Review Discovery and Development of Antiplasmodial Compounds in Thailand During the 21St Century

Discovery and Development of Antiplasmodials in Thailand

REVIEW

DISCOVERY AND DEVELOPMENT OF ANTIPLASMODIAL COMPOUNDS IN THAILAND DURING THE 21ST CENTURY

Saranya Auparakkitanon

Division of Toxicology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

Abstract. This review describes research conducted in Thailand from 2000 to 2013 on the discovery of new compounds from local flora and fauna, including those of marine organisms from coastal regions, which have antiplasmodial activity against Plasmodium falciparum growth in culture. These antiplasmodials comprised alkaloids, angucyclinones, anthraquinones, azaanthraquinone, azaphilones, ben- zoquinones, bioxanthracenes, carbazomycins, chalcones, chromone, clerodane, coumarins, cyclomarin, cyclopeptides, cytochalasins, depsidones, depudecin, flavaglines, flavonoids,furans, isoflavonoids, limonoids, macrolides, nucleoside, oxepin, peptides, phloroglucinol, polylactone, polypropionate, preussomerins, prodigiosin, pterocarpans, pyrenocines, pyridones, pyrrolidines, quassinoids, quinone, stilbenes, styryl lactones, terpenoids, tetramic acids, tetronic acids, trinorcadalenes, tropolones, xanthones, and a variety of miscellaneous molecules (a total of 293 compounds). The review also describes the screening and synthesis of novel chemicals targeted against parasite enzymes, (carbonic anhydrase, cytochrome bc1, dihydrofolate reductase and orotidine 5’-monophosphate decarboxylase), which have the potential of being developed into antimalarial drugs. Possible future trends in antimalarial drug research in Thailand are discussed. Keywords: antimalarial development, antiplasmodial discovery, flora and fauna antimalarials, marine antimalarials, Thailand

INTRODUCTION deaths, mainly in children in sub-Saharan Africa (WHO, 2013). Although a new Malaria still remains a major public attenuated sporozoite vaccine holds health problem, especially in sub-Saharan promise (Seder et al, 2013), treatment Africa. In 2011 WHO reported 219 mil- of malaria still continues to depend on lion new cases of malaria, with 800,000 the use of antimalarial drugs. However, human malaria parasites, in particular Correspondence: Saranya Auparakkitanon, Division of Toxicology, Department of Patho- Plasmodium falciparum, the most virulent logy, Faculty of Medicine Ramathibodi Hospi- of the five plasmodial parasites P.( vivax, tal, Mahidol University, Rama VI Road, Bang- P. malariae, P. ovale and most recently P. kok 10400, Thailand. knowlesi) infecting humans have become Tel: 66 (0) 2201 1338; Fax: 66 (0) 2354 7174 resistant to all currently used antimalari- E-mail: [email protected] als, including the Chinese drug artemi-

Vol 45 No. 4 July 2014 761 Southeast Asian J Trop Med Public Health sinin (also known as qinghaosu) and its DISCOVERY OF NEW analogs [dihydroartemisin (the active ANTIPLASMODIAL COMPOUNDS form), arteether, artmether and artesunate (water soluble form)] (Dorndorp et al, During the period of the literature 2009). New antimalarials in clinical use are survey there were some 293 new com- mainly artemisinin combination therapies pounds isolated from various species of (ACTs), of which there are five combina- flora and fauna in Thailand, and those tions (WHO, 2010), with at least one other from marine organisms from coastal combination undergoing multi-center regions, which show inhibitory activity clinical trials in Africa and Asia (Duparc against P. falciparum in culture (summa- et al, 2013). rized in Table 1). The majority of compounds with antiplasmodial activity were The successful discovery of artemis- discovered during examination of bioac- inin isolated from the Chinese herbal tive substances from insect and seed fungi plant qinghao (sweet wormwood) tradi- (reviewed earlier by Isaka et al, 2005a). The tionally used to treat jungle fever (Miller new chemical compounds include alka- and Su, 2011) has spurred similar efforts loids, angucyclinones, anthraquinones, to identify compounds from local flora azaanthraquinone, azaphilones, benzo- and fauna with antiplasmodial proper- quinones, bioxanthracenes, carbazomy- ties, which then could be developed di- cins, chalcones, chromone, clerodane, rectly or as lead compounds for further coumarins, cyclomarin, cyclopeptides, chemical modifications to become novel cytochalasins, depsidones, depudecin, and if possible inexpensive antimalarial flavaglines, flavonoids, furans, isoflavo- drugs. This review has gathered together noids, limonoids, macrolides, nucleoside, reports in the literature (from 2000 to oxepin, peptides, phloroglucinol, poly- 2013) of new chemicals (but not of crude lactone, polypropionate, preussomerins, extracts) with inhibitory activities against prodigiosin, pterocarpans, pyrenocines, P. falciparum. In addition, reports of re- pyridones, pyrrolidines, quassinoids, search in Thailand on the development quinone, stilbenes, styryl lactones, terpe- of novel compounds directed against P. noids, tetramic and tetronic acids, trinor- falciparum enzymes with potential for cadalenes, tropolones, xanthones, and a future development as antimalarial drugs variety of miscellaneous compounds, but are reviewed. However, pharmacological they were not more potent than chloro- studies and clinical trials conducted in quine. However, there are some excep- Thailand during the period covered by tions: metacycloprodigiosin (IC50 = 5 ng/ this article were not included. ml), and fimbricalyx B, two flavaglines Unless indicated otherwise, anti- (aglafoline, rocaglamide), a macrolide plasmodial inhibition studies employed (bafilomycin A1) and two pyridones the Thai parasite isolate, P. falciparum K1 (cordypyridones A, B) with IC50 values (Thaithong and Beale, 1981), resistant to ranging from 20 to 70 ng/ml. However, µ both chloroquine (IC50 = 3.6 g/ml/0.59 there have been no reports on the phar- µ µ M) and pyrimethamine (IC50 = 30 M), macological and toxicology properties of where IC50 is defined as the concentra- these promising lead compounds. tion required to inhibit malaria parasite Only one study attempted to modify growth in culture by 50%. a naturally occurring bioactive compound

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(α-mangostin, a xanthone) to generate must depend on de novo biosynthesis of more active analogs (lowest IC50 = 50 these precursors of nucleic acids (Gero nM), but the limited number of analogs and O’Sullivan, 1990). synthesized was not sufficient to show a The most extensive work has been structure-activity relationship (SAR), but carried out on the synthesis and testing of did indicate that the presence of a prenyl novel compounds directed against P. falci- side chain in the xanthone molecule im- parum (Pf)DHFR, the target of previously proves antiplasmodial activity. effective antimalarials, pyrimethamine The number of compounds isolated (PYR) and cycloguanil (CG). PfDHFR to- from marine organisms off the shores of gether with parasite thymidylate synthase Thailand with antiplasmodial property (PfTS) and serine hydroxymethyltransfer- was limited to 17: malyngamide X, from ase are involved in dTMP cycle. However Bursatella leachii, a marine gastropod mol- through a series of point mutations in lusc, commonly known as sea hare; cou- Pfdhfr, PfDHFR has acquired a highly marin, cytochalasin Q, sesterterpenoids, PYR-resistant quadruple mutant (QM) and tetramic and tetronic acids from (N51I, C59R, S108N, and I164L) form. marine fungi; and terpenoids and mac- The elucidation of the crystal structures rolides from marine sponges. A review of of wild-type bifunctional PfDHFR-TS (in the literature from 2006 to 2008 listed 82 Plasmodia DHFR and TS are synthesized natural compounds and synthetic deriva- as a single bifunctional enzyme) and QM tives with antiplasmodial activity from forms has allowed an understanding of marine and freshwater sources around the structural basis for reduced binding of the world (Gademann and Kobylinska, PYR and CG to PfDHFR QM due to a rigid 2009), and another review of marine p-chloropheny substituent at the 5-posi- antimalarials covering a similar period tion of PYR resulting in steric clash with listed some 60 secondary metabolites with the mutated amino acids (Yuvaniyama antiplasmodial properties (Fattorusso et al, 2003). This has enabled rationale de- and Taglialatela-Scafati, 2009). However, sign of compounds based on pyrimidine reports of Thai antiplasmodial marine and triazine scaffolds, which are flexible in natural products in these two reviews order to avoid such steric hindrances with were apparently overlooked. the bulkier mutant amino acid side chains in the PfDHFR binding site. Following DEVELOPMENT OF NOVEL synthesis and evaluation of hundreds ANTIPLASMODIAL COMPOUNDS of such compounds, P218 (2, 4-diamino- 6-ethyl-5-(3-(2-(2-carboxyethyl) phenoxy) Compounds screened or developed propoxy) pyrimidine was arrived at, against P. falciparum specific targets were which includes pyrimidine side-chain limited to only four enzymes, namely, flexibility and a carboxylate group that carbonic anhydrase (CA), cytochrome makes charge-mediated hydrogen bonds bc1, dihydrofolate reductases (DHFR) with conserved R122 of PfDHFR and not and orotidine 5’-monophosphate decar- of human DHFR, providing an explana- boxylase (OMPDC), mainly involved in tion of its high selectivity (Yuthavong et al, pyrimidine biosynthesis (Table 2). This 2012). P218 binds both wild-type and QM is not unexpected as the malaria parasite PfDHFR tightly almost entirely within lacks pyrimidine salvage pathway and the chemical space of DHFR substrate,

Vol 45 No. 4 July 2014 763 Southeast Asian J Trop Med Public Health , 2006 , 2006 , 2003 , 2013 , 2002 , 2013 , 2010 et al et al et al et al , 2006a et al , 2009 , 2011 et al et al , 2011 , 2011 et al , 2012 , 2011 , 2010 et al et al , 2006 , 2000 , 2006 , 2012 et al et al Reference et al et al et al et al et al et al et al Sripisut Cheenpracha Lekphrom Kanokmedhakul Yenjai Thongthoom Sripisut Panseeta Chinworrungsee Isaka Karaket Panseeta Wirasathien Rukachaisirikul Chinworrungsee Boonlarppradab Isaka Ichino Panthama Source BCC 3975 (seed fungus) BCC 3975 (seed fungus) Craib (herbal plant) (Finet & Gagnep.) Ban (Annonaceae) (tree) (Finet & Gagnep.) Ban (Annonaceae) (tree) (saprophytic ascomycetes) (saprophytic (Pierre) Guillaumin (Rutaceae) (herbal plant) (Pierre) Guillaumin (Rutaceae) (herbal plant) (Pierre) (Apocynaceae) (tree) (“Tung Fa”) (“Tung (Apocynaceae) (tree) (Roxb.) Merr. (Rubiaceae) (tree) (Roxb.) Merr. Lam. (Rhamnaceae) (“Phut-sa”) Lam. (Rhamnaceae) (“Phut-sa”) (King) J. Sinclair (Annonaceae) BCC 21906 (soil gram-positive bacteria) Burm. f. (Rutaceae) (herbal plant) (“San Soak”) Annonaceae) (herbal plant) (“Kon Krok”) (Scheff.) Swingle (Rutaceae) (tree) (“Masung” in Thai) in (“Masung” (tree) (Rutaceae) Swingle (Scheff.) sp BCC 7579 (seed fungus) Hunter (Piperceae) (herbal plant) Hunter (Piperceae) Table 1 Table sp BCC 28517 (leafhopper pathogenic fungus) Feroniella lucida Feroniella Alstonia macrophylla Goniothalamus laoticus (“Khao-lam-dong”) Polyalthia debilis Clausena harmandiana Clausena harmandiana Clausena excavata Ziziphus mauritiana theobromae Menisporopsis Trichoderma Neonauclea purpurea Ziziphus mauritiana Pseuduvaria setosa Piper chaba theobromae Menisporopsis Saccharopolyspora Torrubiella Goniothalamus marcanii Chaetomium longirostre b b ml) / g , 4.2 b µ , 0.6 b b ( a b , 10.3 , 3.9 , 3.7 b b b c b b b b IC50 4.1 3.1, 0.3 2.5 0.6 0.34 7.6 0.3 5.4, 4.1 5.5-10.7, 3.2-6.4 3.3, 2.9 6.7 7.3 2.9 4.2 6.6 3.7 2.8 2.7 28.8 , ) S E , 5a S -pyrazine- H New antiplasmodial compounds discovered in Thailand from 2000 to 2013. to 2000 from Thailand in discovered compounds antiplasmodial New octenoic acid, ] indol- 5- yl ester, (6 a 5’] pyrrolo[1’, 4’’:4’, - oxepino[3’’, 8, ) - 5, 5a, 7a, 8, 14a, 15- hexahydro- H R , 14 H , 14a R , 8 R -methylmukonal)} 8-acetonyldihydronitidine aporphine ((-)-nordicentrine) (bidebiline C, D) bis-dehydroaporphine carbozole {clausine H, heptaphylline (mukonal, 7-methoxymukonal O A, nummularine B, H) cyclopeptide (hemsine dithiodiketopiperazine (6- 2, 4, 6- trimethyl- 5- oxo- , 3- hydroxy- (5 7a, 14a- bis(methylthio) - 7, 14- 12- dihydroxy- dioxo- 7 2’:4, 5] pyrazino[1, 2- hirsutellone F indole (α-dihydrocadambine) mauritine M oxoaporphine liriodenine piperine dimer (chabamide) pyrazinedione (5-benzyl-1-hydroxy- A, B saccharosporone A, B torrubiellin A marcanine A, B, C longirostrerone

Compound Alkaloid alstonisine 7a 3-(hydroxyphenylmethylene)-3 2,6-dione) Angucyclinone Anthraquinone Azaanthraquinone Azaphilone

764 Vol 45 No. 4 July 2014 Discovery and Development of Antiplasmodials in Thailand , , 2001 , 2006 et al et al , 2006b et al , 2011 , 2011 , 2003 , 2002 , 2000 , 2002 , 2003a , 2000 , 2009 , 2001; Isaka et al et al et al , 2012 et al , 2006 et al et al et al et al et al , 2000 et al et al Reference et al et al et al , 2001b Karaket Dettrakul Kittakoop Jaturapat et al Intaraudom Wirasathien Tuntiwachwuttikul 2006a Ichino Yenjai Chinworrungsee Kongsaeree Intaraudom Rukachaisirikul Nilanonta Nilanonta Nilanonta Nilanonta Source BCC 1449 (pathogenic fungus) (insect pathogenic fungus) (Pierre ex Finet & Gagnep.) R. E. Fr. ex Finet & Gagnep.) R. E. Fr. (Pierre (Pierre) Guillaumin (Rutaceae) (Pierre) (marine fungus) BCC 1614 (insect pathogenic fungus) BCC 1614 (entomopathogenic fungus) (Roxb.) Merr (Rubiaceae) (tree) Roxb. (Fabaceae) (purple orchid tree) Roxb. (Fabaceae) (purple orchid (Blanco) Merr. (Simaroubaceae) (Simaroubaceae) (Blanco) Merr. Crib (Anonaceae) (herbal plant) W. W. Smith (Boraginaceae) (tree) (“Sak Hin”) Smith (Boraginaceae) (tree) W. W. sp BCC 26924 sp BCC 26924 sp (endophytic fungus) sp 1788 (insect pathogenic fungus) Table 1 (Continued). 1 Table Neonauclea purpurea Cordia globifera Bauhinia malabarica Cordyceps pseudomilitaris Streptomyces Ellipeiopsis cherrevensis (Annonaceae) (herbal plant) Harrisonia perforate (herbal plant) Polyalthia viridis Clausena harmandiana oceanica Halorosellinia Geotrichum Streptomyces Cordyceps Paecilomyces tenuipes Paecilomyces tenuipes hemipterigenum Verticillium ml) / g µ ( a b b IC50 11.3 3.1, 1.5, 0.2, 0.3, 3.6, 2.1 2.0, 18.0, 3.0, 0.9 1.1-64 2.4, 2.1 7.1 10.5 3.6 0.1-0.7, 8.5-12.3 4 4.7, 2.6 0.2 5.3 2.0, 2.4, 1.6 1.6, 1.8, 2.3 0.3, 0.2, 1.1, 0.5, 1.9, 0.2

)-pentylisochro- R )-pent-11-enylisochroman-1-one; R -methylalloptaeroxylin 2,6-dimethoxy-1,4-benzoquinone ring (alliodorin, 10-membered meroterpene, C, cordiaquinol B, cordiachrome cordiachrome C, elaeagin, globiferin) racemosol (demethyl racemosol; preracemo- A, B; racemosol) sol compounds 11 carbazomycin B, C 2’,4’-dihydroxy-3’-(2-hydroxybenzyl)-6’- O clausarin; dentatin 5-carboxymellein cyclomarin C A) cycloheptapeptide (cordyheptapeptide CB, A, (allobeauvericin cyclohexadepsipeptide A, B beauvericin, beauvericin enniatin B, B4, C, G, H, I

Compound Benzoquinone Bioxanthracene Carbazomycin Chalcone methoxychalcone Chromone Clerodane 16-hydroxycleroda-3,13(14)Z-dien-15,16-olide Coumarin (7-butyl-6,8-dihy- dihydroisocoumarin droxy-3( 7-butyl-6,8-dihydroxy-3( man-1-one Cyclomarin Cyclopeptide

Vol 45 No. 4 July 2014 765 Southeast Asian J Trop Med Public Health , 2001 , 2008 , 2007 , 2009 et al , 2013 et al et al , 2002 , 2007 , 2006 et al , 2012 , 2004 , 2013 et al et al et al et al et al , 2009 et al , 2010 , 2005c , 2007 , 2000 , 2000 et al Reference et al et al et al et al et al et al Vongvilai Vongvilai Isaka Vongvanich Isaka Chinworrungsee Isaka Khumkomkhet Isaka Astelbauer Antia Rajachan Namdaung Moosophon Rukachaisirikul Boonphong Rukachaisirikul Innok Source BCC 9616 (insect pathogenic fungus) (fungus) (marine fungus) Merr. (Leguminosae) (herbal plant) Merr. Van Heurck & Müll. Arg. (Combretaceae) (tree) (Combretaceae) Arg. & Müll. Heurck Van BCC 1660 (insect pathogenic fungus) Blume (Moraceae) (Monkey Jackfruit tree) Blume (Moraceae) (Monkey Jackfruit L. (Leguminosae) (tree) “Chong Kho” or L. (Leguminosae) (tree) (Kurz) Nervling (Thymelaeceae) (herbal plant) (“Po plant) (herbal (Thymelaeceae) Nervling (Kurz) Roxb. (Fabaceae) (tree) BCC 2594 (insect pathogenic fungus) Lour. (Fabaceae) (tree) (“Thong Long”) (Fabaceae) (tree) Lour. Heckel (Guttiferae) (herbal plant) sp BCC 1067 (wood-decayed fungus) sp BCC 1067 (wood-decayed fungus) sp (Meliaceaea) (herbal plant) Table 1 (Continued). 1 Table Unidentified fungus BCC 2629 Hirsutella nivea Hirsutella kobayasii Paecilomyces cinnamomeus oceanica Halorosellinia Xylaria Chaetomium brasiliense Xylaria Aglaia kola Garcinia Enkleia siamensis Hai”) Tao Artocarpus rigidus griffithii Combretum Erythrina subumbrans Bauhinia purpurea “Siao Dok Daeng”) Erythrina stricta Erythrina fusca ml) / g , b µ b ( , a b,d b,d b b , 15.7 b b b IC50 3.3, 3.4 (1:1 of M1 mixture and M2), 3.4 5.8 2.8 4.9 17 0.6 4.7, 9.1, 3.2, 4.9, 1.2, 3.4, 2.9 5.8-11.2 0.054 0.061 1-10 2.3 2.4, 3.7, 7.9 9.7 13.0 7.0, 3.7 9.5 2.5 9.2 M2, N / enniatin L, M1 A hirsutellide A) paecilodepsipeptide cytochalasin Q 19,20-epoxy-cytochalasin Q mollicellin B, C, E, J, K, L, M (-)-depudecin aglafoline, rocaglamide biflavonoid (3′′,4′,4′′′,5,5′′,7,7′′-heptahy droxy-3,8-biflavanone) chamaaejasmine cycloartobiloxanthone, 7-demethy- artonin F, lartonol E flavan ((2S)-3′,4′-dihydroxy-5,7- dimethoxyflavan; griffinoid C, D) flavanone lespedezaflavanone B (abyssinone V, demethoxymatteucinol 5-hydroxysophoranone lonchocarpol A)

hirsutatin B Cytochalasin Depsidone Depudecin Flavagline Flavonoid Compound

766 Vol 45 No. 4 July 2014 Discovery and Development of Antiplasmodials in Thailand , 2006 , 2008 , 2007 , 2004a , 2004 , 2010 et al et al et al et al , 2007 , 2009 et al , 2009 et al , 2006 , 2008 , 2008 , 2013 et al et al et al , 2011 , 2013 , 2004 et al et al et al , 2002a , 2002b Reference et al et al et al et al et al et al Yenjai Yenjai Khaomek Kanokmedhakul Rukachaisirikul Limmatvapirat Songsiang Rukachaisirikul Maneerat Isaka Isaka Dramae Sirilak Sirilak Rukachaisirikul Boonphong Kamolkijkarn Thongtan Seephonkai Source Boerl. (Euphorbiaceae) (Trinidad chevron tarantula) chevron (Trinidad BCC 4785 (soil fungus) Merr. (Leguminosae) (tree) Merr. Merr. (Leguminosae) (tree) Merr. Craib (Meliaceae) (tree) (‘‘Ta Suea’’) (‘‘Ta Craib (Meliaceae) (tree) (Zingiberaceae) rhizome Roxb. (Leguminosae) (herbal plant) (entomopathogenic fungus) L. (Leguminosae) (tree) “Chong Kho” or L. (Leguminosae) (tree) L. (Fabaceae)) (herbal plant) (sea sponge) (sea sponge) (Pierre) Finet & Gagnep (Annonaceae) (Pierre) BCC 5311 (lignicolous mangrove Ascomycete) (lignicolous mangrove BCC 5311 Lour. (Fabaceae) (tree) (“Thong Long”) (Fabaceae) (tree) Lour. sp BCC 33756 sp BCC 1528 (insect pathogenic fungus) Table 1 (Continued). 1 Table Kaempferia parviflora Erythrina fusca Polyalthia evecta (“Nam-tou-lang” or “Tong-lang”) Erythrina subumbrans Abrus precatorius parviflora Dalbergia Erythrina subumbrans Chisocheton siamensis spectabilis Streptomyces Aigialus parvus Streptomyces Pachastrissa nux Pachastrissa nux Cordyceps militaris Bauhinia purpurea “Siao Dok Daeng” Psalmopoeus cambridgei Hirsutella fimbricalyx Strophioblachia , b ml) / , g b µ , 1.9 b b b ( a , 10.8 b , 4.8 , 0.4 , 2.6 b b b b b b IC50 4.1, 3.7 5.0, 1.6, 12.5, 3.9 50, 3.7 2.8 1.5 8.2 3.2 6.3, 2.9, 2.1, 3.2, 2.9 0.04 6.6, 2.2 3.6, 3.2 1.7 0.3 4.5 4.5 11.2 5.8 2.7 8.0 2.7, 3.2 5,7,3’,4’-tetramethoxyflavone, 5,7,4’-trime- thoxyflavone flavone (citflavanone, lonchocar- prenylated A, lupinifolin, 8-prenyldaidzein) pol 19-(2-furyl)nonadeca-5,7-diynoic acid, isoflavanone (vogelin C) Q) isoflavanquinone (abruquinone isoflavone (dalparvone erysubin F) 6α-acetoxyepoxyazadiradione, azadiradione, dysobinin, epoxyazadiradione, mahonin A1 bafilomycin (aigialomycin D, hypothemycin) resorcylic A, B samroiyotmycins trisoxazole (kabiramide B, C, D, J, K kabiramide I, L) cordycepin (bauhinoxepin H, bauhi- dihydrobenzoxepin noxepin I, bauhinoxepin J) cysteine knot (psalmopeotoxin II) A) tetrapeptide (hirsutellic acid 9-O-demethyltrigonostemone, 3,6,9-trime Flavone Furan 19-(2-furyl)nonadeca-5,7-diynmethylester Isoflavonoid Limonoid Macrolide Nucleoside Oxepin Peptide Phenanthrenone thoxyphenanthropolone Compound

Vol 45 No. 4 July 2014 767 Southeast Asian J Trop Med Public Health , , 2004 , 2007 , 2007 , 2004b et al , 2004 et al et al et al et al , 2002 , 2000 et al , 2003b , 2002 , 2012 et al et al et al et al , 2002a , 2002a , 2001c , 2010 et al Reference et al et al et al et al Hiranrat Chinworrungsee Isaka Seephonkai Isaka Rukachaisirikul Rukachaisirikul Nilanonta Isaka Isaka Rukachaisirikul Tuntiwachwuttikul 2006b Jiwajinda Limmatvapirat Boonlaksiri Source BCC 1449 (insect pathogenic fungus) BCC 4162 (seed fungus) BCC 4785 BCC 4785 (soil fungus) (Aiton) Hassk. (Myrtaceae) (herbal plant) Merr. (Leguminosae) (tree) Merr. Jack. (Simaroubaceae) (herbal plant) Jack. (Simaroubaceae) (insect pathogenic fungus) Roxb. (Piperaceae) (herbal plant) (“Cha-plu”) Roxb. (Piperaceae) herbal plant) (“Cha-plu”) Merr. (Moraceae) (tree) Merr. L. (Fabaceae) ) (herbal plant) sp BCC 3050 (lichen fungus) Roxb. (Fabaceae) (tree) sp BCC 2165 (insect pathogenic fungus) Table 1 (Continued). 1 Table Rhodomyrtus tomentosa theobromae Menisporopsis spectabilis Streptomyces Microsphaeropsis spectabilis Streptomyces Erythrina stricta Erythrina subumbrans hemipterigenum Verticillium Cordyceps nipponica Torrbiella Piper sarmentosum Piper sarmentosum Eurycoma longifolia Abrus precatorius Artocarpus integer , b,e ml) , / g b,e µ ( a , 5.0 , 5.5-13.7 b,e b b b,e b,e IC50 1.5 4.0 7.8 3.2, 2.4, 2.2, 2.9, 2.7, 2.2, 0.9 0.005 3.8 3.4, 5.5 7.1, 22 0.07, 0.04 8.1 6.5, 18.9 4.5, 3.9 5.3 23.8 5.3 1.5 9.4, 8.2, 1.7 - E -ethenyl) -demethylpreus- trans -4-(3-methyl- O trans -4-isopentenyl-3,5,2 ‘,4’- trans tomentosone A tomentosone A menisporopsin spectinabilin A, 3’- deoxypreussomerin G, H, I E, F, somerin I, preussomerin metacycloprodigiosin A erstagalin A, erythrabyssin II erybraedin A, B pyrenocine A torrbiellone sarmentine pyrrolidine, 1-piperettyl sarmentosine sarentine; longilactone, 11-dehydroklaineanone, 15β-O-acetyl-14-hydroxyklaineanone, 14,15β-dihydroxyklaineanone, 15β-hydroxyklaineanone B) isoflavanquinone (abruquinone (4-methoxy-2,2-dimethyl- prenylated but-1-enyl)-3,5,2 ‘,4’- tetrahydroxystilbene) Phloroglucinol Polylactone, macrocyclic Polypropionate Preussomerin Prodigiosin Pterocarpan Pyrenocine Pyridone A, B cordypyridone Pyrrolidine Quassinoid Quinone Stilbene 6-(2-(2,4-dihydroxy)phenyl- chromene, tetrahydroxystilbene, Compound

768 Vol 45 No. 4 July 2014 Discovery and Development of Antiplasmodials in Thailand , et al , 2009 , 2009 , 2005 , 2009 , 2009 , 2010 et al et al , 2003 et al et al et al et al et al Reference Lekphrom Lekphrom Rangkaew Chanthathamrongsiri 2012 Sutthivaiyakit Sutthivaiyakit Monkolvisut and Sutthivaiyakit, 2007 Thongnest Thongtan Lekphrom Source L. (Euporbiaceae) (herbal plant) (Finet & Gagnep.) Ban (Annonaceae) Doan ex Sudddee & A. J. Paton (Lamiaceae) Doan ex Sudddee & Carey (Zingerberaceae) (herbal plant) Carey Jacq. (Euphorbiaceae) Jacq. (Euphorbiaceae) (Carter) (marine sponge) Gagnep. (Euphorbiaceae) (herbal plant) (Blume) Petermann (Myristicaceae) (herbal plant) massa cf. Table 1 (Continued). 1 Table Goniothalamus laoticus (“Khao-lam-dong”) (tree) Knema glauca Stylissa integerrima Jatropha integerrima Jatropha Pedilanthus tithymaloides Sam Si”) Yaek or “Sa Yaek” (“Sa Kaempferia marginata Mup”) (“Tup kongensis Croton (“Plao Ngeon” or “Plao Noi”) Anisochilus hamandii b ml) / g µ , 8.1 b ( a , 0.5 b IC50 2.6, 7.9 2.8 8.8 7.9, 3.3 4.1, 5.4 4.0, 3.4, 4.3, 4.4 8.8, 3.2 2.8, 1.0, 1.0 3.0, 4.7, 7.2, 2.9 - - O seco ,- )-1,11- S R -8,9- ,9 S ,13 ent ,5 R S -7α,11β- ,11 ,2 S R seco ,10 S ,9 -8,9- -triptobenzene L; 12- S -acetyl-19- acetyloxycoleon ,5 ent epi O S -acetyl-18- acetyloxycoleon Q; )-1,2,11-trihydroxypimara- O -8,14-epoxy-7α-hydroxy-11β- R ,13 seco R -deacetyl-6- ,11 O -8,9- S (+)-3-acetylaltholactone, (+)-altholactone, A) diterpenoid acylphenol (malabaricone amphilectane (8-isocyanato-15-formamido- 8-isocyano-15-for- amphilect-11(20)-ene; 8-isothiocya- mamidoamphilect-11(20)-ene; caniojane 1,11-bisepi-caniojane, A jatropholone 2-hydroxyjatropholone, diterpenoid O-acylated jatrophane (1α,13β,14α-trihydroxy-3β,7β-dibenzoyloxy- E-diene; 9β,15 β-diacetoxyjatropha-5,11 1α,8β,9β,14α,15β-pentaacetoxy- 3β-benzoyloxy-7-oxojatropha-5,12-diene; 7,8β,9β,14α,15β-pentaacetoxy-3β-benzoyloxy- 1α,7, 1α,5β-dihydroxyjatropha-6(7),12-diene; 8β,9β,14α,15β-hexaacetoxy-3β-benzoyloxy-5β- oxygenated primarane ((1 8(14),15-diene; 1 8,9-secokaurane ( ent β-acetoxykaura-8(14),16- 7α -hydroxy-11 miscellaneous (9α-13α-epidioxyabiet-8(14)- en-18-oic acid; 4- Styryl lactone goniotriol Terpenoid nato-15-formamidoamphilect-11(20)-ene) hydroxyjatropha-6(7),12-diene) 10 dihydroxypimara-8(14),15-diene) diacetoxykaura-8(14),16-dien-9,15-dione, acetoxy-16-kauren-9,15-dione, dien-9,15-dione) deacetyl-6- 12- Q) Compound

Vol 45 No. 4 July 2014 769 Southeast Asian J Trop Med Public Health , 2009 , 2002 , 2001 , 2001 , 2005 , 2005 , 2007 , 2011 et al et al et al et al et al , 2006 , 2003 , 2006 , 2006 , 2003 et al et al , 2006 , 2004 et al , 2011 et al et al et al et al et al et al , 2006 et al et al , 2000 Reference et al et al Isaka Vongvanich Pittayakhajonwut Chinworrungsee Lhinhatrakool Hemtasin Pittayakhajonwut Chinworrungsee Sawadjoon Rukachaisirikul Kanokmedhakul Suksamrarn Suksamrarn Suksamrarn Suksamrarn Suksamrarn Rukachaisirikul Saewan BCC 3900 (fungus) (Mont.) (fungus) E.T. Geddes (tree) E.T. Ding Hou (Celastraceae) BCC 5149 (marine fungus) (marine fungus) Corr. (Meliaceae) (tree) (“Langsat Khao”) (Meliaceae) (tree) Corr. Pierre (Rhamnaceae) Pierre (Rhamnaceae) Pierre (Rhamnaceae) Pierre BCC 3878 (seed fungus) Kitamura (Compositae) (weed) (endophytic fungus) Geddes (Rubiaceae) (herbal plant) Geddes (Rubiaceae) (herbal plant) BCC 8996 (fungus) Merr. (Leguminosae) (herbal plant) Merr. sp BCC 1067 (wood-decayed fungus) Table 1 (Continued). 1 Table Xylaria Camchaya calcarea Xylaria ianthinovelutina oceanica Halorosellinia Maytenus mekongensis (herbal plant) (“Naam Kaan Chaang”) Phomopsis archeri Kionochaeta pughii oceanica Halorosellinia Stachybotrys nephrospora Lentinus conatus Prismatomeris fragrans Ziziphus cambodiana Gardenia saxatilis Ziziphus cambodiana Ziziphus cambodiana Gardenia saxatilis Erythrina stricta Lansium domesticum , b ml) Source / g µ , 3.1 b b , 3.9 , 3.5 b b IC50a ( 0.5, 0.3 3.0, 1.6, 1.2, 2.1, 1.6, 0.3, 0.7 2.7 13, 19 3.1 2.5 0.8 2.4 13, 19 0.8, 0.1 3.1, 2.1, 3.4 5.9 3.0 2.9 3.7 6.5, 0.9 1.5, 3.8 4.6 3.2, 2.4, 6.9 - - - - - epi - -coumar -benzoyl- -mekongensine, O O-E-p uncarinic acid / epi -benzoyl-1-deacetyl-9’- -isocentratherin, 5- O epi Compound -vanillylceanothic acid) O centratherin, lychnophorolide B) centratherin, lychnophorolide / elemophilane ((+)-phaseolinone, (+)-phome- (5- germacrolide isogoyazensolide, goyazensolide, isocen tratherin, isogoyazensolide, lychnophorolide A lactone (7β-hydroxy-3,11(13)-eudesmadien- 12,8-olide) ide derivative) acid-containing (9’-de oxygenated wilfordic acetoxymekongensine, 7- mekongensine, 1- deacetoxymekongensine, 1- 1-deacetylmekongensine) B phomoarcherin A pughiinin (stachybotrydial spirodihydrobenzofuran and lactone derivative) pan triquinane (dihydrohypnophilin, epoxydione, panepoxydone) β-acetylolean-12-en-28-olic acid) acid) ceanothane (zizyberenalic acid coumaroyloxyursolic (mixture) ester (3- lupine (betulinaldehyde, 2- oylalphitolic acid ) A, B messagenic acid soyasapogenol B tetranortriternenoid (domesticulide B, C, D) Sesquiterpenoid none) acid and aceton ophiobolane (halorosellinic Sesterterpenoid acid and acetonide derivative halorosellinic Triterpenoid

770 Vol 45 No. 4 July 2014 Discovery and Development of Antiplasmodials in Thailand - = 50 , 2002 , 2007 , 2006 et al et al , 2009 , 2009 , 2006 , 2009 et al , 2008 , 2008 , 2005 , 2013 , 2009 , 2001 , 2013 , 2010 et al et al et al et al et al et al et al et al et al , 2013 et al et al et al , 2009 , 2005b , 2001a , 2000 Reference et al et al et al et al et al Kasettrathat Kasettrathat Wongsa Seephonkai Pittayakhajonwut Isaka Isaka Laphookhieo Laphookhieo Mahabusarakam Laphookhieo Laphookhieo Haritakun Moosophon Seephonkai Suntornchashwej Isaka Innok Moosophon Suksamrarn strain 94 (chloroquine resistant, IC resistant, strain 94 (chloroquine isolates from Myanmar (resistant to 4-ami Myanmar (resistant isolates from P. falciparum P. f P. falciparum P. M); d µ (Lour.) Blume (Clusiaceae) (herbal plant) (Lour.) Blume (Clusiaceae) (herbal plant) (Lour.) Boerl. (Euphorbiaceae) (herbal plant) (Lour.) Blume (Clusiaceae) (herbal plant) (Lour.) (Wight & Arn.) (Santalaceae) (tree) & (Wight (Kurz) (Malvaceae) (shrub) (Lour.) Blum (Clusiaceae) (herbal plant) (Lour.) L. (Clusiaceae) (fruit tree) (“mangkhut”) tree) L. (Clusiaceae) (fruit Van Heurck & Müll. Arg. (Combretaceae) Arg. & Müll. Heurck Van (Ascomycota) (fungus) BCC 3878 (seed fungus) BCC 4651 (marine gastropod mollusc, commonly known (marine gastropod Lour. (Leguminosae) (tree) (“Thong Long”) (Leguminosae) (tree) Lour. sp CRIF1 (marine-derived fungus) sp BCC 8401 (insect pathogenic fungus) sp BCC 1323 (teak endophytic fungus) sp BCC 1681 (insect pathogenic fungus) minimum inhibitory concentration; minimum sp BCC 1067 (wood-decayed fungus) c M; µ Table 1 (Continued). 1 Table b strain (chloroquine resistant, IC50 = 0.39 resistant, strain (chloroquine unidentified marine fungus CRI247-01 (Order Pleosporales) unidentified marine fungus CRI247-01 (Order Nodulisporium Decaschistia parviflora Cordyceps Kionochaeta pughii Aschersonia Phomopsis Cratoxylum cochinchinense Cratoxylum maingayi mangostana Garcinia Cratoxylum cochinchinense Cratoxylum cochinchinense terreus Aspergillus griffithii Combretum fimbricalyx Strophioblachia Bursatella leachii as sea hare) Xylaria Erythrina fusca Emericella rugulosa wallichianum Scleropyrum ml) Source / g b µ b b , 3.9 P. falciparum P. b , 6.8 b,f b,f b b b IC50a ( 1-10 1-10 11.4 2.2 0.3 0.2 0.1, 0.3 3.0 1.2, 1.7, 1.3 0.05-17 4.9, 2.6, 7.2, 3.2 0.7, 3.9, 2.0 7.9 14.4 0.019 5.4 19 9.1 1.9 7.2 ACC Niger e mixture) mixture) -methylcelebixanthone E/Z O E/Z Compound M). µ vermelhotin (1:2 ( A nodulisporacid parvifloral B, F cordytropolone pycnidione A dimer (ascherxanthone phomoxanthone A, B) 1,3,7-oxygenated (fuscaxanthone E) 1,3,5,6-oxygenated (formoxanthone C, I, macluraxanthone) gerontoxanthone (27 derivatives of α-mangostin) prenylated miscellaneous (celebixanthone, cochinchinone C, β-mangostin, 5- vismione B, E, F V butyrolactone (1-(4-hydroxy-3,5-dimethoxy- diarylpropane phenyl)-3- (4-hydroxy-3-methoxyphenyl) A fimbricalyx B, fimbricalyxanhydride malyngamide X (E)-methyl-3-(4-methoxyphenoxy)propionate (phaseollidin) pterocarpan rugulosone acid scleropycric

Tetramic acid Tetramic acid Tetronic (phytoalexin) Trinorcadalene Tropolone Xanthone Miscellaneous propane) Concentration required to inhibit parasite growth in culture by 50%; in culture to inhibit parasite growth Concentration required a noquinolines, antifolates and mefloquine); 0.29

Vol 45 No. 4 July 2014 771 Southeast Asian J Trop Med Public Health

which should render it less susceptible to further resistance mutations. The high in vivo efficacy in a SCID mouse model ofP. , 2010 , 2012 , 2012 falciparum malaria, good oral bioavailabil- et al et al et al ity, favorable enzyme selectivity, and good safety characteristics bode well for P218 Reference as a potential candidate for pre-clinical development. Yuthavong Yuthavong Krungkrai and Krungkrai 2011 Krungkrai, Khonkathip Takashima The malaria parasite synthesizes pyrimidines de novo from bicarbonate -

M) (HCO3 ), ATP, glutamine, aspartate, and µ

( 5-phosphoribosyl-1-pyrophosphate. a - Ki 0.0005 0.18 0.005, 0.008 170 HCO3 is formed from the ionization

of carbonic acid produced from CO2 catalyzed by CA. Pfca encodes an α-type targets. Zn2+-metalloenzyme possessing catalytic properties distinct from that of the human host CA (reviewed by Krungkrai and Krungkrai, 2011). Screening of a collection of 34 aromatic/heterocyclic sulfonamides, most of which are Schiff’s bases derived from sulfanilamide/homosulfanilamide/4- aminoethylbenzene sulfonamides re- Plasmodium falciparum Plasmodium Table 2 2 Table vealed inhibitors specific to PfCA at moderate to low µM and some at sub-µM quadruple mutant (N51I, C59R, S108N and I164L). quadruple b concentrations. SAR showed that groups

Lead inhibitor substituting the aromatic ureido or aromatic azomethine moieties and variations in the lengths of the parent sulfonamide are critical parameters governing their inhibitory properties. One derivative, 4-(3,4-dichlorophenylureido)thioureido- Drugs developed against developed Drugs benzenesulfonamide, is the most effective 2, 4-diamino-6-ethyl-5-(3-(2-(2-carboxyethyl)phenoxy) thioureido-benzenesulfonamide 4-(3,4-dichlorophenyl-ureido) 3-(1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-3-yl)-2, octanoate; 3-(1,4-dihydro-2-hydroxy-1, 2-dimethylpropyl tetradecanoate 4-dioxonaphthalen-3-yl)-2,2-dimethylpropyl (P218) propoxy)pyrimidine acid 4-(2-hydroxy-4-methoxyphenyl)-4-oxobutanoic inhibitor of PfCA activity and is also the most potent in inhibiting P. falciparum growth in culture as well as that of P.

b berghei in vivo. In the de novo biosynthesis pathway of pyrimidines, the final two steps of gen- erating uridine 5’-monophosphate (UMP) require addition of ribose 5-phosphate from 5-phosphoribosyl-1-pyrophosphate to orotic acid, catalyzed by orotate phos-

Target carbonic anhydrase bc1 cytochrome reductase dihydrofolate 5’-monophosphate orotidine decarboxylase phoribosyltransferase (OPRT) to form Concentration required to inhibit enzyme activity by 50%; Concentration required a orotidine 5’-monophosphate (OMP),

772 Vol 45 No. 4 July 2014 Discovery and Development of Antiplasmodials in Thailand followed by decarboxylation of OMP by (Acanthacaea) commonly known as snake orotidine 5’-monophosphate decarbox- jasmine and used in Thailand for the treat- ylase (OMPDC) to produce UMP. These ment of cancer, were synthesized and 24 two enzymes exist as a heterotetrameric show significant antiplasmodial activity

(OPRT)2(OMPDC)2 complex, and inhibi- with IC50 values in the range of 0.03-16 tion of PfOMPDC is lethal to malaria µM, and SAR indicates that the length parasite (Krungkrai et al, 2005). In silico of the aliphatic chain and the presence screening of 156 compounds identified of C-20 substituents on the propyl chain 14 putative inhibitors against PfOMPDC affect activity (Kongkathip et al, 2010). with IC50 values ranging from 60 to 250 Compounds with 7 (namely 3-(1,4-di- µM, while further analysis of the crys- hydro-2-hydroxy-1,4-dioxonaphthalen- tal structure of PfOMPDC complexed 3-yl)-2,2-dimethylpropyl octanoate) and with 4-(2-hydroxy-4-methoxyphenyl)- 13 (namely 3-(1,4-dihydro-2-hydroxy-1,4- µ 4-oxobutanoic acid (IC50 = 170 M) re- dioxonaphthalen-3-yl)-2,2-dimethylpro- vealed that the inhibitor occupies a part pyl tetradecanoate) carbon side chains of the active site that overlaps with the have promising antiplasmodial activity phosphate-binding region in OMP- and (0.13 and 0.03 µM against P. falciparum UMP-bound complex and that the space K1, respectively) and acceptable in vitro occupied by pyrimidine and ribose rings therapeutic index (IVTI) (IC50 against of OMP and UMP is not blocked by this Vero cell line/ IC50 against P. falciparum) inhibitor (Takashima et al, 2012). The (> 1,990 and 1,825, respectively); both carboxyl group of the inhibitor causes inhibit P. falciparum 3D7 mitochondrial a dramatic movement of two loops (L1 cytochrome bc1 with IC50 value of 5 and and L2), which play a pivotal role in the 8 nM, respectively, being 3,000-fold more recognition of substrate and product, and sensitive than against the rat cytochrome thus combining parts of the inhibitor with bc1, suggesting that such naphthoqui- pyrimidine and ribose rings of OMP and none ester scaffolds have good potential UMP represents a promising avenue for in being developed into antimalarials. further development of these compounds However, it is worth noting that both P. as potential potent antimalarials. falciparum strains employed in the study Cytochrome bc1 complex (ubiquinol: are atovaquone-sensitive. cytochrome c oxidoreductase, respiratory Complex III) catalyzes the transfer of CONCLUDING REMARKS electrons from ubiquinol to cytochrome c in the mitochondrial electron-transfer As can be seen from Table 1, the likeli- chain and in P. falciparum cytochrome bc1 hood of discovering from local flora and can be effectively inhibited by the antima- fauna potent antiplasmodial compounds larial atovaquone, a naphthoquinone, but that have the potential of gaining interest this drug’s current clinical use has been of pharmas to invest in developing them severely curtailed by the appearance of re- into antimalarials is exceedingly small. A sistant parasites (reviewed by Nixon et al, search of 86 Thai medicinal plant samples 2013). In an effort to discover alternatives representing 48 species from 35 genera to atovaquone, 26 novel naphthoquinone in 16 families revealed only two new aliphatic esters derived from rhinacan- compounds with antiplasmodial activity, thin, isolated from Rhincanthus nasutus namely, marcanine A (azaanthraquinone

Vol 45 No. 4 July 2014 773 Southeast Asian J Trop Med Public Health from Polyalthia viridis) and 16-hydroxy- a chromene isolated from Encelia farinosa cleroda-3,13(14)Z-dien-15,16-olide (clero- Gray (Asteraceae), known as brittlebush, dane from Goniothalamus marcanii) with a common desert shrub of northwestern µ IC50 value of 2.5 and 3.6 g/ml, respective- Mexico and southwestern United States, µ ly (Table 1) (Ichino et al, 2006). Learning having IC50 value of 0.02 and 0.01 M, from the Chinese experience of discover- respectively against P. falciparum K1, ing artemisinin, concerted efforts should and IVTI (compared with L6 rat skeletal be directed to identify a local herbal myoblasts) of 6800 and 1800, respectively plant and/or medicinal concoction used (Harel et al, 2013). traditionally in treating jungle fever, not In Thailand, a possible candidate is only colds or flu-like symptoms. A start in α-mangostin, a xanthone from Garcinia this approach is the recent report of anti- mangostana L. (Clusiaceae), commonly plasmodial activity of ethanolic extract of known as mangosteen and “mangkhut”, Dracaena loureiri Gagnep. (Dracaenacae) and its fruit is considered among Thais and “Benjakul” Formulaton 1, composing as being the “queen of fruits”. Other than of 5 dried medicinal plants, namely Piper their antiplasmodial property, xanthones chaba Hunt. (Piperaceae), Piper interruptum extracted from mangosteen exhibit a Opiz. (Piperaceae), Piper sarmentosum variety of biological activities including Roxb. (Piperaceae), Plumbago indica Linn. antibacterial, antifungal, antiinflamma- (Plumbaginaceae), and Zingiber officinale tory, antioxidant, cytotoxic, and poten- Rosc. (Zingiberaceae ) (IC50 values of 1.0- tial cancer chemopreventive (Chin and 10 µg/ml against P. falciparum K1 and 3D7) Kinghorn, 2008). However, only a limited (Thiengsusuk et al, 2013). number of antiplasmodial SAR studies of A neglected area of antiplasmodial xanthone analogs have been undertaken, drug research in Thailand is the chemical although by such simple modifications as modifications of promising lead natural the addition of alkyl groups containing products in order to generate SAR that protonable nitrogen atoms in order to can lead to analogs having more desir- allow accumulation and interaction with able pharmacological properties in terms heme in the malaria parasite acidic food of specificity, bioavailability and lack of vacuole for enhancement of inhibition of toxicity. For example, Mancini et al (2008) P. falciparum growth in culture are readily have reported the synthesis of a series of achievable (Riscoe et al, 2005). analogs, with SAR when possible, derived In spite of the fact that target-based from natural antiplasmodial compounds rationale-driven drug designs have and of marine organisms (mainly sponges), will produce clinical efficacious thera- which include endoperoxides (peroxy- peutics, their useful life spans in the field plakoric acid methyl esters, plakortin), will ultimately be limited by the even- isonitriles (amphilectane diterpenes, ka- tual evolution of drug-resistant malaria lihinol A), alkaloids (6-bromoaplysinop- parasites. In order to accelerate the drug sin, cycloprodigiosin, heptylprodigiosin, discovery process, a complementary ap- manzamine A, metacycloprodigiosin) and proach currently advocated is phenotypic 2 miscellaneous compounds (aplasmomy- screening of large chemical libraries using cin, 15-oxopuupehenol). A more recent ex- high throughput techniques, (Butera, 2013 ample is the synthesis of benzylamine and and references therein). A limited number phenylpropylamine analogs of encecalin, of highly potent (sub nM) novel antiplas-

774 Vol 45 No. 4 July 2014 Discovery and Development of Antiplasmodials in Thailand modial compounds from such screening antiplasmodial activities of a biflavonoid efforts are now available (known as ma- GB1 from Garcinia kola stem bark. Planta laria box) (Guiguemde et al, 2012), which Med 2010; 76: 276-7. should be exploited in screening against Astelbauer F, Gruber M, Brem B, et al. Activity P. falciparum enzyme and non-enzyme of selected phytochemicals against Plasmo- targets studied by Thai researchers, viz. dium falciparum. Acta Trop 2012; 123: 96-100. DNA β-like polymerase (Nunthawarasilp Auparakkitanon S, Wilairat P. Cleavage of DNA et al, 2007), 3’-5’ DNA helicase (Sun- induced by 9-anilinoacridine inhibitors of tornthiticharoen et al, 2006), β-hematin topoisomerase II in the malaria parasite (hemozoin) formation (Auparakkitanon Plasmodium falciparum. Biochem Biophys Res et al, 2003), hydroxymethylpterin pyro- Commun 2000; 269: 406-9. phosphokinase-dihydropteroate synthase Auparakkitanon S, Noonpakdee W, Ralph

(Rattanachuena et al, 2009), plasmepsin RK, Denny WA, Wilairat P. Antimalarial II (Sriwilaijaroen et al, 2006) and serine 9-anilinoacridine compounds directed at hematin. Antimicrob Agents Chemother hydroxymethyltransferase (Sopitthum- 2003; 47: 3708-12. makhun et al, 2012). Boonlaksiri C, Oonanant W, Kongsaeree P, Kit- Interestingly, in the past attempts takoop P, Tanticharoen M, Thebtaranonth have been made to convert anticancer Y. An antimalarial stilbene from Artocarpus drugs into antimalarials, viz. analogs of integer. Phytochem 2000; 54: 415-7. amsacrine (Auparakkitanon and Wilairat, Boonlarppradab C, Suriyachadkun C, Rach- 2000) and of rhinacanthin (Kongkathip et tawee P, Choowong W. Saccharosporones al, 2010), the reverse process is gaining A, B and C, cytotoxic antimalarial anugu- interest, as demonstrated by the potent cyclinones from Saccharopolyspora sp. BCC antiproliferative abilities of artemisinins, 21906. J Antibiot (Tokyo) 2013; 66: 305-9. synthetic peroxides and DHFR inhibitors Boonphong S, Puangsombat P, Baramee A, (including P218) against 91 human cancer Mahidol C, Ruchirawat S, Kittakoop P. lines (Hooft van Huijsduijnen et al, 2013). Bioactive compounds from Bauhinia pur- A merger of these two pipelines in drug purea possessing antimalarial, antimyco- discovery and development should be bacterial, antifungal, anti-inflammatory, a win-win situation in the treatment of and cytotoxic activities. J Nat Prod 2007; malaria and cancer. 70: 795-801. Butera JA. Phenotypic screening as a screening component of drug discovery programs ACKNOWLEDGEMENTS targeting novel antiparasitic and antimy- The author is grateful to Associate cobacterial agents: an editorial. J Med Chem Professor Maliwan Phakpraphai for her 2013; 56: 7715-8. careful reading of the manuscript and Pro- Chanthathamrongsiri N, Yuenyongsawad S, fessor Prapon Wilairat for proof-reading Wattanapiromsakul C, Plubrukarn A. the final draft. Bifunctionalized amphilectane diterpenes from the sponge Stylissa cf. massa. J Nat Prod 2012; 75: 789-92. REFERENCES Cheenpracha S, Ritthiwigrom T, Laphookhieo Antia BS, Pansanit A, Ekpa OD, Ekpe UJ, Ma- S. Alstoniaphyllines A-C, unusual nitroge- hidol C, Kittakoop P. Alpha-glucosidase neous derivatives from the bark of Alstonia inhibitory, aromatase inhibitory, and macrophylla. J Nat Prod 2013; 76: 723-6.

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