while oxidation with
excess oxone® led to the formation of sulfone 5 in reasonable yields (Scheme 1).[30] Imidation of
sulfoxide 8a upon treatment with a mixture of (diacetoxyiodo)benzene (DIB) and NH2COONH4
provided the desired sulfoximine 6a in 90% yield with retention of stereochemistry at the sulfur atom.
The stretching frequency of the quasi–broad N–H band at 3250 cm–1 and also the appearance of the
singlet signal at H 3.00 confirmed the presence of the NH moiety in sulfoximine 6a. Likewise,
sulfoximine 6b was successfully synthesized and characterized (Scheme 1).
Furthermore, the absolute stereochemistry of the stereogenic centre at the sulfur atom was confirmed
by X–ray crystallography (Figure 3). As expected, the fused pyran and thiopyran rings adopted a chair
and an envelope conformation, respectively, with the NH–group in the pseudo–axial position.[33] To
find out the bonding nature around the sulfoximine functional group, the presence or absence of
double bonds between the sulfur and oxygen atoms, as well as between sulfur and nitrogen atoms of
the sulfoximine 6a were analyzed on the X–ray crystal structure. Interestingly, using OLEX2
(structural refinement program), no double bond was observed about the expected S=N bond. Thus it
is reasonable to conclude that the bonding between the sulfur and nitrogen atoms of the sulfoximine
functional group is of a polar nature and can be represented with a single bond as opposed to the
expected double bond. This is in agreement with previous reports which indicated that, π–bonding
between 3p orbitals of sulfur and 2p orbitals of another atom such as carbon and nitrogen, are less
effective than π–bonds formed via overlap of 2p orbitals only.[34–36]
After the successful synthesis of sulfoximine 6, various sulfoximine derivatives were synthesized for
structural activity relationship studies and are discussed below.
Sulfonamide derivatives of sulfoximine 6a
The sulfonamide group is a well–known structural unit found in a number of drugs that are used to
treat a wide spectrum of diseases including malaria, as exemplified by sulfadoxine and
sulfamethoxypyridazine.[37] Hence a nosyl unit was incorporated into the sulfoximine 6a as shown in
This article is protected by copyright. All rights reserved.

Scheme 2. Since treatment of sulfoxide 8a with an in situ generated nitrene source (PhINNs) from the
reaction of nosyl amide and DIB led to the formation of the sulfonamide 10 in low yields, the desired
product 10 was synthesized via a two–pot synthesis, whereby the nitrogen source 9 was prepared by
treating nosyl amide with DIB in the presence of KOH.[38,39] The isolated compound was then reacted
with sulfoxide 8a in the presence of Cu(OTf)2 to provide sulfonamide 10 in reasonable yield as shown
in Scheme 2.[40] Among others, the appearance of the characteristic two doublets of the para–
substituted benzene ring at H 8.25 and 8.13 confirmed the formation of the desired product.
Alkylation of sulfoximine 6a
By exploiting the acidity of the NH group of sulfoximine 6a, alkylated derivatives 11a–i were
successfully synthesized according to Scheme 3. The reaction involved treatment of sulfoximine 6a
with KOH in DMSO, followed by addition of alkyl halides to provide a series of alkylated derivatives
upon column chromatography–mediated purification using trimethylamine–doped silica gel. A variety
of alkylated sulfoximines 11a–i were synthesized possessing short, medium and long chain aliphatic
alkyl moieties and the results are summarized in Scheme 3. Interestingly, of all the alkylated
sulfoximines synthesized, the sulfoximine 11d with the branched alkyl group underwent
epimerization at the anomeric centre of the sugar moiety. This could be due to the high steric demand
of the branched alkyl group and hence the competitive abstraction of the acidic anomeric proton to
form the more stable –arylglycoside might have taken place prior to alkylation at the NH group. A
similar phenomenon was observed when sulfone 5 was treated with a base in our previous study.[28]
The epimerization was confirmed by an upfield shift of the anomeric proton signal from around H
5.23 of the starting material 8a to H 4.57, as well as an increase in the coupling constant of the
anomeric proton to J = 10.5 Hz from J = 4.4 Hz, indicating a trans–diaxial relationship with the
adjacent proton (H–2 of the sugar moiety).
In a similar fashion, the minor sulfoximine 6b was alkylated to provide sulfoximines 12–17 and the
results are summarized in Scheme 4. Unlike in the case of the alkylation of sulfoximine 6a, alkylation
of sulfoximine 6b led to a concomitant epimerization at the anomeric centre in most cases and
provided separable diastereomeric mixtures.
N–S coupling reaction
In addition, separable diastereomeric mixtures of 18a and 18b were obtained via a simple substitution
reaction of sulfoximine 6a with 3–nitro–2–pyridinesulfenyl chloride (Npys–Cl) under basic condition
as shown in Scheme 5.
Though this protocol is simple, the unavailability of various commercial sulfenyl halides limited its
scope. Thus we opted to use a general N–S coupling methodology to synthesize N–S–coupled
sulfoximine derivatives. Following the methodology reported by Zhu et al,[39–41] a solution of
sulfoximine 6a in DMSO was treated with a disulfide and sodium acetate in the presence of CuI as a
catalyst, to provide the N–S coupled sulfoximines 18c–g in quantitative yields, the results are
summarized in Scheme 6. The structures of the products were established using NMR and HRMS
spectroscopy. The disappearance of the NH signals and the increase of the integration of the aromatic
protons were a clear indication of the successful synthesis of this class of compounds.
Antiplasmodial activity
Encouraged by the excellent antiplasmodial activity of the sulfone 5, we synthesized the sulfoximine
6 analogues (Scheme 1), motivated by the notion that replacing the sulfone moiety with the
sulfoximine could potentially enhances physicochemical properties. Since the compounds previously
This article is protected by copyright. All rights reserved.

tested showed almost similar activities against both strains of the chloroquine–sensitive (3D7) and
chloroquine–resistant (FCR3) P. falciparum, the sulfoximine derivatives in the current study were
evaluated for their activity against the 3D7 strain only. Determination of the parasite viability using a
single 20 µM concentration of each of the sulfoximines (6a and 6b) and sulfone 5 resulted in a
reduction of parasite viability to 6.2%, 8.0% and 3.7% of untreated controls (Table 1), respectively
that warranted the determination of their respective IC50 values. Interestingly while the minor isomer,
sulfoximine 6b, displayed a ~20% improvement in activity with an IC50 value of 0.8 µM (vs 1.0 µM
of the sulfone 5),[42] the major isomer, sulfoximine 6a, was found to be inactive. Although replacing
the sulfone with the sulfoximine indeed improved the antiplasmodial activity as anticipated, the
activity was highly dependent on the absolute configuration of the sulfoximine stereogenic centre.
The fact that both the sulfone 5 and sulfoximine 6b were found to be active thus suggests the active
site of the host prefers a hydrogen bond–acceptor on the endo–face of the fused ring of the
thiochroman scaffold.
With this finding in hand, we decided to convert the major sulfoximine 6a to its alkylated derivatives,
thereby transforming it from being a hydrogen–bond donor to an accepter. Accordingly, a series of
alkylated sulfoximine derivatives 11a–i were successfully prepared and evaluated for their
antiplasmodial activities. As expected, the alkylation sulfoximine 6a resulted in compounds with
improved activity; from being inactive to highly active (Table 1, 6a Vs 11a–i except 11f). This further
proves that the endo face of the thiochroman scaffolds indeed requires a hydrogen–bond acceptor not
a donor. However, the activity was found to be dependent on the chain length of the alkyl group with
the methyl group exhibiting the highest activity (Table 1, 11a vs. 11f). With increase in the chain
length of the alkyl substituents, the activity diminished and this might be attributed to the increased
hydrophobicity and steric hindrance. Transforming sulfoximine 6b from being a hydrogen–bond
donor to an acceptor reduced the activity (Table 1, 6b vs. 12, 13, 14a and 16a). The multiple bond
possessing alkyl substituents also displayed similar activities (Table 1, 11g–i) with the π–bonds
exhibiting no influence on the possible guest–host interaction. In agreement with our previous
report,[25] the activity of the sulfoximine derivatives was also dependent on the stereochemistry of the
anomeric centre of the sugar moiety. A –glycosidic bond led generally to inferior activity when
compared with the corresponding –glycosylated sulfoximines (Table 1, 14a and 16a vs. 14b and
16b, respectively). A cytotoxicity study of all the active compounds was investigated and they were
all found to be non–toxic at 20 µM against the human HeLa cell line (Table 1).
Since sulfur has high enzyme binding affinity,[43] the hydrogen–bond donor sulfoximine 6a was
transformed into a hydrogen bond–acceptor via N–S coupling reactions, as well as by SN2 reactions,
in the hope of improving the potency of these thiochroman derivatives. Accordingly, sulfoximine
derivatives 18a–g were successfully prepared as described in the experimental section and evaluated
for their antiplasmodial activities. Unfortunately, all of them exhibited above 25% parasite viability
and were not considered further for IC50 value determination. The poor activity of these N–S coupled
products could perhaps be attributed to the weak N–S bond, which probably dissociates in the
bioassay medium to give the inactive free sulfoximine 6a.[33] Similarly, the sulfonamide derived
analogue was also found to be inactive (Table 1, entry 18a–b).
Conclusion
The main objective of the current study was to evaluate the effect of replacing the sulfone functional
group of the antiplasmodial thiochroman scaffolds with a sulfoximine moiety. Various novel
sulfoximine derivatives were successfully synthesized, characterized, and evaluated for their
antiplasmodial activity. The in vitro antiplasmodial activity results confirmed that the presence of the
free–sulfoximine unit enhanced the activity, but this effect was highly dependent on the configuration
of the stereogenic centre at the sulfur atom. These results demonstrate the importance of the
stereogenicity of the sulfoximine unit that is commonly overlooked in the literature reports. Better
This article is protected by copyright. All rights reserved.

activity was exhibited with the presence of the hydrogen–bond donor NH on the exo–face of the
molecule, while a hydrogen–bond donor on the endo–face of the molecule completely suppressed the
activity. Encouragingly, transforming the endo–NH from being a hydrogen–bond donor into an
acceptor via simple alkylation reactions forming a strong bond with the nitrogen atom, improved the
activity significantly, suggesting exploration of further derivatization might lead to better activity.
Although there is a growing interest in the development of methodologies for the synthesis of
sulfoximines and their use in medicinal chemistry, to the best of our knowledge, there is no report on
the bonding nature of sulfoximines. On the basis of the crystal structure of sulfoximine 6a, we suggest
that the bond between the sulfur and nitrogen atoms is not a true double bond but rather a polarized
single bond. Computational studies on simple sulfoximine derivatives is currently underway in our
group to fully understand the properties of bonding between the sulfur and nitrogen atoms.
Acknowledgements
We thank the University of Johannesburg (UJ), the Research Centre for Synthesis and Catalysis of the
Department of Chemistry at UJ, Sasol Ltd and the National Research Foundation (NRF) for funding as
well as UJ–Spectrum for providing NMR spectroscopy facilities. The bioassays were supported with
funding from the South African Medical Research Council and from Rhodes University. We also thank
Gershon Amenuvor for solving the crystal structure.
Figure 1. Examples of sulfur–containing drugs and biologically active sulfoximines.
Figure 2. Sulfone 5 and the proposed sulfoximine 6 analogue of the thiochroman scaffold.
Scheme 1. Synthesis of sulfoxide 8, sulfone 5 and sulfoximine 6. i. Wet Al2O3, oxone®, DCM, 3 h, rt,
63% (3:1, 8a:8b); ii. Wet Al2O3, excess oxone®, DCM, 4 h, 80%; iii. DIB, NH2CO2NH4, MeOH, 30
min, rt, 6a (90%) and 6b (84%).
Figure 3. ORTEP diagram of sulfoximine 6a with ellipsoids drawn at 50% probability. Crystal Data
for C38
H
43NO
5
S (M =625.79 g/mol): monoclinic, space group P2
1
(no. 4), a = 16.253(3) Å, b =
3
6.0345(10) Å, c = 17.334(3) Å, β = 105.345(5) °, V = 1639.5(5) Å , Z = 2, T = 99.98 K, μ(MoKα) =
–1
3
0.144 mm , Dcalc = 1.268 g/cm , 18020 reflections measured (4.006° ≤ 2Θ ≤ 56.544°), 7709
unique (Rint = 0.0771, Rsigma = 0.1171) which were used in all calculations. The final R was
0.0594 (I > 2σ(I)) and wR was 0.1353.
1
2
Scheme 2. Synthesis of sulfonamide 10: Cu(OTf)2 (10 mol%), CH3CN, 30 min, rt, 70%.
Scheme 3. Alkylation of sulfoximine 6a: i) a. KOH, DMSO, 5 min, rt; b. RX, 6 h, rt.
Scheme 4. Synthesis alkylated–sulfoximine 12–17 using the minor sulfoximine 6b as the precursor. i)
a. KOH, DMSO, 5 min, rt; b. RX, 30 min (with 4 equiv. of RX), rt,
Scheme 5. Sulfonamide 18 synthesis. Npys–Cl, KOH, DMSO, 6 h, rt.
Scheme 6. Thioetherification of sulfoximine 6a. ArS–SAr, NaOAc, CuI (10 mol %), DMSO.
Table 1. Antiplasmodial and cytotoxicity assay of sulfone 5 and the sulfoximine derivatives.a
Note: The authors declare no competing financial interest.
This article is protected by copyright. All rights reserved.

References
1.
Bhatt S., Weiss D.J., Cameron E., Bisanzio D., Mappin B., Dalrymple U., Battle K.E., Moyes C.L.,
Henry A., Eckhoff, P.A., Wenger E.A., Briët O., Penny M.A., Smith T.A., Bennett A., Yukich J.,
Eisele T.P., Griffin J.T., Fergus C.A., Lynch M., Lindgren F., Cohen J.M., Murray C.L.J., Smith
D.L., Hay S.I., Cibulskis R.E., Gething P.W. (2015) The effect of malaria control on Plasmodium
falciparum in Africa between 2000 and 2015. Nature;526:207–211.
2.
O’Meara W.P., Mangeni J.N., Steketee R., Greenwood B.M. (2010) Changes in the burden of
malaria in sub–Saharan Africa. Lancet;10:545–555.
3.
4.
Teklehaimanot A., Mejia P. (2008) Malaria and poverty. Ann N Y Acad Sci;1136:32–37.
Greenwood B.M., Fidock D.A., Kyle D.E., Kappe S.H.I., Alonso P.L., Collins F.H., Duffy P.E.
(2008) Malaria: progress, perils, and prospects for eradication. J Clin Invest;118:1266–1276.
5.
6.
7.
Barat L.M. (2006) Four malaria success stories: how malaria burden was successfully reduced
in Brazil, Eritrea, India, and Vietnam. Am J Trop Med Hyg;74:12–16.
López del Prado, G.R., García C.H., Cea L.M., Espinilla V.F., Moreno M.F.M., Márquez A.D.,
Polo M.J.P., García I.A. (2014) Malaria in developing countries. J Infect Dev Countries;8:1–4.
World
Health
Organization.
(2017)
World
Malaria
Report.
Available:
http://www.who.int/malaria/publications/world–malaria–report–2017/report/en/. Accessed
03 May 2018.
8.
9.
Enserink, M. (2007) Malaria treatment: ACT two. Science;318:560–563.
Mutabingwa T.K. (2005) Artemisinin–based combination therapies (ACTs): best hope for
malaria treatment but inaccessible to the needy! Acta Trop;95:305–315.
10.
11.
Nosten F., White N.J. (2007) Artemisinin–Based Combination Treatment of Falciparum
Malaria. Am J Trop Med Hyg;77:181–192.
Visser B.J., Wieten R.W., Kroon D., Nagel I.M., Bélard S., van Vugt M., Grobusch M.P. (2014)
Efficacy and safety of artemisinin combination therapy (ACT) for non–falciparum malaria: a
systematic review. Malar J;13:1–18.
12.
13.
14.
15.
Burrows J.N., van Huijsduijnen R.H., Möhrle J.J., Oeuvray C., Wells T.N.C. (2013) Designing the
next generation of medicines for malaria control and eradication. Malar J;12:187–207.
Ashley E.A., et al. (2014) Spread of artemisinin resistance in Plasmodium falciparum malaria.
New Engl J Med;371:411–423.
Spitzmüller A., Mestres J. (2013) Prediction of the P. falciparum target space relevant to
malaria drug discovery. PLoS Comput Biol;9:e1003257.
Gradmann C. (2008) Book Review: The first miracle drugs: how the sulfa drugs transformed
medicine. Med Hist;52:416–417.
This article is protected by copyright. All rights reserved.

16.
17.
18.
19.
Bentley R. (2009) Different roads to discovery; Prontosil (hence sulfa drugs) and penicillin
(hence –lactams). J Ind Microbiol Biotechnol;36:775–786.
Kalaitzakis E., Björnsson E. (2007) A review of esomeprazole in the treatment of
gastroesophageal reflux disease (GERD). Ther Clin Risk Manag;3:653–663.
Sheu J.S., Divito S.J., Enamandram M., Merola J.F. (2016) Dapsone therapy for pustular
psoriasis: Case series and review of the literature. Dermatology;232:97–101.
Sirvent J.A., Lücking U. (2017) Novel pieces for the emerging picture of sulfoximines in drug
discovery: Synthesis and evaluation of sulfoximine analogues of marketed drugs and
advanced clinical candidates. ChemMedChem;12:487–501.
20.
a) Sehgelmeble F., Janson J., Ray C., Rosqvist S., Gustavsson S., Nilsson L., Minidis A., Holenz
J., Rottocci D., Lundkvist J., Arvidsson P.I. (2012) Sulfonimidamides as sulfonamides
bioisosteres: rational evaluation through synthetic, in vitro, and in vivo studies with g-
secretase inhibitors. ChemMedChem;7:396–399. b) Goldberg F.W., Kettle J.G., Xiong J., Lin D.
(2014) General synthetic strategies towards N-Alkyl sulfoximine building blocks for medicinal
chemistry and the use of dimethylsulfoximine as a versatile precursor. Tetrahedron;70:6613–
6622. c) Frings M., Bolm C., Blum A., Gnamm C. (2017) Sulfoximines from a medicinal
chemist's perspective: Physicochemical and in vitro parameters relevant for drug discovery.
Eur J Med Chem;126:225–245.
21.
a) Johnson C. R. (1985) Applications of Sulfoximines in Synthesis. Aldrichimica Acta.;18;3. b)
Reggelin M, Zur C.(2000) Sulfoximines: Structures, Properties and Synthetic Applications.
Synthesis;1:1-64. c) Branca J.C., Vanier N.R., Bordwell F.G., Johnson C.R. (1980) Acidities of
Sulfoximines and Related Oxosulfonium Cations. Cyclopropyl Effects and Structures of α-
Sulfonyl-Type Carbanions. J Org Chem;45:3884-3889. d) Lücking U. (2013) Sulfoximines: A
neglected opportunity in medicinal chemistry. Angew Chem Int Ed;52:9399–9408.
22. Dolle R.E., McNair D. (1993) Antiviral. Tetrahedron Lett;34:133.
23.
24.
25.
Horspool K.R., Stevens M.F.G., Newton C.G., Lunt E., Walsh R.J.A., Pedgrift B.L., Baig G.U.,
Lavelle F., Fizames C. Anti-tumor. (1990) J Med Chem;33:1393.
Jackson T.E. (1997) U.S patent, US4031227. (Sandoz-Wander, Inc., USA).
https://patents.google.com/patent/US4031227A/en. Accessed March 23, 2018.
Kinfe H.H., Moshapo P.T., Makolo F.L., Gammon D.W., Ehlers M., Schmuck C. (2014)
Preparation and antimalarial activity of a novel class of carbohydrate–derived, fused
thiochromans. Eur J Med Chem;87:197–202.
26.
27.
Madumo G.K., Moshapo P.T., Kinfe H.H. (2018) Effects of lipophilicity, protecting group and
stereochemistry on the antimalarial activity of carbohydrate–derived thiochromans. Med
Chem Res;27:817–833.
Perrin D.D., Armarego L.F. (1988) Purification of Laboratory Chemicals. 3rd ed. Oxford:
Pergamon Press.
This article is protected by copyright. All rights reserved.

28.
29.
30.
31.
Kinfe H.H., Makolo F.L., Moshapo P.T., Phasha Z.H. (2013) New carbohydrate–derived S,S–
dioxothiochroman derivatives and their unexpected easy epimerization at the anomeric
position. J Carbohydr Chem;32:193–204.
Makler M.T., Ries J.M., Williams J.A., Bancroft J.E., Piper R.C., Gibbins B.L., Hinrichs A.D.
(1993) Parasite lactate dehydrogenase as an assay for Plasmodium falciparum drug
sensitivity. Am J Trop Med Hyg;48:739–741.
Zenzola M., Doran R., Degennaro L., Luisi R., Bull J.A. (2016) Transfer of electrophilic NH using
convenient sources of ammonia: Direct synthesis of NH sulfoximines from sulfoxides. Angew
Chem Int Ed;55:7203–7207.
Tota A., Zenzola M., Chawner S.J., St John–Campbell S., Carlucci C., Romanazzi G., Degennaro
L., Bull J.A., Luisi R. (2017) Synthesis of NH–sulfoximines from sulfides by chemoselective
one–pot N– and O–transfers. Chem Commun;348:348–351.
32.
33.
Kinfe H.H., Moshapo P.T., Makolo F.L., Muller A. (2013) Facile diastereoselective synthesis of
carbohydrate–based thiochromans. J Carbohydr Chem;32:139–157.
The crystallographic data is deposited at the Cambridge Crystallographic Data Centre and the
CCDC # of 6b is 1841754. Copies of this information may be obtained free of charge from the
Director, CCDC. 12 Union Road, Cambridge, CB2 1EZ, UK (fax +44 1223 336063;
deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk
34.
35.
36.
37.
Leusser D., Henn J., Kocher N., Engels B., Stalke D. (2004) S=N versus S+–N–: An experimental
and theoretical charge density study. J Am Chem Soc;126:1781–1793.
Tang T.H., Bader R.F.W., MacDougall, P.J. (1985) Structure and bonding in sulfur–nitrogen
compounds. Inorg Chem;24:2047–2053.
Yu B., Reynisson J. (2011) Bond stability of the “undesirable” heteroatom–heteroatom
molecular moieties for high–throughput screening libraries. Eur J Med Chem;46:5833–5837.
World Health Organization. (2015) Guidelines For Treatment of Severe Malaria. third
edition.71-88. ISBN 978 92 4 154912 7.
38. Yamada Y, Yamamoto T, Okawara M.(1975) Synthesis And Reaction Of New Type I–N Ylide, N–
Tosyliminoiodinane. Chem Lett;4:361–362.
39.
40.
41.
42.
Gillespie K. (2001) N–tosyliminobenzyliodinane – PhINTs from Iodobenzene diacetate. Chem
Spider Synth Pages. http://cssp.chemspider.com/123: Accessed March 24, 2018.
Muller J.F.K., Vogt P. (1998) Copper catalysed sulfoximination. Tetrahedron Lett;39:4805–
4806.
Zhu H., Yu J.T., Cheng J. (2016) Copper–catalyzed N–thioetherification of sulfoximines using
disulfides. Chem Commun;52:11908–11911.
The difference between the current and our previously reported Ref 11 and 12 could be as a
result of the set up used for the bioassay study. The previous study was conducted at Council
This article is protected by copyright. All rights reserved.

for Scientific and Industrial Research (CSIR) but the current bioassay study was condcucted at
Rhodes University.
43.
Meriläinen G., Schmitz W., Wierenga R.K., Kursula P. (2008) The sulfur atoms of the substrate
CoA and the catalytic cysteine are required for a productive mode of substrate binding in
bacterial biosynthetic thiolase, a thioester–dependent enzyme. FEBS J;275:6136–6148.
This article is protected by copyright. All rights reserved.

Table 1. Antiplasmodial and cytotoxicity assay of sulfone 5 and the sulfoximine derivatives.a
Compound at 20 μM
Parasite % viability
IC50 value
μM
HeLa cell %
viability
5
6a
6b
10
11a
11c
11d
11e
11f
11g
11h
11i
3.7 ± 0.2
89.4 ± 11.1
8.0 ± 1.7
59.6 ± 2.0
6.5 ± 3.6
9.4 ± 0.0
1.0 ± 0.6
N/A
0.8 ± 0.3
N/A
0.9 ± 0.4
2.8 ± 0.6
17.0 ± 11.0
3.0 ± 1.1
N/A
4.6 ± 0.7
7.3 ± 3.5
0.9 ± 1.0
2.8
3.1 ± 1.7
1.7 ± 1.4
NA
6.4 ± 0.6
2.6 ± 0.5
3.3 ± 1.1
20.0 ± 5.9
16.7 ± 3.8
N/A
100.9 ± 3.2
89.4 ± 11.1
80.5 ± 0.8
98.3 ± 8.8
62.6 ± 5.0
98.3 ± 2.7
91.0 ± 0.7
98.2 ± 5.5
83.6 ± 7.0
103.3 ± 8.8
101.7 ± 1.7
52.5 ± 1.5
96.3 ± 25.0
111.8 ± 4.5
111.8 ± 4.5
111.5 ± 8.9
99.3 ± 26.2
101.5 ± 8.4
65.3 ± 2.2
55.1 ± 1.5
66.2 ± 5.4
98.0 ± 4.8
53.9 ± 0.1
108.5 ± 13.0
83.3 ± 11.6
71.1 ± 1.6
116.8 ± 0.4
105.9 ± 5.7
N/A
8.1 ± 2.7
11.9 ± 5.3
107.3 ± 0.7
11.3 ± 0.8
14.4 ± 0.6
6.9 ± 1.9
10.9 ± 0.7
13.9 ± 8.1
22.6 ± 8.1
64.5 ± 12.6
36.0 ± 6.3
15.1 ± 1.2
8.4 ± 4.1
32.4 ± 0.4
46.4 ± 0.9
37.9 ± 0.6
58.3 ± 11.6
103.4 ± 4.2
72.8 ± 3.5
111.7 ± 4.8
80.4 ± 1.6
112.6 ± 0.4
N/A
12
13
14a
14b
15b
16a
16b
17a
17b
18a
18b
18c
18d
18e
18f
N/A
N/A
N/A
N/A
N/A
N/A
0.019 µM
18g
Chloroquine
a Compounds were incubated with P. falciparum (3D7) parasites and HeLa cells at 20 µM for 48 h.
Following the incubation, percentage parasite and HeLa cell viability was calculated relative to
untreated control samples. IC50 values against P. falciparum are also shown.
This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.