Synthesis and antiplasmodial activity of purine-based C-nucleoside analogues

Article abstract of DOI:10.1039/c8md00098k

A series of homologous C-nucleoside mimics have been synthesized via an efficient and facile synthetic protocol involving the conjugate addition of purine to sugar derived olefinic ester in good yields. The synthesized compounds were evaluated for their a

Full text of DOI:10.1039/c8md00098k

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R. Mahar, P. Baranwal, S. K. Shukla, R. Tripathi and R. P. Tripathi, Med. Chem. Commun., 2018, DOI:
10.1039/C8MD00098K.
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DOI: 10.1039/C8MD00098K
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ARTICLE
Synthesis and Antiplasmodial Activity of Purine Based C-
Nucleoside Analogues
Received 00th January 20xx,
Accepted 00th January 20xx
Kartikey Singha,#, Prince Joshib,#, Rohit Maharc, Pragati Baranwala, Sanjeev Shuklac, Renu
Tripathib,*, Rama Pati Tripathia,d,
*
DOI: 10.1039/x0xx00000x
A series of homologous C-nucleoside mimics have been synthesized via an efficient and facile synthetic protocol involving
the conjugate addition of purine to sugar derived olefinic ester in good yields. The synthesized compounds were evaluated
for their antiplasmodial activity in vitro against both the CQ sensitive and resistant strains of P. falciparum. Interestingly all
the synthesized nucleoside analogs exhibited IC50 of < 5 µM, while compounds 22a, 23a, and 23b showed promising
antiplasmodial activity with IC50 of 1.61, 0.88, 1.01 μM against CQ sensitive Pf3D7 strain and 1.14, 1.01, 2.57 μM against
CQ resistant PfK1 strain, respectively.
www.rsc.org/
Plasmodium parasites are purine auxotroph as they are unable
to perform de novo purine biosynthesis.7 The parasite depends
upon the salvage of purine from the host for its survival and
1. Introduction
Malaria, an infectious disease caused by the protozoan
parasite Plasmodium falciparum (P. falciparum), P. ovale, P.
vivax and P. malariae is transmitted by the bite of the
Anopheles mosquito. P. falciparum is mainly responsible for
the most severe form of human malaria and millions of death
globally. As per World Health Organization reports malaria
affected about 216 million people in 2016, resulting 445,000
deaths and mostly in infants.1 Resistance to chloroquine and
other conventionally used antimalarial drugs such as
pyrimethamine/sulfadoxine in P. falciparum is reported in
many endemic areas.2,3 The emergence of resistance to almost
all the quinolones and antifolate drugs in P. falciparum
malaria4, artemisinin, and its derivatives are the mainstay to
treat malaria. The artemisinin combination therapies (ACTs)
act as the frontline treatments against P. falciparum malaria.5
Resistance to artemisinins in several areas (WHO 2015) have
led to the development of novel drugs that could selectively
target P. falciparum urgently needed.6
proliferation.8 Several unique enzymes for the purine
metabolism in parasites hold significant promise as drug
targets. Purine based nucleosides exhibit antiplasmodial
activity by inhibiting these crucial enzymes involved in purine
biosynthesis of parasites.9-13 Purine based acyclic nucleosides
are a potent inhibitor of PfHGXPRT, an enzyme essential for
the synthesis of nucleoside monophosphates.14-16
5'-
Methylthiocoformycin ( ) and its analogs are reported to
1
selectively inhibit P. falciparum adenosine deaminase (PfADA)
N6-diphenylethyl-5’-
to
the
human
(hADA).17
phenylcarboxamidoadenosine (
2
) exhibits activity against CQ
resistant strains (IC50 1.8 µM).18 Methylthio-immucillin-H (MT-
immucillin-H,
nucleoside phosphorylase of P. falciparum (PfPNP).19 A purine
nucleoside MDL73811 ( ) exhibited good antimalarial activity
3) is reported to selectively inhibit purine
4
IC50 of 2–3 μM against P. falciparum strains by inhibiting S-
adenosylmethionine decarboxylase (AdoMetDC) against both
CQ sensitive and CQ resistant strains.20 Another nucleoside
analog (6’R)-6’-C-methylneplanocin A (RMNPA, 5) effectively
inhibits S-Adenosyl-L-homocysteine (AdoHcy) hydrolase having
significant antimalarial activity (IC50 0.10 µM) (Figure 1).21, 22
In view of the above we thought to access few nucleoside
analogs which could inhibit the crucial enzymes of Plasmodium
parasite and exhibit antimalarial activity against both the CQ
sensitive (pf3D7) and resistant (pfK1) strains.
a.Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
Lucknow 226031, India.
b.Parasitology Division, CSIR-Central Drug Research Institute, Lucknow 226031,
India.
c. Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute,
Lucknow 226031, India.
d.Current Address:National Institute of Pharmaceutical Education and Research,
Raebareli 229010, India
#Equal Authors
*Corresponding Authors
*(RPT) Tel: 9415004443, Email: rpt.cdri@gmail.com
*(RT) Tel:09415349883; Email: renu1113@rediffmail.com
Electronic Supplementary Information (ESI) available: [Additional information
includes spectral copies, HPLC chromatogram of compounds, 2D NMR spectral
copies. This material is available free of charge via the Internet at
http://pubs.rsc.org].
See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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of purines to the olefinic ester was regioselective, and in each
reaction, a diastereomeric mixture of two compounds was
formed with only the N-9 attachment of purine ring, and two
diastereomers have S (β-L-ido) and R (α-D-gluco) configuration
at C-5′ in the sugar units (Scheme 1). The formation of
diastereomers was evident from TLC and NMR spectral data.
The diastereomers were isolated from the column
chromatography, and structures were confirmed by the
various 1D (1H, 13C), 2D (COSY, NOESY, HSQC, and HMBC) NMR
experiments and ESI-MS analysis. 2D-NMR spectroscopy’s
revealed the structures of 20a and 20b and configuration at C-
5′ of sugar unit. HMBC correlation of CH2-7′′ to C-3′ revealed
the connectivity of benzyl moiety to sugar ring. H-5′ showed
HMBC correlations with C-4 and C-8. H-8 showed HMBC
correlation with C-5′. These essential HMBC correlations
confirmed the N-9 connectivity of adenine moiety to the sugar
unit. HMBC correlations of the 20a and 20b were similar and
were suggested that the adenine moiety was attached to the
sugar moiety through N-9 in both the compounds. Few nOe
correlations of the above compounds were found different. In
compound 20b nOe correlations of H-5′ to H-3′ established
that the adenine moiety is above the plane, i.e. α-D-gluco (R)
configuration at C-5′ in sugar units, whereas these nOe
correlations is absent in compound 20a and indicated that the
adenine moiety in compound 20a is in below the plane at C-5′
having β-L-ido (S) configuration (Fig. 2).
Fig. 1 Purine nucleoside-based antimalarial nucleosides and general structure of
synthesized nucleoside analog
2. Result and discussion
2.1. Chemistry
The synthesis of compounds was accomplished starting from
1′,2′:5′,6′-di-O-isopropylidene-α-D-glucofuranose 723 easily
prepared from D-glucose. The latter was transformed to 3-O-
benzyl
and
3-O-(2-nitrophenyl)
glycofuranosylenoate
derivatives 15 and 16 in good yields (>95%) by earlier reported
methods of Horner-Wadsworth-Emmons olefination of the
respective aldoses (13 and 14) with triethylphosphonate
(
Scheme 1).23
The glycofuranosylenoate (15 and 16) on DBU catalyzed
conjugate addition of purine derivatives (17-19) in ethanol
gave the diastereoisomeric mixture of respective
glycoconjugates of purines (20a-23a
& 20b-23b). The addition
Scheme 1 Synthesis of glycosyl esters (15, 16) and purine-based C-nucleoside analogues (20a-23a
TBAB (20 mol%), THF, 0 C- 25 C 12 h, 90-95%; (b) 70% AcOH aq., 25 C, 8h, 98%; (c) NaIO4 aq.(1 equiv.), MeOH, 0
equiv.), THF, 25 C, 8h, 92-94%; (e) DBU (10 mol %), MeOH or EtOH, reflux, 16-18 h; (f) LiAlH4 (1 equiv.), anh. THF, N2 atm., 0
&
20b-23b) and (24-29). Reagent and conditions: (a) NaH (1 equiv.),
C- 25 C, 3 h 90-92%; (d) TEPA (1equiv.), LiOH (1
C- 25 C, 3 h 88-94%.
̊
̊
̊
̊
̊
̊
̊
̊
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Scheme 2 Synthesis of Amino Ester (30) and Amino Acid (31) based C-Nucleoside
analogues. Reagent conditions: (a) Pd-C (10 mol%), H2 atm., 2h, 98%; (b) Et3N (3
equiv.), 50% EtOH aq., 36h, 88%.
Fig. 2 Important NOESY and HMBC correlation of 20a and 20b
.
The reduction of the above ethanoates/methanoates 20a-23a
20b-23b with LiAlH4 led to the formation of respective
alcohol analogs (20-29) in excellent yields (Scheme 1).
For SAR activity we have also synthesized
&
a
3-O-(2-
aminophenyl) enoate derivative (30) by Pd/C reduction of the
nitro group in nitrophenyl ring of 21a. The ester group in
compound 30 was hydrolyzed to respective acid derivative (31
)
by Et3N in THF in good yield (Scheme 2).
In order to explore the role of sugar unit and to check the
activity of arylated purines, N-9 arylated adenine derivative
24
Scheme 3 Synthesis of N-9-phenyl and alkyl-purine derivatives. Reagent and
conditions: (a) K2CO3 (2.5 equiv.), DMSO, 140 ̊C, 36h, 62%; (b) NaBH4 (1 equiv.),
MeOH, 25 ̊C, 2h, 99%; (c) EtONa (1 equiv.), EtOH, reflux, 3h, 98%.
(
33)
were also synthesized by reaction of adenine (17) with
4-fluoroacetophenone (32) via SNAr reaction in DMSO in the
presence of K2CO3 at 140 C. The reduction of the ketone to
respective alcohol 34 was carried out using NaBH4.
̊
(
)
Carboxyethyloxy propyl derivative (36) was synthesized by the
Michael addition of adenine (17) to the ethylacrylate (35) in
refluxing ethanol in the presence of NaOEt (Scheme 3).25
2.2. Biology
In vitro antiplasmodial activity
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Table 1. In vitro antiplasmodial activity and cytotoxicity of final compounds.
IC50 (µM)a,b
Pf3D7
SI (µM)e
RI
CC50
(µM)d
Comp.
Structure
(µM)c
PfK1
Pf3D7
PfK1
H2
N
O
N
N
N
N
O
O
O
O
20a
4.44±0.31
4.12±0.22
3.56±0.43
4.24±0.06
4.79±0.25
1.07
0.99
1.38
1.00
68.43
86.31
96.31
118.99
15.41
14.28
O
H2N
N
N
N
O
N
O
O
O
20b
21a
21b
4.09±0.03
4.93±0.15
4.25±0.005
20.94
27.05
28.06
21.10
19.53
27.99
O
O
H2N
N
N
N
N
O
O
O
O
O
O
O2N
22a
1.61±0.09
1.14±0.14
0.70
57.49
35.70
50.42
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22b
3.60±0.01
2.27±0.17
0.63
53.27
14.79
23.46
23a
0.88±0.01
1.13±0.02
1.28
81.46
92.56
72.08
23b
1.01±0.25
2.57±0.86
2.54
44.95
44.50
17.49
24
4.31±0.12
4.99±0.2
1.15
97.14
22.53
19.46
25
3.62±0.37
4.70±0.19
1.11
148.07
37.11
33.34
HN
N
N
N
N
26
3.99±0.03
4.44±0.21
0.75
61.24
19.56
25.83
O
O
HO
O
O
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27
4.52±0.16
3.13±0.10
4.11±0.04
4.09±0.05
2.37±0.46
4.99±0.35
1.29
148.07
51.80
74.87
40.90
11.46
18.21
31.50
12.66
15.00
28
0.90
HN
N
N
N
29
1.21
N
O
O
HO
O
O
30
4.47±0.09
>5
>1.11
89.68
20.06
17.93
31
4.82±0.75
3.72
67.07
13.91
18.02
33
>5
ND
ND
NA
NA
34
>5
ND
ND
NA
NA
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36
>5
ND
ND
NA
NA
Chloroquine
0.0049±0.0001
0.83±0.01
169.3
a50% Inhibitory concentration against chloroquine sensitive (3D7) and resistant (K1) strains of P. falciparum. bvalues are represented as average of at least duplicate
determinations cResistance index(RI) = IC50 K1/IC50 3D7. d50% Cytotoxic concentrations, the monkey kidney cell line (VERO) was obtained from the tissue culture lab,
f
CDRI. eSelectivity index (SI) = CC50/IC50. ND = Not done. NA = Not applicable. We had used human RBCs and were obtained from blood bank under the approval
CDRI/IEC/2017/A4 (The CDRI Human Ethics Committee clearance number for the P. falciparum culture in human RBCs).
All of the above-synthesized compounds (20a-23a
,
20b-23b
,
potent drug should have a little value of RI. Delightfully, the
24-29, and 30-36) were evaluated for their in vitro majority of the synthesized nucleoside analogs have RI values
antiplasmodial activity against CQ sensitive (3D7), and CQ <1.5, whereas RI of reference drug, chloroquine was found to
resistant (K1) strains of P. falciparum with chloroquine as a be 169.3 (Table 1).
reference drug (Table 1)
The nucleoside analogs having 3-O-benzyl (20a and 20b) or 3-
3. Conclusion
O-(2-nitrophenyl) (21a and 21b) substituent’s have shown
In summary, purine-based derivatives, C-nucleoside analogs
activity (IC50 = <5 µM) against both the strains. 6-Amino N-
were synthesized and evaluated for their in vitro
alkylated purine nucleoside analogs 22a (IC50 1.61 µM and 1.14
antiplasmodial activity against chloroquine sensitive and
µM) and 23a (IC50 0.88 µM and 1.13 µM) displayed
resistant strains of P. falciparum. All of the nucleoside analogs
antiplasmodial activity only at the lower concentration with
exhibited IC50 of < 5 µM; however, the nonglycosylated purines
the IC50 <2 µM against both CQ sensitive and resistant strains.
did not show any significant activity against either of the
Compounds 22a (IC50 1.61 µM & 1.14 µM) and 23a (IC50 0.88
sensitive or resistant strains. Among these, three nucleoside
µM & 1.13 µM) with β-L-ido (S) configuration showed better in
analogs exhibited IC50 of < 2 µM against either of the strains.
vitro antiplasmodial activity as compared to compound 22b
From the initial SAR study, it has been found that compounds
(IC50 3.60 µM & 2.27 µM) and 23b (IC50 1.01 µM & 2.57 µM)
with β-L-ido (S) configuration (22a
activity than compounds with α-D-gluco (R) configuration (22b
23b), and 6-amino alkylated purine nucleoside ester
analogues (22a 23a, and 23b) exhibited good antiplasmodial
& 23a) showed better
with α-D-gluco (R) configuration against CQ sensitive and
resistant strains respectively. Comparing the antiplasmodial
&
activity of nucleoside analogs (20a-23a
& 20b-23b) with ester
,
and alcohol (24-29) groups, esters showed better activity as
compared to alcohol analogs. However, between the
nucleoside analogs with carboxyl and ester groups, the former
activity having IC50 of 0.88-2.57 µM.
(
31) has IC50 value 4.82 and 3.72 µM while the latter (30)
Conflicts of interest
displayed antiplasmodial activity with IC50 value 4.47 and >5
µM against sensitive and resistant strains respectively. The
adenine derivatives 33 and 34 with aryl group rather than
sugar as N-9 substituent did not display any significant activity
(IC50 >5 µM) indicating the importance of sugar unit in
antiplasmodial response. Adenine derivative 36 with N-9
propanoate substituent also did not display any significant
activity against either of the strains in vitro (IC50 > 5 µM). All
the sixteen nucleoside analogs having IC50 of <5 µM against
either of the strains, were further evaluated for their
cytotoxicity against VERO cell line and their CC50 and selectivity
The authors declare no competing interest.
Acknowledgements
K.S and R.M. are thankful to UGC and PJ to DBT New Delhi for
fellowships. Financial assistance from Indo-France project
(CEFIPRA-5303-2) is also greatly acknowledged. We sincerely
thank SAIF division, CSIR-CDRI for the analytical facilities.
index (SI) against both Pf strains are reported in table 1. Notes and references:
Results showed that all these compounds have no discernible
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2
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&
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Graphical Abstract