Published online: 2019-03-25 Original Papers Antiplasmodial Lycorane Alkaloid Principles of the Plant Family Amaryllidaceae Authors Jerald J. Nair, Johannes van Staden Affiliation ABSTRACT Research Centre for Plant Growth and Development, The spread of malaria is thought to have followed human ex- University of KwaZulu-Natal Pietermaritzburg, Scottsville, pansion out of Africa some 60–80 thousand years ago. With South Africa its prevalence in pantropical countries of the world and epi- center localized in Africa, malaria is now considered an un- Key words necessary burden to overworked and under-resourced health- alkaloid, amaryllidaceae, antiplasmodial, malaria, medicinal care structures. Plants have long afforded a fertile hunting plant ground for the search and identification of structurally diverse antimalarial agents, such as quinine and artemisinin. This sur- received January 17, 2019 vey examines the antiparasitic properties of the family Ama- revised March 12, 2019 ryllidaceae via the antiplasmodial activities demonstrated for accepted March 14, 2019 its lycorane alkaloid principles. Of these, 24 were natural com- Bibliography pounds identified in 20 species from 11 genera of the Amaryl- DOI https://doi.org/10.1055/a-0880-5414 lidaceae family, whilst the remaining 28 were synthetically Published online March 25, 2019 | Planta Med 2019; 85: 637– derived entities based on the lycorane skeleton. These were 647 © Georg Thieme Verlag KG Stuttgart · New York | screened against ten different strains of the malarial parasite ISSN 0032‑0943 Plasmodium falciparum, wherein the parent compound lyco- rine was shown to be the most potent with an IC50 of Correspondence 0.029 µg/mL in the FCR-3 strain seen to be the best. Struc- Prof. Johannes van Staden ture-activity relationship studies revealed that good activities Research Centre for Plant Growth and Development, were detectable across both the natural compounds as well as School of Life Sciences, University of KwaZulu-Natal the synthetically accessed derivatives. Such studies also high- Pietermaritzburg lighted that there are several inherent structural features that Private Bag X01, Scottsville, 3209 Pietermaritzburg, define the lycorane alkaloid antiplasmodial pharmacophore, South Africa such as the nature of its ring systems and properties of its Phone:+27332605130,Fax:+27332605897 substituents. Mechanistically, a limited number of studies [email protected] confirmed that lycorane alkaloids manifest their action by tar- geting enzymes associated with the plasmodial FAS‑II biosyn- thetic pathways. Overall, these alkaloids have provided useful, convenient, and accessible scaffolds for antimalarial-based drug discovery. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Introduction ABBREVIATIONS Despite the implementation of intensive prevention, control, and ED effective dose treatment strategies by world health bodies such as the WHO, EtOH ethanol malaria continues to be a burden to healthcare structures, partic- IC inhibitory concentration ularly in tropical and subtropical regions of the world [1]. There MeOH methanol were over 200 million cases of malaria in 2017, 90% of which oc- SI selectivity index curred in Africa, mainly in its sub-Saharan region [1]. Over 400000 TM traditional medicine deaths from malaria were recorded during 2017, again mostly on WHO World Health Organization the African continent [1]. Although global incidence rates have di- minished by as much as 18% between 2010 and 2017, substantial Nair JJ, van Staden J. Antiplasmodial Lycorane Alkaloid … Planta Med 2019; 85: 637–647 637 Original Papers increases were unexpectedly realized during this period for several noline alkaloid constituents [8]. Apart from their significant array countries in the Americas [1]. Around US$3 billion worth of invest- of structural diversity, these alkaloids are also characterized by a ment in 2017 alone was channelled towards programs across dis- wide range of biological properties, particularly in the cancer and ciplines involved in the struggle against malaria [1]. The areas motor neuron disease arenas [9]. In the microbial area, promising funded, amongst others, included studies on (i) the insect vector antibacterial and antifungal activities have been described for sev- and insect resistance, (ii) insecticides, (iii) the pathogen and path- eral members of the family [10, 11]. The lycorine alkaloids are the ogen resistance, (iv) bioengineering, (v) the search for new drugs, largest of the nine alkaloid groups discernible for the Amaryllida- (vi) multidrug resistance, (vii) development of vaccines, (viii) in- ceae [8]. Biologically, they have shown the most promise as po- fection, and (ix) epidemiology [1]. tential anticancer agents [12]. This survey examines the antipara- Malaria is caused by a group of parasitic protozoans belonging sitic properties of the Amaryllidaceae via the antiplasmodial activ- to the genus Plasmodium [2]. Although there are over one hun- ities described for its lycorane alkaloid constituents. It covers the dred species of Plasmodium, five, including Plasmodium falcipa- activities of both natural compounds isolated from the various rum, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, species of the family as well as their semisynthetically accessed and Plasmodium knowlesi, are known to cause infections in hu- derivatives against different strains of the malaria pathogen P. fal- mans [3]. P. falciparum is the chief malaria-causing pathogen in ciparum. Also considered are structure-activity relationship stud- humans [3]. It is transmitted by various insect vectors, but mainly ies that have sought to improve activities as well as to grasp the by representatives of the mosquito genus Anopheles such as underlying elements of the lycorane antiplasmodial pharmaco- Anopheles gambiae [3]. Requiring both insect and vertebrate hosts phore. to survive, following the initial mosquito bite, the pathogen can remain sequestered as an hypnozoite for several months in the liv- Crinum L. er or other host tissue, or become active as a merozoite once in- fection sets in [3]. These then pass from liver cells into the blood With around 150 known species, Crinum is one of the largest where they undergo continuous cycles of erythrocytic infection, genera of the Amaryllidaceae [13]. Nearly 30 of its members are passing from the trophozoite and schizontic stages into new mer- found with a fairly wide distribution in South Africa [13]. It holds ozoites, at which point the cell bursts, releasing these bodies to the distinction of affording the first alkaloid constituents of the repeat the infection cycle [3]. Other merozoites can also develop family that were studied for antiplasmodial effects [14]. In this re- into mature gametocytes that are taken up with the blood follow- gard, phytochemical studies were carried out on ethanolic ex- ing a bite from a fertilized female mosquito [3]. These then ma- tracts of Crinum amabile Donn ex Ker Gawl. from a bulb collection ture in the insect gut, where male and female gametocytes also made in Bangkok, Thailand, accompanied by antiplasmodial activ- fuse to form ookinetes, which differentiate into new sporozoites ity screening [14]. The parent compound lycorine (1)(▶ Fig. 1) that migrate to the salivary glands of the bug in advance of the was identified via spectroscopic means including 2D NMR data first step of the infection process [3]. analysis and thereafter subjected to a screen against the chloro- There has been a long and close involvement of plants in tradi- quine-sensitive and chloroquine-resistant P. falciparum strains D- tional systems of medicine associated with the remediation of 6 and W-2, respectively [14]. It exhibited similar activities in both malaria [4]. In fact, well over 1000 individual plant taxa from vari- plasmodial strains with ED50s of 0.32 and 0.30 µg/mL, respectively ous regions around the globe have been ratified with such partic- [14]. In order to establish whether this effect was due to direct ular functions in TM [4]. These have led to the discovery of life-sav- antiplasmodial effects rather than to cellular toxicity, lycorine ing medications such as quinine and artemisinin, which subse- was concurrently also screened against the human oral epider- quently set the stage for the advent of the modern day antimalar- moid KB cell line, where it exhibited an ED50 of 0.30 µg/mL [14]. ial drug discovery initiative [2, 5]. As a consequence, commercial The SI of 1 for lycorine, taking these values into consideration, drugs such as chloroquine and mefloquine, which have loosely was dwarfed in comparison to those calculated for artemisinin been modelled on the active quinine pharmacophore, served to (SIs > 33 300 and > 40 000 in both strains, respectively) [14]. Lyco- perpetuate discovery efforts in the synthesis-based sector [5]. rine has also been described in bulbs of the popular South African This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. There has also been significant interest in the vaccine develop- medicinal plants Crinum macowanii Baker and Crinum bulbisper- ment arena, although a commercially viable product is still to mum (Burm.f.) Milne-Redh. & Schweick., respectively [15, 16]. In reach the market [2]. This, together with the progressive loss of the first instance, it was shown to be active against the P. falcipa- efficacies of contemporary drugs as well as multidrug resistance, rum