Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

Antimalarial Fluoroartemisinins: Increased Metabolic and Chemical Stability 155

AIBN. The ease of the allylic bromination of 18 has been attributed to the presence of the

endoperoxide, which can initiate the radical reaction [44] . Similar results were obtained

with Br

2

without initiator, whereas Br

2

reacts with glycal 10 through an electrophilic addi-

tion on the double bond [44, 67] .

6.3.3.2 Reactions of the Allyl Bromide 22 with Nucleophiles

Triﬂ uoromethyl allyl bromide 22 reacted selectively with amines and alcoholates, leading

to 16 - substituted compounds 23 (S

N

2 - type products), with no trace of the allylic rearrange-

ment product (see Scheme 6.13 and Table 6.5 ) [57] . However, conditions were also found

to provide predominantly the allylic rearrangement [71] . Excellent yields in 23 were

obtained with secondary amines. With primary amines, polyalkylation could be avoided

by using dilute conditions. Since reductive conditions to convert an azide into a primary

amine are not compatible with the endoperoxide bridge [72] , the primary amine at C - 16

was prepared using NH

3

as nucleophile, in a very large excess to avoid polyalkylation.

Sodium alkoxides, generated in situ with sodium hydride, also reacted well to generate

corresponding ethers in good yield, but addition of a catalytic amount of KI was required

(see Table 6.6 ). Dimethyl sodium malonate reacted with bromide 22 , leading to the diester

23q in excellent yield (90%). A large series of new compounds 23a – r were obtained.

6.3.3.3 Biological Activity of Products 23

Most of the 16 - functionalized ﬂ uoroartemisinins exhibited strong antimalarial activity

in vitro (see Table 6.7 ) and in vivo (see Table 6.8 ) [46, 57] . Only the diester 23q and the

diacid 23r were found to be inactive against Plasmodium falciparum . The more promising

O

H

Br

CF

3

O

H

CF

3

18

NBS, AIBN, CCl

4

, reflux (72 %)

NBS, CCl

4

, reflux (90 %)

Br

2

, CH

2

Cl

2

, 1 h, 0°C (70 %)

22

Scheme 6.12 Allylic bromination reactions of glycal 18 .

Br

O

CF

3

Nu

O

CF

3

22

23

Nu = Amines, alcoholates, malonate, etc...

Nu

Scheme 6.13 Reactions of bromide 22 with N - , O - , and C - nucleophiles.

156 Fluorine in Medicinal Chemistry and Chemical Biology

Table 6.5 Reactions of bromide 22 with N - nucleophiles

N - Nucleophile

a

Equiv. Time (h) 23 Yield

Morpholine 4 6 a 90%

Piperazine ethanol 4 6 b 87%

EtNH

2

10 4 c 85%

MeNH

2

10 3 d 98%

NH

2

CH

2

CH

2

NH

2

10 3 e 95%

NaN

3

b

1.5 1 f 95%

NH

3

c

4 g 77%

a

Reactions performed in THF.

b

Reaction performed in DMSO.

c

Large excess of NH

3

in a mixture NH

3

/THF 1 : 1.

Table 6.6 Reactions of bromide 22 with O - and C - nucleophiles

Nucleophile

a

Equiv. NaH (equiv.) Solvent Time (h) 23

Yield

b

EtOH 20 3 THF 18 h 98%

BnOH 1.5 3 THF 18 i 97%

MeOCH

2

CH

2

OH 3 2 DMSO 1 j 96%

CH

2

=CH - CH

2

OH 3 2.5 DMSO 2 k 81%

HOCH

2

CH

2

OH 4 1.5 DMSO 2 l 69%

CH

2

(COOMe)

2

1.5 1.8 THF 5 q 90%

a

In presence of KI (0.1 equiv.).

b

Isolated yield.

Table 6.7 In vitro activities of compounds 23 and artemether on the chloroquine - resistant

Plasmodium falciparum F c B 1 and W 2 clones and calculated log P values ( C log P )

Nu

IC

50

(nM)

a

Clog P

b

Artemether

3.5 ± 1.2

c

2.92

23a – Morpholino –

3.1 ± 0.5

c

3.89

23b – Piperazinoethanol

15.2 ± 6.7

d

2.43

23c – NHEt

13.4 ± 4.5

d

3.40

23d – NHMe

9.2 ± 2.4

c

2.87

23e – NHCH

2

CH

2

NH

2

1.2 ± 0.7

c

2.50

23f – N

3

10.0 ± 7.6

c

4.97

23g – NH

2

4.4 ± 0.4

c

3.13

23h – NHSO

2

CH

3

20.0 ± 6.3

c

3.07

23i – NHSO

2

C

6

H

4

CH

3

19.1 ± 3.5

c

5.25

23h – OEt

25.0 ± 7

d

3.73

23i – OBn

20 ± 5

d

5.72

23j – OCH

2

CH

2

OMe

2.7 ± 0.4

c

3.26

23k – OCH

2

CH = CH

2

6.0 ± 1.7

c

4.43

23l – OCH

2

CH

2

OH

2.4 ± 0.4

c

3.09

23m – OCOCH

3

1.7 ± 0.5

c

3.97

23n – OH

7.5 ± 0.8

c

3.05

23p – OCH

2

CHOHCH

2

OH

3.7 ± 0.5

c

2.27

23q – CH(COOMe)

2

> 1000

d

3.79

23r – CH(COOH)

2

> 1000

d

3.00

a

Mean ± standard deviation was calculated for n = 3 experiments.

b

Log P values were calculated using the program available from http://www.daylight.com/cgihyphen;bin/contrib/

pcmodels.cgi .

c

FcB1 and

d

W2 clones.

Antimalarial Fluoroartemisinins: Increased Metabolic and Chemical Stability 157

Table 6.8 In vivo data for amines 23a – c , ether 23h and N a artesunate ( P. berghei N .)

subcutaneous (s.c.) and oral (p.o.) administration

Route ED

50

(mg/kg) ED

90

(mg/kg) Reduction of parasitemia

at D - 4 at 10 mg/kg (%)

Na artesunate s.c. 2.8 10.5 90

Na artesunate p.o. 5.4 15.3 –

23a s.c.

< 10 < 10

98.1

23a p.o.

< 10 < 10

93.3

23b s.c.

< 10 < 10

100

23b p.o.

< 10 < 10

100

23c s.c.

< 10 < 10

98.1

23c p.o.

< 10 < 10

96

23h s.c.

< 10 < 10

100

23h p.o.

> 10

nd 15.6

candidates for oral treatment are the amines 23a – c , which are more active than sodium

artesunate, as shown by ED

50

and ED

90

values (see Table 6.8 ).

Pharmacokinetic studies performed on compound 23b exhibited a signiﬁ cantly better

bioavailability in rats than artemether (see Tables 6.9 and 6.10 ) [56] . C

max

and T

max

values

Table 6.9 Log P / D values and equilibrium solubilities of 23b and artemether, after

incubation at 25 ° C for 72 h

Artemether 23b

Log P

3.36 3.52

Log D (pH 7.4)

– 3.46

p K

a

– 6.59

Solubility

I.v. formulation ( µ g/mL)

a

> 3000 > 3000

Oral formulation ( µ g/mL)

b

256 675.9

PBS (pH 7.4) ( µ g/mL)

63.4 234.5

a

I.v. formulation is 0.1 M Captisol ™ in water for artemether and 10% ethanol – 0.1 M Captisol ™ , pH 3 for 23b .

b

Oral formulation contains 0.5% w/v carboxymethyl cellulose, 0.5% v/v benzyl alcohol, 0.4% v/v Tween 80 in 0.9%

w/v NaCl for artemether, and 0.5% w/v hydroxypropylmethyl cellulose, 0.5% v/v benzyl alcohol, 0.4% v/v Tween

80 in 0.9% w/v NaCl for 23b .

Table 6.10 Pharmacokinetic data for artemether and 23b

Artemether

a

23b

C

max

(ng/mL)

168.4 ± 50.2

607.9

t

max

(min)

20.4 ± 7.6

60

t

1/2

(min)

b

52.2 ± 5.8

55.3

Plasma clearance ([mL/min]/kg)

114.1 ± 20.6

148.7

Volume of distribution (L/kg)

b

8.4 ± 1.7

11.8

Oral bioavailability (%)

1.4 ± 0.6

34.6

a

Artemether pharmacokinetic parameters from previous studies [57] .

b

After 10 mg/kg (i.v. administration).

158 Fluorine in Medicinal Chemistry and Chemical Biology

for 23b , determined from the oral dosing studies, were 607.9 ng/mL and 60 min, respec-

tively, compared with 168.4 ± 50.2 ng/mL and 20.4 ± 7.6 min, respectively, for artemether.

At a 50 mg/kg oral dose, oral bioavailability was 34.6%, a signiﬁ cant improvement over

the 1.4% observed for artemether. However, the piperazine ethanol derivative 23b exhib-

ited a faster metabolic clearance than the hemiketal 12 . Current experiments are in progress

to exploit this new series by optimization of the polar substituent at C - 16.

6.4 Conclusion

With the increasing resistance of Plasmodium falciparum toward most available antima-

larial drugs, artemisinin derivatives constitute the greatest hope in the ﬁ ght against malaria.

First - generation artemisinin derivatives feature in all ﬁ xed combination therapies clinically

available. Drawbacks stemming from their instability and short plasma half - life prompted

medicinal chemists to design and prepare more efﬁ cacious derivatives while retaining

the 1,2,4 - trioxane pharmacophore. With this aim, the concept of “ ﬂ uorine substitution ”

appeared to be useful to obtain an improved pharmacological proﬁ le. By taking into

account the main sites of oxidative and hydrolytic degradation, various series of ﬂ uorinated

derivatives of artemisinin have been designed, synthesized, and evaluated against

Plasmodium .

The uncommon structural artemisinin framework, and the well - known difﬁ culty in

selectively introducing a ﬂ uorinated motif into a molecule, faced us with numerous chemi-

cal challenges. The evaluation of the effects of ﬂ uorine on physicochemical and antima-

larial properties is reported. These data and preclinical data of lead compounds are

encouraging, with strong and prolonged antimalarial activity of ﬂ uoro - artemisinins.

Acknowledgments

We thank Benoit Crousse, Ahmed Abouabdellah, Truong Thi Thanh Nga, Fabienne Grel-

lepois, Fatima Chorki, Guillaume Magueur, and Constance Chollet for their contributions

and Mich è le Our é vitch for NMR experiments. The authors are also grateful to Jean -

Charles Gantier, Florence Chr é tien, E. Dumarquez (Parasitology, Ch â tenay - Malabry),

Bruno Pradines, V é ronique Sinou, Daniel Parzy (Institut de M é decine Tropicale, SSA, Le

Pharo, France), Philippe Grellier, S é bastien Charneau, (Museum, Paris, France), Kylie A.

McIntosh, William N. Charman (Monash University, Australia), Vu Dinh Hoang, G. Diem

Pham, Nguyen Van Hung, (Institute of Chemistry, VAST, Hanoi, Vietnam), Le Dinh Cong,

T. N. Hai, P. D. Binh, Truong Van Nhu, Doan Hanh Nhan (NIMPE, Hanoi, Vietnam) and

Dr. Marie - Annick Mouries, (WHO DDR/TDR). Work at BIOCIS on ﬂ uoroartemisinins

was funded by CNRS, University Paris - South, PAL+ program from Research and Technol-

ogy French Ministery, the D é l é gation G é n é rale de l ′ Armement and the GDR Parasitology

(CNRS).

Antimalarial Fluoroartemisinins: Increased Metabolic and Chemical Stability 159

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7

Synthesis and Biological Activity of

Fluorinated Nucleosides

Tokumi Maruyama , Masahiro Ikejiri , Kunisuke Izawa , and Tomoyuki Onishi

7.1 Introduction

There are several reasons for introduction of ﬂ uorine atom(s) into drug - candidate com-

pounds. Most of these involve the unique properties of the ﬂ uoro group, such as the simi-

larity of its Van der Waals radius to that of hydrogen, its high electronegativity, and the

stability of the C – F bond. The small size of the ﬂ uoro group makes it possible to replace

almost any C – H bond in organic compounds with a corresponding C – F bond. For instance,

ﬂ uorinated nucleosides bearing C – F bonds in their sugar moiety would not cause signiﬁ -

cant steric hindrance while penetrating into a pocket of their target enzymes. The ﬂ uoro

group is the most electronegative of all elements and has one of the highest ionization

potentials. Therefore, the ﬂ uorine substituent in the sugar moiety brings about a strong

electron - withdrawing effect on C – F bonds, which induces intramolecular electrostatic

interactions that can change the conformation of the molecule. Since the C – F bond is

stronger than the corresponding C – H bond, the C – F bond distance becomes short enough

to protect its carbon center from various nucleophilic attacks. Moreover, the carbon center

of the C – F bond resists oxidation due to the strong electronegative nature of ﬂ uorine. Thus,

the ﬂ uorine substituent makes organic compounds chemically more stable. Because

ﬂ uorinated compounds often exhibit potent biological activities, they are attracting

considerable attention in the pharmaceutical ﬁ eld. In addition, the unique properties of the

ﬂ uoro group also contribute to improving pharmacokinetic properties, such as ADME

(absorption, distribution, metabolism, and excretion), and reducing undesired effects.

Fluorine in Medicinal Chemistry and Chemical Biology Edited by Iwao Ojima

Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

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