Synthesis and biological evaluation of novel 11-azaartemisinin derivatives
Abstract
Malaria is a devastating mosquito-borne disease caused by several species of Plasmodium protozoa, of which the most important is Plasmodium falciparum (Pf). Globally, the disease caused approximately 438 000 deaths in 2014; disease prevalence is highest in the African region. Artemisinin and its derivatives have emerged as the drugs of choice for treatment of malaria where they are used in artemisinin combination therapies (ACTs). However, emergence of resistance to artemisinins poses a global threat to current treatment regimens.
Chapter 3 comprises a review article that examines a relatively new artemisinin derivative, 11-azaartemisinin, and its scientific evolution throughout the past 20 years. Various routes to azaartemisinin derivatives are critically discussed and the biological activities of the azaartemisinin derivatives are examined in order to evaluate if this class of compound is suitable for carrying forward for development into new drugs in the fight against malaria. In general, the azaartemisinins that have been examined display promising antimalarial activities, and would appear to have several advantages over their artemisinin predecessors in being more stable and chemically robust. Decisively, the azaartemisinins cannot provide dihydroartemisinin (DHA) through metabolism or via hydrolysis. As the current clinical artemisinins, against which resistance is now emerging, characteristically provide DHA on metabolism or hydrolysis in vivo, the newer azaartemisinins will not have this disadvantage, especially as DHA has been fingered as the actual drug that induces resistance among the current clinical artemisinins. In Chapter 4 the synthesis of N-sulfonyl-11-azaartemisinin derivatives are described and the evaluation of the antimalarial activities against intraerythrocytic stages of chloroquine (CQ) sensitive Pf NF54 and CQ resistant Pf K1 and W2 parasites. The gametocytocidal activities were assessed against Pf NF54 blood-stage gametocytes using the luciferase and pLDH assays. Cytotoxicities of the compounds were also evaluated against the human fetal lung fibroblasts WI-38 cell line (HFLF) and were shown to be relatively non-toxic. The p-trifluoromethylbenzenesulfonyl-11-azaartemisinin derivative was the most active antimalarial compound with IC50 values between 2 – 3 nM, whereas the 2'-thienylsulfonyl derivative demonstrated the best late-stage (IV-V) activity against gametocytes with an IC50 value of 8.7 nM. These two compounds are thus potential candidates for further development. In Chapter 5 the evaluation of nine of the active antimalarial N-sulfonylazaartemisinin derivatives against the apicomplexan parasite Neospora caninum responsible for bovine abortion in beef and dairy cattle, are described. The antitumor activities were also determined in order to assess their parasitic versus intracellular activities in general. The 2,5-dichlorothienylsulfonyl-11-azaartemisinin was the most active against neosporosis with an IC50 value of 40 nM, whereas the hexadecanesulfonyl derivative demonstrated prominent antitumor activity against breast cancer cells.
Overall, the current study has resulted in the identification of compounds that exhibit varying antimalarial activities, some of which are comparable to the current clinically available artemisinins. These compounds serve as suitable candidates for additional research in order to evaluate their potential as future lead compounds for development into drugs against malaria. Also, several compounds display promising activities against the causative parasite of neosporosis, and likewise require further investigation to evaluate their potential. Malaria is 'n ernstige muskiet-oordraagbare siekte wat veroorsaak word deur spesies van Plasmodium protosoë, waarvan die belangrikste Plasmodium falciparum (Pf) is. Die siekte veroorsaak wêreldwyd ongeveer 438 000 sterftes per jaar waarvan die voorkoms van die siekte die hoogste is in die Afrika-streek. Artemisinien en sy derivate geniet voorkeur as geneesmiddels vir die behandeling van malaria waar dit gebruik word in kombinasie met artemisinien terapie. Die ontwikkeling van weerstand teen artemisinien hou ongelukkig 'n wêreldwye bedreiging in vir die huidige behandelingsvorm. Hoofstuk 3 bevat 'n oorsig artikel wat 'n relatiewe nuwe artemisinien derivaat, 11-azaartemisinien, en sy wetenskaplike evolusie van die afgelope 20 jaar, ondersoek. Verskeie sintetiese metodes om derivate van azaartemisinien te bekom, word krities bespreek. Die biologiese aktiwiteite van die azaartemisinien derivate word bestudeer om uiteindelik te bepaal of hierdie klas van geneesmiddels geskik is vir verdere ontwikkeling as nuwe geneesmiddels wat gebruik kan word in die stryd teen malaria. Oor die algemeen vertoon die azaartemisiniene wat ondersoek is belowende anti-malaria aktiwiteit. Dit wil voorkom asof hierdie klas van geneesmiddels menigte voordele inhou in vergelyking met hul artemisinien voorgangers. Die nuwer verbindings is meer stabiel, asook chemies meer robuus. Die azaartemisiniene kan nie dihydroartemisinien (DHA) deur middel van metabolisme of hidrolise voorsien nie. Die huidige kliniese artemisiniene, waar weerstand nou algemeen voorkom, vorm kenmerkende DHA in vivo wanneer dié gemetaboliseer word, of hidrolise ondergaan. Die nuwe azaartemisiniene sal dus nie oor hierdie nadelige eienskap beskik nie, veral noudat dit bewys kan word dat DHA die werklike oorsaak is van weerstand onder huidige kliniese artemisiniene. Hoofstuk 4 beskryf die sintese van N-sulfoniel-11-azaartemisinien derivate asook die evaluering van malaria-aktiwiteite teen intra-eritrositiese fases van chlorokien (CQ) sensitiewe Pf NF54 en CQ bestande Pf K1 en W2 parasiete. Die gametosiet aktiwiteite word ook bepaal teenoor Pf NF54 bloed-fase gametosiete met behulp van die lusiferase en pLDH toetse. Sitotoksisiteite van die verbindings is ook geëvalueer teenoor menslike fetale long fibroblaste WI-38 sellyn (HFLF) en het getoon dat die verbindings relatief veilig is. Die p-trifluorometielbenseensulfoniel-11-azaartemisinien derivaat was die mees aktiewe malaria verbinding met IC50 waardes tussen 2 – 3 nM, terwyl die 2'-tiofeensulfoniel derivaat die beste laat stadium (IV-V) aktiwiteit teen gametosiete gedemonstreer het met 'n IC50 waarde van 8,7 nM. Hierdie twee verbindings is potensiële kandidate vir verdere ontwikkeling. Hoofstuk 5 beskryf die evaluering van nege van die aktiewe malaria N-sulfonielazaartemisinien derivate teenoor die apikompleksia parasiet Neospora caninum, wat verantwoordelik is vir misgeboortes in vleis- en melkbeeste. Die antikanker aktiwiteite van die verbindings word ook bepaal sodat hul parasitiese aktiwiteite teenoor intrasellulêre aktiwiteite beoordeel kan word. Die 2,5-dichlorotiofeensulfoniel-11-azaartemisinien was die mees aktiewe verbinding teenoor neosporose met 'n IC50 waarde van 40 nM, terwyl die heksadekaansulfoniel derivaat prominente anti-kanker aktiwiteit teenoor borskankerselle gedemonstreer het.
Die huidige studie het gelei tot die identifisering van verbindings wat wissellende malaria aktiwiteite het, waarvan sommige verbindings se aktiwiteite vergelykbaar is met die huidige klinies beskikbare artemisiniene. Hierdie verbindings dien as geskikte kandidate vir verdere navorsing om hul potensiaal as toekomstige leidraadverbindings vir ontwikkeling as geneesmiddels teen malaria te evalueer. Van die verbindings toon belowende aktiwiteite teenoor neosporose en vereis ook verdere ondersoek om hul potensiaal te evalueer.
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