Bhakuni, Rajendra S

Bhattacharya, Asish K

Jain, Dharam C

Sharma, Ram P

Shrimali, Meenakshi

NOPR

Indian Journal of Chemistry,Vol. 37B, November 1998, pp. 1161 - 1163Sodium artelinate : A potentialantimalarial tMeenakshi Shrimali, Asish K Bhattacharya,Dharam C Jain*, Rajendra S Bhakuni &Ram P SharmaCentral Institute of Medicinal and Aromatic Plants,Lucknow 226 015, IndiaReceived 30 June 1997; accepted (revised) 25 February 1998An economically viable process is developed for thesynthesis of sodium artelinate, a potential antimalarial drug.Artemisinin 1 is a sesquiterpene endoperoxide, a potentantimalarial agent'? isolated in 1972 from the Chineseplant Qinghao (Artemisia annua) and used in thetreatment of fever for over 2000 years as a herbalremedy for malaria". The practical value of artemisininhowever is impaired by its high rate of recrudesence,poor solubility in oil and water, short plasma half lifeand poor oral abilities5• Chemical modification ofartemisinin has resulted in a number of analogs withimproved efficacy and increased solubility in oil.Arteether and artemether are more lipophilic and moreefective than artemisinin. A water soluble derivativesodium artesunate was prepared and found useful in thetreatment of cerebral malaria but utility of sodiumartesunate is impaired by its poor stability in aqueoussolution due to the facile hydrolysis of the ester linkageand extremely short plasma half life (20-30 min)".Sodium artelinate possesses comparable antimalarialactivity in vitro as well as in vivo to artemether orarteether. Because of its encouraging chemical andbiological properties, it is currently being subjected topreclinical testing and has been considered the bestcandidate among the available water soluble analogs",Dihydroartemisinin 2, prepared by reduction ofartemisinin 1, was converted into a mixture of a- and ~-artelinic esters 3a and 3b which were separated bycoloumn chromatography". ~-Isomer was hydrolysed. toyield ~-artelinic acid 4a which inturn was converted intoits sodium salt Sa, a potent, stable and water solublet CIMAP Publication No. 97-671NoteR1 =02 -OH3a ~-OCH2C6H4COOCH3-P3b u-OCH2C6H4COOCH3-p4a ~-OCH2C6H4COOH4b u-OCH2C6H4COOHSa ~-OCH2C6H4COONa5b u-OCH2C6H4COONaantimalarial agent. Similarly, an attempt was also madeto prepare sodium o-artelinate 5b. The overalladvantage of this method lies in the initiation andcompletion of the reaction at room temperature withoutusing inert atmosphere.The IH NMR data of 3a, 3b,4a and 4b were found tobe similar with those available in literature't", and we arereporting the 13CNMR data of these derivatives for thefirst time (cf. Table I).Experimental SectionGeneral. Melting points were determined in opencapillaries and are uncorrected. EI mass spectra wererecorded on a Jeol D 300 mass spectrometer, FAB-masson a Jeol SX - 102 mass spectrometer (10 KVaccelerating potential) using 6 KV xenon beam. NBAwas used as matrix. IR spectra was recorded on aPerkin-Elmer spectrometer in neatlKBr, IH NMRsf.ectra on a Bruker WM (400 MHz) spectrometer andI C NMR spectra on a Bruker DRX-3oo (300 Mhz FTNMR) spectrophotometer using TMS as internalreference. Solvent CDCh and standard software were1162 INDIAN J CHEM, SEe. B, NOVEMBER 1998used for data acquisation. TLC was performed on 5 x 20ern precoated silica gel glass plates.Table 1- I3C NMR spectral data of compounds3a,3b,4a and 4b.Artelinic ester Artelinic acidAtom 3b 3a 4a 4bNo. (a) (~) (a) (~)C-l 51.8 52.5 51.6 52.0C-2 24.6 24.6 24.7 24.1C-3 36.2 36.4 36.3 36.0C-4 104.2 104.1 104.4 104.0C-5 91.2 88.0 91.3 87.2C-6 80.2 81.0 80.4 80.4C-7 45.3 44.3 45.3 44.0C-8 22.1 24.5 22.2 24.0C-9 34.1 34.6 34.1 34.1C-lO 37.2 37.4 37.3 37.2C-ll 32.5 30.8 32.7 30.2C-12 99.1 101.5 99.3 101.1C-13 12.6 13.0 12.7 11.0C-14 20.1 20.2 20.2 19.5C-15 25.9 26.1 26.0 25.4C-1 69.1 69.1 69.2 68.2C-2' 143.1 143.6 144.6 144.1c-3'i 127.1 126.8 127.2 126.4C-4'6' 129.4 129.6 130.2 129.9C-5 129.1 129.2 128.3 128.0OMe 51.6 51.9CO 166.8 166.8 171.6 171.8Dihydroartemisinin 2. Artemisinin (1) (lOg) in 40ml methanol was cooled in an ice bath to 0-5 "C. To thecooled solution was added in small portions 0.25 g ofsodium borohydride over a period of 30 minutes and thesolution was stirred at 0-5 °C for 3 hrs. The reactionmixture was neutralized with 30% acetic acid/methanoland evaporated to dryness under reduced pressure. Thewhite residue was extracted with ethyl acetate (3x50ml). The ethyl acetate extracts were combined, filteredand evaporated to dryness to give white needles ofdihydroartemisinin m.p. 153°C, yield 8.5 g (85%).Methyl p-[(12-dihydroartemisininoxy)methyl]-benzoate (artelinic esters 3a+3b. A solution ofdihydroartemisinin (5g) in 80 mL benzene was treatedwith 5g of methyl p-hydroxymethylbenzoate. To this1.2 mL of chlorotrimethylsilane (CTMS) was added insuccessive three portions of 0.4 mL each during 30 minwith stirring. The reaction mixture was further stirred atroom temperature for 2 hr. It was then washedsuccessively with saturated solution of sodium acetateand water, dried over anhyd. sodium sulphate andevaporated to dryness under reduced pressure affordinga viscous mass. Yield 8.5 g (85%); IR (Neat): 1720 ern"(0-C-O). The resultant viscous mass (3a+3b) waspurified by column chromatography using silica gel asadsorbent (60-120 mesh). Elution was carried out usingsolvent systems with increasing percentage of ethylacetate in hexane. Fractions (Fr No. 27-53) eluted from6% ethyl acetate in hexane contained pure ~-artelinicester 3a. It was a viscous liquid, yield 5.5g (60%); R,0.4 (in 10% ethyl acetate in hexane); IH NMR: 8 8.02(d, 2H, 1=9Hz, H-3' and H-7\ 7.39 (d, 2H, 1=9Hz, H-4' and H-6\ 4.98 (d, IH, 1=12.5 Hz, H-l\ 4.92 (d, lH,1=3.5 Hz, H-12), 4.95 (d, IH, 1=12.5 Hz, H-l\ 3.92 (s,3H, COOMe); l3C NMR data of 3a are given in Table I;FABMS: 433 (M+H/.Fractions (Fr.No 54-69) eluted from 7% ethyl acetatein hexane was the mixture of a- and ~-artelinic estersyield 19(11.8%).Fractions (Fr No 70-73) eluted from 8% ethyl acetatecontained pure e-artelinic ester 3b as viscous mass,yield 120 mg (1.4%); Rf value 0.37 (in 10% ethyl1 racetate in hexane); H NMR: 88.02 (d, 2H, 1=9Hz, H-Jand H-7\ 7.43 (d, 2H, 1=9Hz, H-4' and H-6\ 5.02 (d,lH, 1=12Hz, H-l\ 4.68 (d, lH, 1=12Hz, H-l\ 4.54 (d,IH, 1=9Hz, H-12), 3.92 (s, 3H, COOMe); l3C NMRdata of 3b are reported in Table 1. FABMS: rnIz 433(M+H/.p-[ ( 12- ~- Dihydroartemisinoxy ) methyl ]benzoicacid 4a. ~-artelinic acid. A solution of ester 3a (O.4g)in IOmL of 1.5% methanolic NaOH was allowed tostand at room temperature for 2 days. The solvent wasevaporated to dryness under reduced pressure. Theresidue was dissolved in 10 mL water and the solutionwashed two times with an equal amount of ether. Theaqueous layer was acidified with 5% acetic acid andextracted twice with solvent ether. The ether extractswere combined, dried over anhy?rous sodium sulphateand evaporated to dryness to get a gummy mass whichwas crystallised from chloroform to give white crystals,m.p. 145°C, yield 0.2g (55%); IH NMR: 88.09 (d, 2H,1=8.2 Hz, H-3' and H-7\ 7.41 (d, 2H, 1=8.2 Hz, H-4'and H-6\ 4.98 (d, lH, 1=13.5Hz, H-() 4.92 (d, IH,1=2.7 Hz, H-12), 4.59 (d, IH, 1=13.5 Hz, H-l\ 2.70(rn, IH); l3C NMR data of 4a are given in Table I;FABMS: mlz 419 (M+H/.Similarly O.4g of 3b in 10 mL 1.5% methanolicNaOH was allowed to stand at room temperature for 2days. The procedure adopted to extract pure a-isomer4b from the reaction mixture was the same as describedabove, yield 0.21g (55.0%); IH NMR: 8 8.05 (d, 2H,1=8.2 Hz, H-3' and H-7\ 7.45 (d, 2H, 1=8.2 Hz, H-4'and H-6\ 5.02 (d, lH, J=13.2Hz, H-l\ 4.70 (d, lH,J=13.2Hz, H-t\ 4.53 (d, m, J=9.3Hz, H-12), 2.57 (m,IH); \3C NMR data of 4b are given in Table I; FABMS:mJz 419 (M+Ht.Sodium p-[(12-~-dihydroartemisininoxy- )methyl]-benzoate Sa (sodium-ji-artelinate). ~-Artelinic acid(0.5g) was dissolved in minimum quantity (2 mL) ofmethanol and loaded on a column (length 35 em,diameter 1.5 em), containing 35 g amberlite IR-120 Na+resin. The material was kept adsorbed on column for 2hrs and then elution was carried out with distilled water.The process was repeated four times. Lastly, the columnwas washed with distilled water and washings weremixed with eluate and lyophillised to get a creamcoloured solid, m.p. 1600 (decomp), yield 4.5g (90%).An attempt was also made to prepare sodium ex-artelinate Sb following the above procedure.AcknowledgementThe authors are thankkful to the Director, CIMAP, forhis constant encouragements. One of the author (M.S.)is thankful to CSIR, New Delhi for the award of" aResearch Associateship.ReferencesKlayman D L, Science, 228, 1985, 1049.2 Luo Xuan De & Shen Chia Chiang, Medicinal researchreviews, 7,1987,29-52.NOTES 11633 Jain D C, Bhakuni R S, Kahaol A P & Thakur R S,(1991), An improved process for isolation of artemisininfrom Arternisia annua L. No 6471DEU91.4 Lusha X, China reconstructs, Aug. 1979, pA8.5 China Cooperative Research group on Qinghasu and itsderivatives as antimalarials, J Tradi Clini Med, 2, 1982, 9-16.6 Lin A J, Klayman D L & Milhous W K, J Med Chern, 30,1987,2147.7 Lin A J & Miller R E, J Med Chern, 38, 1995, 764.8 Vishwakarma R A, Mehrotra R, Tripathi R & Dutta G P, JNat Prod, 55, 1992, 1142-1144.9 Bhakuni R S, Jain D C & Sharma R P, Indian J Chern,34B, 1995, 529.10 Prakash 0, Roy R, Kapil R S & Vishwakarma R A, IndianJ Chern, 29B, 1990, 103.11 Pathak A K, Jain D C & Sharma R P, Indian J Chern,34B, 1995,992.12 Madhusudanan, K P, Vishwakarma R A, Balachandran S& Popli S P, Indian J Chern, 28B,1989, 751.13 Fales H M, Sokoloski E A, Panel! L K, Quan-lang Pu,Klayman D L, Lin A J Brossi & Kelly A, J A Anal Chern,62, 1990, 2494.14 Belic I, Kastellic S T, Kavcic R, Marshe1 J, Kramer V,Kraj B, Tetrahedron, 32, 1976, 3045.15 Fraser R T M, Paul N C & Phillips L, J Chern Soc, B,1970,1278.16 Ledaal T, Tetrahedron Leu, 41,1969,3661-3664.17 Berland M, Fliszer S & Rousseau Y, J Org Chern, 33,1968,1931

Sodium artelinate: A potential antimalarial

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Sodium artelinate: A potential antimalarial

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