フェブリフジンをリードとする薬理活性新規キナゾリン型アルカロイドの網羅的探索

フェブリフジンをリードとする薬理活性新規キナゾ

リン型アルカロイドの網羅的探索

著者

大島 吉輝

n LZ il 工 ∴･ †∴ .LlH卜ー

∵∴∵ 二㌧

っー･JI･･, u IH･･‖h 日..ー小1-･

7HjJ.)

毎払V柵JJ-戟

瀧=:葦迂遠

･1-､1-_1.-㌧･. `･･ノ･∵ ･lr :-T JJ･ /･1 1 卜iFiJe E:/:･ .T . j.-t i･1㌧一､ - --1-･-･ 1=-一1､,lr ∫-∫ ∴㌧■十･1 ･jl+I ･,._. -I-･Jl ････ --･･_ ‥･ 1L l--ト I I -JI･1-､....I:よn折r ､＼J㌦- ･､ト .,･I･.卜､ ー一1J 上..;;･バー∵.り .Lpl ど

･･.16390030

_ ･ド･1 rl LIjt/) ･ J.HhH√いじ  ∼7.---. .-･ -:...:･:･･;. ･■.1-I.   ･

挙傭聾紺

.n J･･I I I■-I-･J .(.. ,-iL八  .ll.E.- ･･･1-l･. ･ ▲･一､-.;--･ --′ X,_

料諸鮒軸

∵･.I.I , ノ r･.) . ･  /卜･＼ ->r ヽ ･-｢-･･ _ -i

l･-...I I.).I 1････III J･:･･JJ. I

..■一■∼一 事･･A

h･ 1-淋㌦畢t叫 濁

1. r.  J l-トしか 1 -. 日り′-     p.:=

平成1 6年度∼平成1 7年度科学研究費補助金

(基盤研究(B))研究成果報告書

研 究 課 題

フェブリフジンをリードとする薬理活性新規キナゾリン型アルカロイドの網羅的

探索

研究課題番号

16390030 研 究 組 織

研究代表者:大島 吉輝  (東北大学大学院薬学研究科教授)

研究分担者:菊地 晴久  (東北大学大学院薬学研究科助手)

交付決定額(配分額)       (金額単位:円) 直接経費   間接経費   合  計 平成16年度    7, 000, 000  0   7, 000, 000 平成17年度    5, 800, 000  0   5, 800, 000 総  計   12, 800, 000  0 12, 800, 000

研 究 発 表

1.一般論文

( 1 ) HaruhisaKikuchi, Keisuke Yamamoto, Seiko Horoiwa, Shingo Hirai, Norimitsu Hariguchi, Makoto Matsumoto, and Yoshiteru Oshima

′

Exploration of a New Type of Antimalarial Compounds Based on Febrifugine

J. 川ed. Chem., submitted (2006)

2.学会発表

2004年度

(1)平井真吾､山本圭介､裳岩靖子､播口徳充､松本真､菊地晴久､大島吉輝

抗マラリアアルカロイドfebrifugineを基盤とした新規誘導体の開発

日本薬学会第1 24年会､大阪

2004年3月

(2)菊地晴久､平井真吾､大島吉輝

キナゾリンアルカロイドfebrifugineを基盤とした新規抗マラリア物質の

創製

第2回次世代を担う有機化学シンポジウム､東京

2004年6月

(3)山本圭介､菊地晴久､平井真吾､裳岩靖子､大島吉輝､播口徳充､松本真

抗マラリアアルカロイドfebrifugineの新規誘導体の合成

第4 8回有機合成化学協会関東支部シンポジウム(新潟シンポジウム)､新潟

2004年11月

(4)裳岩靖子､菊地晴久､平井真吾､山本圭介､大島吉輝､播口徳充､松本真

抗マラリアアルカロイドfebrifugineの芳香環部位に着目した新規誘導体の

開発

第4 3回日本薬学会東北支部大会､秋田

2004年10月

(5)菊地晴久､平井真吾､山本圭介､裳岩靖子､播口徳充､松本真､大島吉輝

新規抗マラリア剤の創製を目指したキナゾリンアルカロイドfebrifugine

関連化合物の合成

第23回メデイシナルケミストリーシンポジウム･第1 2回日本薬学会医薬

化学部会年会､つくば

′ 2004年11月 (6) Yoshiteru Oshima

Fr.m 'old' Quinazolinone-type Alkaloid, Febrifugine, to Novel Antima1年rial Drugs

JSP-KSP一ccTNM Joint Seminar 2004 (International Symposium on Natural

Medicines)､加賀 2004年8月 2005年度

(1)裳岩靖子､平井真吾､山本圭介､播口徳充､松本真､菊地晴久､大島吉輝

キナゾリンアルカロイドfebrifugineを基盤とした新規抗マラリア剤の開発

日本薬学会第1 2 5年会､東京

2005年3月

(2)裳岩靖子､菊地晴久､平井真吾､山本圭介､笠原良太､大島吉輝､播口徳充､

松本真

抗マラリアアルカロイドfebrifugineの芳香環部位に着目した新規誘導体の

合成と生物活性

第5 0回有機合成化学協会関東支部シンポジウム(新潟(長岡)シンポジウム)､

長岡

2005年11月

(3)裳岩靖子､菊地晴久､平井真吾､山本圭介､笠原良太､播口徳充､松本真､

大島吉輝

生薬･常山由来アルカロイドfebrifugineの新規誘導体とその抗マラリア活性

第4 3回日本薬学会東北支部大会､仙台

2005年10月

(4)裳岩靖子､菊地晴久､平井真吾､山本圭介､笠原良太､播口徳充､松本真､

大島吉輝

キナゾリンアルカロイドfebrifugineの芳香環部位に着目した誘導体の合成と

抗マラリア活性

日本薬学会第126年会､仙台 ′

2006年3月

(5) Haruhisa Kikuchi, Shingo Hirai, Keisuke Yamamoto, Seiko Horoiwa, Ryota Kasahara, and Yoshiteru Oshima

creation of NewAntimalarials Based on a Quinazoline Alkaloid, Febrifugine

PACIFICHEM 2005､ホノルル

2005年12月

I ntrodu ctio n

Malaria, which is caused by a proto2:0anParaSite of the genusPlasmodium, is a major

parasitic infection in many tropicaland subtropicalreglOnS･ Malaria affects 300-500

million patients worldwideand leads to morethan2 million deaths each year･ Although

malaria has beenwidely eradicated in many parts of the world, the number of patients

continues to rise mainly due to the emergence of chloroqune-resistant and multiple-drug-resistant strains of malaria parasites･ Thus,the discovery of newand

effectiveantimalarialdrugs is urgently needed.

Roots of Dichroa jTebrlfuga, a plantthat belongs tothe Sa不漁agaceae family, have been used as a traditional antimalarial drug in China. The qulnaZOline-type alkaloids,

febrifugine land its stereoisomer, isofTebrifugine 2, have been identified asthe active

components of these roots (Chart 1). Although1and 2 show powerful in vitroantimalarial

activityagainst bothchloroquine-sensitive P･ falciparum FCR-3and chloroquine-resistant P･

jTalclbarum Kl,the in vivo activityof 1 against mouse malaria, P. berghei, is approximately

200 times more potentthanthat of2･ Due to side effects such as diarrhea, vomiting,and

liver toxicity, I has been precluded asanantimalarialdrug･ However,the potentantimalarial activityof 1 has stimulated medicinalchemists to pursue derivatives of 1, which may provide

valuable leads for novel drugs. We have tried to create active febrifugineanalogs･

However,the role of the structuralcomponents of I in itsantimalarialactivityhas yet to be

elucidated.

Chart 1. Structures offebrifugine (I)and isofebrifugine (2)･

eel"NloV抑鞘

0      0

Febrifugine (1 )      lsofebrifugine (2)

Therefore, we decide to synthesize febrifugine derivatives formed by structural

modifications at either (i)the quinazolinering, (ii)the linker, or (iii) the piperidinering

(Figure 1). Inthis paper, we reportthe syntheses ofthesefebrifugine derivativesand evaluatetheir in vitroand in vivoantimalarialactivities.

Figure 1.  The three parts of febrifugine (1)I

(i) QuinaEOline ring (iiinng

′   人   ヽ

二㌔三二

〇 (ii) Linker

Results and Discussion

Syntheses of Febrifugine Analogs: (i) QuitlaZ:OIinering･ We synthesized quinazoline ring-modifled derivatives 7-9and 14-16 (Scheme 1)･ 6-Fluoroanalog 7and 2-methyl analog 8 are respectively based on febrifugine metabolites feb-Aand -B, which prevent metabolic oxidation. In compounds 9and 14-16,the qunazoline nng of I is replaced by

purine, benzotriazine, thienopyrimidine,and quinoline nngs, respectively･ Kobayashi et al.

have evaluatedthe in vitroantimalarialactivities of synthetic febrifugine (1)and itsantipode. The EC50 Value of synthetic 1 against P. falclbarum was approximately 1/2000 of that of its

enantiomer. In addition, a highselectivity against P. juclbarum was only reported for l･

Based on these results, we synthesized 7-9and 14-16 as racemic compounds･

Ret. 8 ▼li

433高音B,二等崇二〕ユーR笠0 -L R3CO 也 R郡

I l      ⊥.       H H 4 Cbz SA-C Cbz b･C       719

F珊瑚耶齢濃等

0 7        0 8        0 9

㌫笑〕一-R瓢- R二冥六〕.- R郡

I I H H Boc Boc 1 1       12一･C      1 3JL･C      1 4･1 6 ●

二二二 014 伜夷

R

唖

3C bz

/ニ二二二一一‡

Boc 10

scheme l･ Synthesis of7-9and 14-16･a

aReagentsand conditions: (a) correspondingaromatic compound, K2CO3, DMF, rt; @) H2 (I atm), pd(OH)2/C, MeOH, rt (65% (6a), 80% (6b)and 78% (6C) (2 steps)); (C) MeOH, reflux;

(d) Boc20, iPr2EtN, CH2C12, rt; (e) 10 % HCl-MeOH, rt (48% (7), 42% (8)and 40% (9) (3 steps)); (i) 6 M HCl, reflux; (g) Boc20, 5 M NaOH, rt (61% (2 steps)); (h) MOMCl, iPr2EtN, cH2Cl2, rt; (i) mCPBA, CH2C12, NaHCO3T, 0 oC (44% (2 steps)); O) correspondingaromatic compound, KH, DMF, rt; (k) Dess-Martin periodinane, CH2C12, rt (71% (12a), 3 1% (12b)and 39% (12C) (2 steps)); (I) 10 % HCl-MeOH, rt (97% (13a), 98% (13b)and 95% (13C)); (m) MeOH, reflux; (n) Boc20, iPr2EtN, CH2C12, rt; (0) 10 % HCl-MeOH, rt (41% (10), 28% (ll) and 30% (12) (3 steps))･

Racemic 7-9 were synthesized by employlng the synthetic strategy for I developed by

Takeuchi et al. The starting material, 31hydroxypyridine, was used to produce hemiacetal4

via compound 3･ A coupling reaction of 4 wi血血e aromatic component of 7 provided

compound 5&, which was hydrogenolized to give 6a･ Like isomerization of isofebrifugine (2)

into fTebrifugine (I), boiling ofMeOH solution of6a isomerized 6a into 7･Analogs Sand 9

were synthesized in a similar maJmer uSingthe corresponding heterocyclic component･

onthe other hand, Syntheses of 14-16 were carried out in a di飴rent manner fTromthose of

719 becausethe coupling reaction or catalytic hydrogenation wasunsuccessfu1･ Compound 3 was converted into Boc-derivative 10 in two steps. After MOM-etherification of 10, epoxidation by mCPBA afforded ll･ A coupling reactionwiththe aromatic component of 14and subsequent oxidation gave 12a･ Acidic deprotection of 12aand refluxingthe residue in MeOH gave a mixture of 13aand 14･ Isomerization of 13a into 14alSo occurred.

Analogs 15 and 16 were sy血esized in a si血lar mamer to in 3･

(ii) LiAker part. To evaluatethe role of the Cl2'Carbonyl group intheantimalarial activity, we synthesized chiralcompound 29 (Scheme 3), which is a decarbonylated derivative of fTebrifugine l･ The piperidineand linker parts of29 were synthesized byuslng

NN-dibenzylaminoaldehyde as a chiralbuilding block (Scheme 2)･ D-Glutamic acid (17b)

was converted intoamino alcohol 18b by a reactionwithbenzyl bromideand reduction uslng lithiumaluminumhydride･ Compound 18b was reactedwithtert-butyldimethylsilyl chloride

to yield 19b. Swem oxidation of 19b gave NN-dibenzylaminoaldehyde, which wasthen

Hydrolysis of the acetal20b gave hemiacetal2lb. Catalytic hydrogenation followed by

N-protection afforded 22b. Three successive reactions of 22b gave mono-MOM ether 24b, which containedthe piperidineand linker parts of29. In Scheme 2, tosylation of24b afforded

26b, which was coupledwith41hydroxyqulnaZOline to produce 27b. Finally, compound

27b was deprotected under acidic conditions, which resulted in a decarbonylated fTebrifugine

29 as a hydrochloride･      '

H醐帯oH一- RO､ル莞oH --,BDMSO湖上HO

0 0 5H l完J(DD-.Ai;up.:霊caacEIi)…慧  cE 】:::≡ …呂≡ THBDMS     20'･b

-- ｡2｡､芯○吐讐の珊--H｡〈二℃

Boc 21■,b ..iE:芸道: :: Boc Boc R2 ≡ H         25      24￠ H, R2=TBDMS MOM, R2=H

Scheme 2･ Synthesis of the piperidineand linker parts of28-30･a

aReagentsand conditions: (a) BnBr, K2CO3, NaOH, MeOH-H20 (1:1), reflux; O)) LiAIH4,

THF, OoC (34% (18a)and 62% (18b) (2 steps)); (C) TBDMSCl, imidazole, CH2Cl2, 0 oC

(42% (19a)and 56% (19b)); (d) (COCl)2, DMSO, Et3N, CH2C12, -78 oC; (e)

(1,3-Dioxan-2-ylethyl)magnesiumbromide, THF, -78 oC (56% (20a)and 59% (lob) (2 steps)); (i) 2M HCl, acetone, rt; (g) H2 (1 atm), Pd(OH)2/C, MeOH, rt; Ol) Boc20, Et3N, MeOH, rt (66% (22a)and 33% (22b) (3 steps)); (i) TBDMSCl, imidazole CH2C12, 0 oC (82%

(23a)and 55% (23b)); O) MOMCl, iPr2EtN, DME, 50 oC; (k) TBAF, THF, 0 oC (83% (24a) and 93% (24b) (2 steps)); (I) Dess-Martin periodinane, CH2C12, 0 oC; (m) Triethyl phosphonoacetate, NaH, toluene, 0.C (76% (2 steps)); (n) H2 (1 atm), Pd(OH)2/C, THF, rt; (o) DIBAL-H, toluene, -78 oC (84% (2 steps))･

RO二芸範上郡芸Qc

O __

aE…::: …昌≡T"S

scheme 3. Synthesis of28-30･a

aReagentsand conditions: (a) pTsCl, pyridine, rt (69% (26&), 80% (26b)and 78% (26C));

仲) 4-Hydroxyquinazoline, K2CO3, DMF, 50 oC (30% (27a), 72% (27b)and 84% (27C)) ; (C)

10 % HCl-MeOH, 50 oC (90% (28a), 88% (28b)and 93%(28C))･

Inthe same mamer,analogs 28and 30I Which contain a shorterand longer linker,

respectively, were synthesized. D-Aspartic acid (17a) was used as a starting materialto generate 24a (Scheme 2)･ Oxidation of 24afollowed by the Homer-Emmons reactionwith

triethyl phosphonoacetate yielded 25･ After catalytic hydrogenation of 25, reduction by

DIBAL-H gave 24C･ Compounds 24aand 24c were converted into 28and 30, respectively

(Scheme 3)･

we synthesized compound 33, which hasanamide bond forthe linkage between the quinazolineringand linker (Scheme 4)･ Successive oxidation of 24b by PCCand sodium

hypochlorite gave carboxylic acid 31･ A coupling reaction of 31 with

2-amin0-4(3H)-quinazolinone provided compound 32, which was deprotectedunder acidic condition to afford 33.

Scheme 4. Syn血esis of33･d

aReagentsand conditions: (a) Dess-Martin periodinane, CH2C12, 0 oC; (b) NaCIO2,

2-methyll2-butene, NaH2PO4, tBuOH, H20, rt (83% (2 steps)); (C) 2-Amin0-4(3H)-quinazolinone, HATU, iPr2EtN, DMF, CH2Cl2, rt (38%); (d) 10 %

HCl-MeOH, rt (45%).

(iii) PiperidineriJlg. Piperidinering10Penedanalog 41 was synthesized as shownin

scheme 5. Swem oxidation ofaminoalcohol IDA, which was prepared from D-aspartic acid

17&,and a subsequent reactionwithethylmagnesiumbromide diastereoselectively gave 34･

Four successive reactions, 0-protection by MOM group, debenzylation, NIPrOteCtion by a Boc group,and deprotection of the TBDMS group afforded 37･ Dess-Martin oxidation of

37 gavethealdehyde, which was treatedwithtrimethylsulfoxoniumiodideand sodium

hydride to yield epoxide 38･ After N-methylation of 38, a coupling reaction with

4-hydroxyqulnaZ01ine and subsequent oxidation gave 40･ Deprotection of 40 under lO% hydrogen chloride in MeOH, formedtheunstable hydrochloride of 41･ Treatment of 40 with trifluoroacetic acid afforded the stable trifluoroacetate of 41. 1Hand I3c NMR spectra

showed that compound 41 exist as a hemiacetalfbrm･

TB｡MS｡∼CoH _i TB.MS｡へズ二一坐→ R｡ OR 19■     cE;;…呂≡誌｡M

L OMi:iT;C ∈玲深T;C

-30       0 40 NHBoc

〈｣､〈 _吐■臥ズ誓､

OMOM

f E:: :::THBD"S

leX;勺灯へl

38 OMOM Scheme 5･ Syn血esisof41･d

aReagentsand conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, -78 oC; (b) EtMgBr, THF, -78 oc (66% (2 steps)); (C) MOMCl, iPr2EtN, CH2C12, rt (79%); (d) H2 (1 atm), Pd(OH)2/C,

MeOH, rt; (e) Boc20, Et3N, MeOH, 0 oC (98% (2 steps)); (i) TBAF, THF, rt (67 %); (g) DessIMartin periodinane, CH2C12, rt; (h) Trimethylsulfoxomium iodide, NaH, DMSO, rt (75% (2 steps)); (i) MeI, NaH, DMF, 0 oC (91%); Ci) 4-Hydroxyquinazoline, NaH, DMF, 80 oC; (k) Dess-Martin periodinane, CH2C12, rt (41% (2 steps)); (1) TFA, CH2Cl2, rt (44%)･

The position of the linkage betweenthe piperidine nngand linker is changed infebrifugine

analogs 46 and 50. To symthesize 46 (Scheme 6),the hydroxy group of

3-hydroxypIPeridine 42 was protected as TIPS ether by three sequentialreactions to give 43･

Treatment of 43 with epibromohydrin affTorded 44, which was coupled with

4-hydroxyqulnaZOline to yield 45･ Oxidation of 45and subsequent deprotection gave

racemic 46 a§血e hydrochloride･   ′

oH OTIP$ OTI PS

HNC) --HNC]一一L OLWC)

7-3-"aeNr貰NBpL匝詞

Scheme 6･ Synthesis of46･a

aReagentsand conditions: (a) CbzCl, Et3N, CH2C12, 0 oC (96%); (b) TIPSCl, imidazole, DMF,

o oc; (C) H2 (1 atm), Pd(OH)2/C, MeOH, rt (71% (2 steps)); (d) Epibromohydrin, K2CO3, DMF, rt (71%); (e) 4-Hydroxyquinazoline, NaH, DMF, 80 oC (68%); (i) (COCl)2, DMSO, Et3N, CH2C12, -78 oC (72%); (g) 10 % HCl-MeOH, 70 oC (80%)･

To synthesize 50,the N-Boc derivative of 42 was treated with

2,2ldimethy1-1,3-dioxolan-4-ylmethyl tosylate to give 47･ After deprotectionunder acidic conditionsand N-reprotection of 47, epoxidation by N-tosylimidazole afforded 48･ Finally, three successive reactions, a couplingwith4-hydroxyqulnaOline, Dess-Martin oxidation,and

acidic deprotection, yielded racemic 50 as也e hydrochloride (Scheme 7)･

HO

て〕

a･b恕-oて〕 -‰oて〕 -

>

り     47 Boc    48 Boc

三二≡二二二

Scheme 7. Synthesis of50.α

aReagents and conditions: (a) Boc20, Et3N, MeOH, rt (95%); (b)

2,2-Dimethy1-I,3-dioxolan-4-ylmethyl p-toluenesulfonate, NaH, DMF, 80 oC (57%); (C) 1 0 %

HCl-MeOH, 70 oC; (d) Boc20, Et3N, CH2C12, 0 oC (80% (2 steps)); (e) 〟-Tosylimidazole, NaH, THF, rt (32%); (i) 4-Hydroxyquinazoline, NaH, DMF, 80 oC; (g) Dess-Martin

periodinane, CH2Cl2, rt (67% (2 steps)); (h) 10 % HCl-MeOH, 70 oC (89%).

h Vitro Antimalarial Activity of Synthetic Analogs of Febrifugine. In vitro antimalarial activityof febrifugineanalogs 7-9, 14-16, 28130, 33, 41, 46,and 50 against P.

jucl'parumand the cytotoxicityagainst mouse L929 cells were evaluated (Table 1).

Compounds 7-9, 14,and 15 displayedantimalarialactivity(EC50 <0.5 llg/mL). The

antimalarialactivityof 61fluoroanalog 7and thienopyrimidinering-containinganalog 15

were equivalent to that of febrifugine (1). These results suggestthat a suitable method to create more active derivatives is to modifythe quinazolinering of 1. On the contrary,

compound 16 did not displayany activity, indicatingthatthe nitrogen atom at position 3 in

qulnaZOline nng is crucial to activity. Tbeantimalarial activity of decarbonylated

derivative 29 was 1/15 of that of I. Therefore,the carbonyl group at C-2'. was effective, but

not critical tothe activity. Compounds 28and 30, which have twoand four carbon linkers, respectively, did not display activity, suggestingthat a three carbon linker is important fわr

potentantimalarial activity. In addition, compounds 33, 41, 46,and 50 did not exhibit

activity. The pIPeridine nng of febrifugine 1 should be maintained to createuseful

derivatives.

In Vivo Antimalarial Activity of Synthetic Analogs of Febrifugine. In vivo

antimalarialactivities against rodent malaria P･ bergheiandthe acute toxicityin mice was

examined for 7, 15,and 29, which were more potent in vitrothanchloroquine (Table 2)･

Because 7 was highly toxic in mice (LD50 <2.5 mgn'g),the in vivoantimalarial activity of 7

was not evaluated. The antimalarialactivity (ED50 2.95 mgn(g) of 15 was comparable to

chloroquine, a climiCally used medicine. In addition,the toxicityof 15 was much weaker

(LD50 >80 mgn(g)thanthat of landthetherapeutic index of 15 was higherthanl･ These

results suggestthat 15 may be a good arLtimalarialCandidate･ Although no mice died after

receiving 320 mg瓜g of 29 inthe acute toxicity test, itsantimalarial activitywas moderate

(ED50 22.5 mgn(g).

Conclusion

We synthesizedand evaluated a new series offebrifugine derivatives･Amongthem,

thienopyrimidineanalog 15 exhibited potentantimalarialactivityand a hightherapeutic selectivitybothin vitroand in vivo. Further studies on 15 such as a metabolicanalysisand the elucidation of the action mechanism are necessary to develop a novelantimalarial drug.

Table 1.Antimalarialactivities of synthesized febrifugine derivatives against P. juclbarum

in vi廿0. C ompound

Antimalarialactivity

FCR_3a Klb , C ytotoxi cityc EC50 (pg/mL)  EC50 (pg/mL) s el ectivityd Febrifugine (1) 0.00142   0.00140    0. 167 7      0.000730   0.00091 6    0.0790 S     ノ 0.116     0.190    15.6 9 14 15 16 28 29 30 33 41 46 50 0.506     0.943   >100 0. 1 54     N.T.e    16.4 0.00306   0.003 19    0.563 >1      >1      >100 >1      >1      >100 0.0225    0.0236     4.45 >1      >1      >100 >1      >1      >100 >1      >1        6.44 >1      >1     >100 >1      >1     >100 Chloroqune  0.0475   0.375   1 8･6 Artemisinin 0.01 79    0.0 1 1 7   >1 00 118 108 134 >198 106 184 198 <6.44

aAgainst P.falciparum FCR-3 (chloroquine sensitive strain). bAgainst P.juclj'arum Kl

(chloroquine resistant strain). cAgainst mouse L929 cells. dselectivity- EC5.for L929

cells侶C50 f♭r P.juciparum FCRl3. eNot tested.

Table 2.Antimalarialactivities against P. bergheiinvivoand acute toxicities of

synthesized febrifugine derivatives 7, 15and 29･a

Antimalarial  Acute

activityb toxi cityC C ompound ED50 (men(A) LD50 rm Febrifugine (1)  0.41    7.1 7      N.T.e q.5 Therap eutic Indexd 17 15       2.95    >80       >27 29      22.5    >320      >14 ulne 1.53    N.T.e

aAll compounds were administrated by po. bAgainst P. berghei (rodent malaria). cToxicity

in mice･ dTherapeutic index - LD50 inmice侶D50for P･ berghei in mice･ eNot tested･