Table Of ContentProgress in the Chemistry of Organic Natural Products
A. Douglas Kinghorn · Heinz Falk ·
Simon Gibbons · Yoshinori Asakawa ·
Ji-Kai Liu · Verena M. Dirsch Editors
117
Antimalarial
Natural Products
By David G. I. Kingston and
Maria Belen Cassera
Progress in the Chemistry of Organic Natural
Products
SeriesEditors
A.DouglasKinghorn ,CollegeofPharmacy,TheOhioStateUniversity,Columbus,
OH,USA
HeinzFalk ,InstituteofOrganicChemistry,JohannesKeplerUniversity,Linz,
Austria
SimonGibbons ,SchoolofPharmacy,UniversityofEastAnglia,Norwich,UK
YoshinoriAsakawa ,FacultyofPharmaceuticalSciences,TokushimaBunri
University,Tokushima,Japan
Ji-KaiLiu ,SchoolofPharmaceuticalSciences,South-CentralUniversityfor
Nationalities,Wuhan,China
VerenaM.Dirsch ,DepartmentofPharmaceuticalSciences,UniversityofVienna,
Vienna,Wien,Austria
AdvisoryEditors
GiovanniAppendino ,DepartmentofPharmaceuticalSciences,UniversityofEastern
Piedmont,Novara,Italy
RobertoG.S.Berlinck ,InstitutodeQuímicadeSãoCarlos,UniversidadedeSão
Paulo,SãoCarlos,Brazil
Jun’ichiKobayashi,GraduateSchoolofPharmaceuticalSciences,Hokkaido
University,Sapporo,Japan
AgnieszkaLudwiczuk ,DepartmentofPharmacognosy,MedicalUniversityof
Lublin,Lublin,Poland
C.BenjaminNaman ,DepartmentofMarinePharmacy,NingboUniversity,Zhejiang,
China
RachelMata ,FacultaddeQuímica,UniversidadNacionalAutónomadeMéxico,
MexicoCity,DistritoFederal,Mexico
NicholasH.Oberlies ,DepartmentofChemistryandBiochemistry,Universityof
NorthCarolina,Greensboro,NC,USA
DenizTasdemir ,MarineNaturalProductsChemistry,GEOMARHelmholtzCentre
forOceanResearch,Kiel,Schleswig-Holstein,Germany
DirkTrauner ,DepartmentofChemistry,NewYorkUniversity,NewYork,NY,USA
AlvaroViljoen ,DepartmentofPharmaceuticalSciences,TshwaneUniversityof
Technology,Pretoria,SouthAfrica
YangYe ,StateKeyLaboratoryofDrugResearchandNaturalProductsChemistry
Department,ShanghaiInstituteofMateriaMedica,Shanghai,China
Thevolumesofthisclassicseries,nowreferredtosimplyas“Zechmeister”afterits
founder, Laszlo Zechmeister, have appeared under the Springer Imprintever since
theseries’inaugurationin1938.Itisthereforenotreallysurprisingtofindoutthat
thelistofcontributingauthors,whowereawardedaNobelPrize,isquitelong:Kurt
Alder,DerekH.R.Barton,GeorgeWellsBeadle,DorothyCrowfoot-Hodgkin,Otto
Diels, Hans von Euler-Chelpin, Paul Karrer, Luis Federico Leloir, Linus Pauling,
VladimirPrelog,withWalterNormanHaworthandAdolfF.J.Butenandtservingas
membersoftheeditorialboard.
Thevolumescontaincontributionsonvarioustopicsrelatedtotheorigin,distribu-
tion,chemistry,synthesis,biochemistry,functionoruseofvariousclassesofnaturally
occurringsubstancesrangingfromsmallmoleculestobiopolymers.
Each contribution is written by a recognized authority in the field and provides
acomprehensiveandup-to-datereviewofthetopicinquestion.Addressedtobiol-
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orientationinarapidlydevelopingdiscipline.
AllcontributionsarelistedinPubMed.
Moreinformationaboutthisseriesathttps://link.springer.com/bookseries/10169
Progress in the Chemistry of Organic Natural
Products
Volume 117
· ·
A. Douglas Kinghorn Heinz Falk
· · ·
Simon Gibbons Yoshinori Asakawa Ji-Kai Liu
Verena M. Dirsch
Editors
Antimalarial Natural
Products
By David G. I. Kingston and Maria Belen Cassera
Editors
A.DouglasKinghorn HeinzFalk
CollegeofPharmacy InstituteofOrganicChemistry
OhioStateUniversity JohannesKeplerUniversity
Columbus,OH,USA Linz,Austria
SimonGibbons YoshinoriAsakawa
SchoolofPharmacy FacultyofPharmaceuticalSciences
UniversityofEastAnglia TokushimaBunriUniversity
Norwich,UK Tokushima,Japan
Ji-KaiLiu VerenaM.Dirsch
SchoolofPharmaceuticalSciences DepartmentofPharmaceuticalSciences
South-CentralUniversityforNationalities UniversityofVienna
Wuhan,China Vienna,Wien,Austria
ISSN2191-7043 ISSN2192-4309 (electronic)
ProgressintheChemistryofOrganicNaturalProducts
ISBN978-3-030-89872-4 ISBN978-3-030-89873-1 (eBook)
https://doi.org/10.1007/978-3-030-89873-1
©TheEditor(s)(ifapplicable)andTheAuthor(s),underexclusivelicensetoSpringerNature
SwitzerlandAG2022
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Preface
Overthelast200years,higherplantshavecontinuedtoaffordnumerousimportant
single-chemicalentitydrugsforavarietyofhumanillnesses,includingcolchicine,
digoxin,galanthamine,morphine,paclitaxel,andvincristine.Moreover,itisperhaps
surprising that even in the last five years, compounds of plant origin are still
gainingdrugapprovalbytheU.S.FoodandDrugAdministration.Examplesinclude
cannabidiol (for the treatment of Lennox-Gastaut and Dravet syndromes), cocaine
hydrochloride (for use as a local anesthetic in nasal surgery), and d-mannitol (for
adjuncttherapyofadultpatientswithcysticfibrosis).
As detailed in this highly insightful volume by Professors David Kingston and
MariaCassera,theroleofplantcompoundsinproducingantimalarialchemothera-
peuticagentshasbeenespeciallymeritorious.Thetwoleadcompoundsquinineand
artemisininhavebeenextremelyimportantinthisregard,althoughatdifferenttimes
in history. The alkaloid quinine was isolated initially in pure form from Cinchona
barkbytheFrenchinvestigatorsPelletierandCaventouin1820.Asdetailedherein,
quinine and its key semi-synthetic derivatives such as chloroquine and primacrine
havehadveryimportantrolesintreatingmalaria,whichwasrampanteveninsome
temperatecountriesoftheworlduntilquiterecently.Artemisinin(qinghaosu),was
discoveredfromaplantusedinChinesetraditionalmedicineabout50yearsago,and,
for this breakthrough, Professor Youyou Tu shared the Nobel Prize in Physiology
or Medicine in 2015. Artemisinin is a sesquiterpene endoperoxide, and a number
of analogs are now utilized in combination chemotherapy for malarial infections,
including artemether, arteether, and artesunate. The last-mentioned derivative was
approved by the U.S. FDA in 2020, for administration as an intravenous injection
totreatseveremalariainadultsandpediatricpatients.Unfortunately,Plasmodium
falciparum, the main causative organism of many malarial infections, has become
resistanttoquinineanditsderivatives,andalsoisshowingevidenceofresistanceto
analogsofartemisinin.Therefore,thesearchfornewantimalarialagentsofnatural
originiscontinuing, and approaches totheir discovery are surveyed inthepresent
contribution. Toward the end of this volume, a wide range of secondary metabo-
litestructuraltypeswithdemonstratedantimalarialactivity,sourcednotonlyfrom
v
vi Preface
higherplantsbutalsofromterrestrialmicrobialandmarineorganisms,arediscussed
fortheirpromiseforfurtherdevelopment.
The interest of the present authors in the search for new antimalarial agents
emanatesfromtheirinvolvementinanInternationalCooperativeBiodiversityGroups
(ICBG)projectfundedbytheFogartyCenter,NationalInstitutesofHealth,Bethesda,
MD, USA, which was focused, in part, on investigating the bioactive constituents
of selected species of the flora of Madagascar. Later on, they carried out a project
to screen the plant extract collection prepared originally by Merck & Co. Phar-
maceutical Company, which is housed currently at the Baruch S. Blumberg Insti-
tute, Doylestown, PA, USA. The types of compounds shown with antiplasmodial
activitybyProfessorsKingstonandCasseraandtheirassociatesfromtheseprojects
havebeenrepresentativeofarangeofplantnaturalproductstructuraltypes,inclu-
siveofanthraquinone,indoliziniumalkaloid,phloroglucinol,andquinolonealkaloid
derivatives.
Columbus,OH,USA A.DouglasKinghorn
Linz,Austria HeinzFalk
Norwich,UK SimonGibbons
Tokushima,Japan YoshinoriAsakawa
Wuhan,China Ji-KaiLiu
Vienna,Austria VerenaM.Dirsch
Contents
AntimalarialNaturalProducts ........................................ 1
DavidG.I.KingstonandMariaBelenCassera
vii
Contributors
MariaBelenCassera Department of Biochemistry and Molecular Biology, and
CenterforTropicalandEmergingGlobalDiseases(CTEGD),UniversityofGeorgia,
Athens,GA,USA
DavidG.I.Kingston Department of Chemistry and the Virginia Tech Center for
DrugDiscovery,VirginiaTech,Blacksburg,VA,USA
ix
Antimalarial Natural Products
DavidG.I.KingstonandMariaBelenCassera
Contents
1 IntroductionandHistoryofMalaria ........................................... 1
2 MalariaBiology ........................................................... 4
2.1 TheMalariaParasite ................................................. 4
2.2 AMalariaTango:HostandVector ...................................... 6
3 NaturalProductsasAntimalarialAgents ....................................... 8
3.1 Quinine ............................................................ 8
3.2 QuinineAnalogs .................................................... 14
3.3 Artemisinin ......................................................... 18
3.4 OtherClinicallyUsedNaturalProducts ................................. 34
3.5 NaturalProductswithPotentAntiplasmodialActivity ..................... 37
3.6 Conclusion ......................................................... 82
References ..................................................................... 83
1 IntroductionandHistoryofMalaria
Malaria! The very word conjures up visions of sickness and disease, and well it
might.Thediseasehasbeenknownsinceancienttimes,withcuneiformtabletsfrom
Mesopotamia recording malaria-like deadly fevers, and references to tertian and
quartanfeverstypicalofmalariainthe270BCChinesemedicaltext“NeiChin”[1].
B
D.G.I.Kingston( )
DepartmentofChemistryandtheVirginiaTechCenterforDrugDiscovery,VirginiaTech,
Blacksburg,VA24061,USA
e-mail:[email protected]
M.B.Cassera
DepartmentofBiochemistryandMolecularBiology,andCenterforTropicalandEmerging
GlobalDiseases(CTEGD),UniversityofGeorgia,Athens,GA30602,USA
e-mail:[email protected]
©TheAuthor(s),underexclusivelicensetoSpringerNatureSwitzerlandAG2022 1
A.D.Kinghorn,H.Falk,S.Gibbons,Y.Asakawa,J.-K.Liu,V.M.Dirsch(eds.),
AntimalarialNaturalProducts,ProgressintheChemistry
ofOrganicNaturalProducts117,https://doi.org/10.1007/978-3-030-89873-1_1
