The Phytochemistry and Pharmacology of Tulbaghia, Allium, Crinum and Cyrtanthus: ‘Talented’ Taxa from the Amaryllidaceae

Amaryllidaceae is a significant source of bioactive phytochemicals with a strong propensity to develop new drugs. The genera Allium, Tulbaghia, Cyrtanthus and Crinum biosynthesize novel alkaloids and other phytochemicals with traditional and pharmacological uses. Amaryllidaceae biomolecules exhibit multiple pharmacological activities such as antioxidant, antimicrobial, and immunomodulatory effects. Traditionally, natural products from Amaryllidaceae are utilized to treat non-communicable and infectious human diseases. Galanthamine, a drug from this family, is clinically relevant in treating the neurocognitive disorder, Alzheimer’s disease, which underscores the importance of the Amaryllidaceae alkaloids. Although Amaryllidaceae provide a plethora of biologically active compounds, there is tardiness in their development into clinically pliable medicines. Other genera, including Cyrtanthus and Tulbaghia, have received little attention as potential sources of promising drug candidates. Given the reciprocal relationship of the increasing burden of human diseases and limited availability of medicinal therapies, more rapid drug discovery and development are desirable. To expedite clinically relevant drug development, we present here evidence on bioactive compounds from the genera Allium, Tulgbaghia, Cyrtanthus and Crinum and describe their traditional and pharmacological applications.

T. acutiloba leaves are used as a culinary herb and snake repellent. It is used to treat barrenness, flu, bad breath, and as an aphrodisiac. It is also cultivated to keep snakes away from the homestead. [8] T. natalensis Although native to South Africa, but is now grown worldwide. It is used as a culinary herb and snake repellent. [53] T. cernua Commonly found in the Eastern Cape, Free State, Gauteng, KwaZulu-Natal, Limpopo, Mpumalanga, North West and Western Cape Provinces of South Africa.
It is used for ornamental purposes. [8] T. leucantha Widely distributed in southern Africa including Botswana, Lesotho, South Africa, Swaziland, Zambia, and Zimbabwe.
Its rhizome is scraped clean and boiled in stews or roasted as a vegetable. Its leaves and stems are used as a culinary herb and protective charm. [53]

T. ludwigiana
Commonly found in the Eastern Cape, KwaZulu-Natal, Northern Provinces of South Africa and in Swaziland.
It is traditionally used as a love charm. [53] 2

.3. Phytochemistry of Tulbaghia
Tulbaghia produces many different classes of compounds with diverse chemical structures dominated by sulfur-containing natural products ( Figure 1; Table S1).  Most compounds reported have a small molecular weight (<500) and are of a broad lipophilicity ( Figure 2).  Chemical space of compounds identified from T. violacea. Blue circles are sulfur-containing compounds while red circles are compounds devoid of sulfur in their chemical structures. PCA analysis carried out using DataWarrior [54].
Most compounds reported have a small molecular weight (<500) and are of a broad lipophilicity ( Figure 2).

Figure 2.
Analysis of cLogP and molecular weight space occupied by compounds identified in T. violacea. Blue circles are sulfur-containing compounds while red circles are compounds devoid of sulfur in their chemical structures. Plot generated using DataWarrior [54].
Tulbaghia violacea has been the most widely investigated for its phytochemistry and pharmacological properties. To date, close to 100 compounds have been tentatively identified, largely using gas chromatography techniques, from different parts of this species (Supplementary File S1) [55]. Most prominent are the sulfur compounds with reported broad-spectrum pharmacological activity. The thiosulfinate marasmicin (1) is the most prolific antimicrobial compound reported thus far from this genus [56]. This compound is formed from its precursor compound marasmin (2), by the enzyme c-lyase. Marasmicin Figure 2. Analysis of cLogP and molecular weight space occupied by compounds identified in T. violacea. Blue circles are sulfur-containing compounds while red circles are compounds devoid of sulfur in their chemical structures. Plot generated using DataWarrior [54].
Tulbaghia violacea has been the most widely investigated for its phytochemistry and pharmacological properties. To date, close to 100 compounds have been tentatively identified, largely using gas chromatography techniques, from different parts of this species (Supplementary File S1) [55]. Most prominent are the sulfur compounds with reported broad-spectrum pharmacological activity. The thiosulfinate marasmicin (1) is the most prolific antimicrobial compound reported thus far from this genus [56]. This compound is formed from its precursor compound marasmin (2), by the enzyme c-lyase. Marasmicin is responsible for the characteristic garlic odor generated by damaged plants [48]. Other notable compounds produced by this species include phenols, tannins and flavonoids [55], which are also responsible for several observed biological activities. Phytochemical characterization has been carried out, albeit minimally for other Tulbaghia species particularly T. alliacea and T. acutiloba. Unlike other genera in Amaryllidaceae, Tulbaghia is so far devoid of any alkaloids [57,58]. Despite the extensive in vitro pharmacological screening of extracts of Tulbaghia, it is possible that less effort has been made to isolate and identify their active principles. Hence, the phytochemistry of the genus Tulbaghia largely remains understudied. The chemicals structurers of noteworthy compounds isolated from T. violacea have been represented in Figure 3.

Pharmacological Studies of Tulbaghia Species
Because of its perceived medicinal value, Tulbaghia has received marked interest within the scientific community which has meticulously subjected it to various in vitro and in vivo studies experimentally evaluating its pharmacological activities. The volume of published studies generated from these investigations mirror the distribution of the genus with most articles on Tulbaghia having emerged from South Africa (Table 2), a country highly rich in this genus both in terms of species diversity and abundance.
characterization has been carried out, albeit minimally for other Tulbaghia species particularly T. alliacea and T. acutiloba. Unlike other genera in Amaryllidaceae, Tulbaghia is so far devoid of any alkaloids [57,58]. Despite the extensive in vitro pharmacological screening of extracts of Tulbaghia, it is possible that less effort has been made to isolate and identify their active principles. Hence, the phytochemistry of the genus Tulbaghia largely remains understudied. The chemicals structurers of noteworthy compounds isolated from T. violacea have been represented in Figure 3.  (4), β-D-fructofuranosyl-(2→6)-α-D-glucopyranoside (5), methyl-α-D-glucopyranoside (6), bis(methylthiomethyl) disulfide (7)-found to constitute 48% of volatiles in aerial parts of T. violacea [55], methyl-2-thioethyl thiomethyl trisulfide (8)-found to constitute 16% of volatile compounds in aerial parts of T. violacea [55], methyl (methylthio)methyl disulfide (9)-found to constitute 10 % of volatile compounds in aerial parts of T. violacea [55], naphthalene (10)-interestingly observed to significantly increase in concentration in plants infected by the fungus Beauveria bassiana in comparison to untreated controls [59], nonanal (11)-also observed to significantly decrease in concentration in plants infected by the fungi Beauveria bassiana in comparison to untreated controls [59] and finally kaempferol (12)-which possesses multiple biological activities including antioxidant, anticancer and anti-inflammatory properties [60][61][62].  (6), bis(methylthiomethyl) disulfide (7)-found to constitute 48% of volatiles in aerial parts of T. violacea [55], methyl-2-thioethyl thiomethyl trisulfide (8)-found to constitute 16% of volatile compounds in aerial parts of T. violacea [55], methyl (methylthio)methyl disulfide (9)-found to constitute 10 % of volatile compounds in aerial parts of T. violacea [55], naphthalene (10)-interestingly observed to significantly increase in concentration in plants infected by the fungus Beauveria bassiana in comparison to untreated controls [59], nonanal (11)-also observed to significantly decrease in concentration in plants infected by the fungi Beauveria bassiana in comparison to untreated controls [59] and finally kaempferol (12)-which possesses multiple biological activities including antioxidant, anticancer and anti-inflammatory properties [60][61][62].  The greatest numbers of pharmacological screens have been on interrogating the antimicrobial properties of this genus. This is closely followed by cardiovascular, antioxidants and cancer investigations as shown in Table 3. T. violacea prominently features, being the most studied species, with T. alliacea and T. aticulata having received minimal attention.

Antimicrobial and Antiparasitic Activity
As antimicrobial resistance continues to be a global health threat, the need to find therapeutic alternatives has never been more urgent [63]. This has encouraged scientists to search for novel alternatives with natural products having drawn marked interest as a potential oasis of new antimicrobial agents [64][65][66]. Tulbaghia has received significant relevance in this regard, with multiple studies providing ample evidence substantiating its use as an antimicrobial agent. Extracts of T. violacea have potency against many microbial species including those designated as priority by the World Health Organization. These include Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus) and Klebsiella pneumoniae (K. pneumoniae) with MIC values ranging between 20 and 300 µg/mL [67]. This activity was confirmed in another study where the disc diffusion method was used [68]. In addition to bacteriostatic activity, extracts of T. violacea have shown noteworthy potency against yeasts including Candida albicans (C. albicans) and Candida parapsilosis (C. parapsilosis) with MIC and MMC values ranging between 20 and 40 µg/mL [68]. Beyond human pathogens, extracts of T. violacea have activity against microorganisms of agricultural significance, for example against the fungus Aspergillus flavus (A. flavus), which is responsible for significant agricultural produce loss at a global scale due to production of aflatoxins [69]. Extracts of T. violacea compromised cell wall synthesis by significantly reducing β-glucan and chitin synthesis in A. flavus corresponding to a dose-dependent inhibition of the enzymes β-glucan and chitin synthase, respectively [70]. Further studies suggested an alternative mode of action (MoA) via reduction of ergosterol production in fungi [71]. Interestingly, related to value in agriculture, a patent has been filed on the use of extracts of T. violacea as a plant protecting remedy as a substitute for chemical agents [72]. Some thought-provoking studies have shown that growth conditions including light intensities, watering frequency and pH, substantially impact both growth and biological potency of T. violacea extracts against Fusarium oxysporum (F. oxysporum) [73,74]. Likewise, storage conditions of dried plant material also affect the antimicrobial potency of extracts [56]. In addition to antimicrobial activity, T. violacea has shown good antiparasitic activity against the parasitic worm Meloidogyne incognita (M. incognita) on tomato roots and in soil [75]. Antiparasitic activity has also been observed against Trypanosoma brucei (T. brucei) (IC 50 = 2.83 µg/mL) and Leishmania tarentolae (L. tarentolae) (IC 50 = 6.29 µg/mL) [67]. Table 4 highlights the antimicrobial activity of Tulbaghia species. MIC ranging from 20 to 300 µg/mL against Bacillus subtilis, methicillin-resistant S. aureus, S. epidermidis, E. coli, K. pneumoniae, P. aeruginosa, C. albicans and C. parapsilosis. [67]

T. violacea
Hexane and ethanol Flowers and callus cultures Moderate to strong broad-antimicrobial (E. coli, P. aeruginosa, S. aureus, Aspergillus niger and C. albicans) activity observed by zone of inhibition in the agar well disc diffusion method. [68] T. violacea Water Bulbs Significant reduction in A. flavus β-glucan and chitin synthesis corresponding to a dose-dependent inhibition of the enzymes β-glucan and chitin synthase, respectively.This results in inhibition of ergosterol production in the fungus. [70,71] T. violacea Acetone Bulbs Varied light intensities, pH and watering frequencies substantially impacted both growth and potency of plant extracts against the fungi F. oxysporum. [73,74] T. violacea Water Roots, bulbs, leaves and flowers Significantly compromised population densities of the nematode M. incognita race 2 on tomato roots and in the soil. [75] T. violacea Dichloromethane Bulbs Antiparasitic activity against T. brucei (IC 50 = 2.83 µg/mL) and L. tarentolae (IC 50 = 6.29 µg/mL). [67]

Anticancer Activity
Owing to the need for novel anticancer agents [76] and motivated by the success of cancer drug discovery projects from natural products [77], Mthembu and Motadi in (2014), evaluated the in vitro anticancer properties of crude methanol extracts of T. violacea using an MTT assay [78]. Extracts displayed time-and concentration-dependent antiproliferative properties against cervical cancer cell lines with an IC 50 of 150 µg/mL. The MoA was deciphered to be induction of apoptosis by a p53-independent pathway [78]. However, in contrast to this finding, continued work showed a proportional increase in the activity of caspase 3/7, and the expression of p53 genes strongly suggests apoptosis was triggered by a p53-dependent pathway [79]. This latter finding has been partly substantiated by data emerging from a study examining the antineoplastic properties of T. violacea against ovarian tumor cells. These extracts were shown to partially induce both apoptosis and necrosis with the most pronounced activity due to induction of autophagy [80].
Triple-negative breast cancer remains one of the most challenging cancers, being highly aggressive [81]. T. violacea extracts have demonstrated good cytotoxic activity against MDA-MB-231, with an IC 50 of 300 µg/mL [82]. Additionally, extracts inhibited migration of the cancer cell lines (metastasis), an important physiological process in the progression of this cancer [83]. In addition to the gynecological cancers, antineoplastic properties of T. violacea were further observed against pancreatic cancer with 63% inhibition of cell proliferation at a concentration of 250 µg/mL [68]. Against a non-sex-specific cancer, T. violacea showed noticeable activity against oral cancer with an IC 50 of 0.2 and 1 mg/mL for acetone and water-soluble extracts, respectively. Extracts activated caspase activity in a dose-dependent manner leading to induction of apoptosis in the human oral cancer cell line [84]. Using a bioassay guided approach, the active anticancer compounds in T. violacea have been identified to be glucopyranosides D-fructofuranosyl-β (2→6)-methyl-α-D-glucopyranoside and β-D-fructofuranosyl-(2→6)-α-D-glucopyranoside. Both compounds act by mediating induction of apoptosis in Chinese hamster cells by targeting the mitochondrial (intrinsic) pathway [85,86]. A summary of the anticancer activity of Tulbaghia species is shown in Table 5. [78] T. violacea Methanol, butanol, and hexane Leaves Methanol extract was prolific against multiple cell lines. Hela and ME-180 cell lines treated with methanol and hexane extracts showed an increase in caspase 3/7 activity.

Antioxidant Activity
The imbalance of reactive oxygen species (ROS) and antioxidants in the body can lead to oxidative stress [87]. This physiological condition can result in cellular and tissue damage [88]. Oxidative stress is associated with pathologies including cancer, cardiovascular disease, diabetes, and neurodegenerative diseases amongst others [88,89]. To avert the development of oxidative stress, attenuation of ROS has been identified as a viable target, with natural products seen as a potential source capable of neutralizing it [88]. Tulbaghia has generated some interest on this front particularly as it is rich in compounds with proven antioxidant activity including phenols, tannins and flavonoids. Multiple studies have demonstrated that extracts of Tulbaghia have marked antioxidant activity as assessed using different assays in vitro including Trolox equivalent antioxidant capacity (TEAC; also commonly referred to as the ABTS assay), ferric-reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) ( Table 6) [58,80,90,91]. Furthermore, using an in vivo model of Caenorhabditis elegans, T. violacea extracts attenuated oxidative stress produced by a free radical generator, (2,2 -azobis-2-amidinopropane dihydrochloride; AAPH), in the roundworm [80]. Data from these studies strongly suggested continued investigation of other species in the search for more potent antioxidant agents from Tulbaghia. The antioxidant activity of Tulbaghia species is highlighted in Table 6. 2.4.4. Antidiabetic, Anticardiovascular and Antithrombogenic Activity The incidence of diabetes and cardiovascular diseases continues to grow substantially across the globe, with both conditions combined accounting for the highest global morbidity and mortality [93,94]. Both of these chronic conditions are closely linked with cardiovascular disease being responsible for high morbidity and mortality in diabetic patients [95]. Tulbaghia has been documented in ethnopharmacological studies for the treatment of these ailments with emerging scientific data strongly validating its use. In streptozotocin diabetes-induced rat models, T. violacea attenuated diabetes-associated physiological conditions resulting in improved body weights, reduced fasting blood glucose levels, enhanced glucose tolerance and significantly elevated plasma insulin and liver glycogen content [96]. These data were corroborated in another study in which T. violacea noticeably reduced blood glucose and serum lipid (triglyceride (TG), total cholesterol (TC), and very low-density lipoprotein (VLDL)) levels while raising plasma insulin in a streptozotocin-induced diabetic rat model [97]. In an assessment for negating cardiovascular associated conditions, T. violacea in in vivo models markedly reduced systolic blood pressure (BP), diastolic BP, mean arterial pressure (MAP) and the heart rate in both ageinduced and spontaneous hypertensive rats [98]. Furthermore, dosing rats with extracts of T. violacea led to improved kidney function [99]. This is an essential pharmacological property as kidney function is impaired in hypertension leading to high morbidity and mortality in people suffering from cardiovascular diseases [100].
One of the multiple factors strongly associated with cardiovascular disease is atherothrombotic vascular disease (AVD). Platelet aggregation plays a role in development of AVD and subsequent cardiovascular events [90,101]. Against this background, platelet aggregation has been identified as a key process to target to prevent AVD. Encouragingly, T. violacea demonstrated marked potency being able to significantly inhibit platelet adhesion 15 min post-exposure (Table 7) [90,92]. T. violacea Methanol Rhizome Noticeably reduced blood glucose and serum lipid (TG, TC, and VLDL) levels while raising plasma insulin in a streptozotocin-induced diabetic rat model. [97]  Markedly reduced systolic BP, diastolic BP, mean arterial pressure and the heart rate in both age-induced and spontaneous hypertensive rats. [98] T. violacea Methanol Rhizome 50 mg/kg significantly improved kidney function in vivo. [99] T. acutiloba Hydro-methanolic extracts Roots, rhizomes, leaves and flowers All extracts inhibited the Angiotensin-1-Converting Enzyme in vitro (> 50 % inhibition at a concentration range of 125-1000 µg/mL). Extracts of leaves demonstrated activity comparable to that of the control drug ramipril. [91] Antithrombogenic

Miscellaneous Pharmacological Activity
In addition to diabetes and cardiovascular diseases, T. violacea has shown activity against another chronic condition, Alzheimer's disease. In an in vivo Alzheimer's disease transgenic C. elegans strain model, T. violacea significantly reduced 1-42 β-amyloid peptide formation (Table 8) [80]. T. violacea exhibited in vivo anticonvulsant activity by attenuating tonic convulsions induced by either pentylenetetrazole, bicuculline, picrotoxin, strychnine or NMDLA [102] and validating its traditional use for the treatment of epilepsy. T. violacea displayed marked tick repellence properties of fungus-exposed plants at low treatment concentrations (5% w/v and 10% w/v) [59], further enhancing its credentials as a potential agricultural product. Somewhat concerning is that, extracts of T. violacea also induced genotoxic effects albeit at high test concentrations (250, 500 and 1000 µg/mL) in the Allium cepa assay [103]. Furthermore, broad murine macrophage antiproliferative and cytotoxicity activity, influenced by extract test concentrations, type of solvent and plant part used, have been observed (Table 8) [104]. There is consequently a need for rigorous assessment of safety of extracts of this and other species of the genus Tulbaghia.

T. violacea Methanol Leaves
Demonstrated in vivo anticonvulsant activity by attenuating tonic convulsions induced by either pentylenetetrazole, bicuculline, picrotoxin, strychnine or NMDLA. [102] T. violacea Acetone Mixture of leaves and bulbs Marked tick repellence properties of fungus-exposed plants at low treatment concentrations (5 % w/v and 10 % w/v). [59] T. violacea Water Leaves, stems, and roots Induced conspicuous genotoxicity effects at high test concentrations (250, 500 and 1000 µg/mL) in the A. cepa assay. [103] T. violacea Water and ethanol Leaves, stems, and roots Broad murine macrophage antiproliferative and cytotoxicity activity influenced by both extract test concentrations, type of solvent and plant part used. [104]

Botanical Description
Species of the genus Allium are mostly found in warm-temperate and temperate zones of northern hemisphere as well as the boreal zone [105]. They are petaloid perennial herbs with parallel narrow leaves [33] and possess true bulbs, which are sometimes found on rhizomes [106]. Allium species are also characterized by onion or garlic odor and flavor similar to Tulbaghia [106]. Well known species include Allium cepa (A. cepa), Allium sativum (A. sativum), Allium ascalonicum (A. ascalonicum,), Allium porrum (A. porrum), and Allium schoenoprasum (A. schoenoprasum) (chive) [33] Allium has over 500 species making it the largest genus of Amaryllidaceae [6,7]. There are plethora of species, notably A. cepa and A. sativum [107][108][109]. Other examples grown for their medicinal and nutraceutical value are Allium ducissae (A. ducissae), Allium strictum (A. strictum), Allium umbilicatum (A. umbilicatum), Allium victorialis (A. victorialis), A. ascalonicum, Allium chinense (A. chinense), Allium tuberosum (A. tuberosum), Allium griffithianum (A. griffithianum), Allium oreoprasum (A. oreoprasum), and Allium oschaninii (A. oschaninii). Species tolerate varying climatic conditions, hence are geographically distributed across several continents, including Asia, Africa, the Americas, and Europe [107,110]. Fernandes et al. identified A. cepa that colonizes four different geographical regions of the Madeira island, an archipelago near the North Atlantic ocean with a hot and/or warm-summer Mediterranean climate conditions [107]. As the world's second-most relevant and cultivated horticulture vegetable crop, the onion (A. cepa), is distributed in over 175 countries and covers approximately six million hectares of the total land size of the world. Approximately two-thirds (66%) of global onion production emanates from the Asia, with China and India being the world's largest producers [111]. The maximal diversification of A. cepa is found in Iran and Afghanistan's Mediterranean basin. A. cepa thrives in areas with boreal, temperate, and tropical climates [108]. Similarly, A. sativum (garlic) bears close resemblance to onions and originates from Central Asia but has spread to include regions in Europe, America, and Africa [112]. The global garlic production estimates show that out of the 28.5 million tonnes (MT) of A. sativum cultivated, the majority (91.6%; 26.1 MT) were from Asia, followed by Europe  [113]. Furthermore, A. strictum, a Eurasian species, is distributed across China, Europe, Russia, Kazakhstan, Kyrgyzstan, and Mongolia [114,115]. A. umbilicatum, also called gladiolus or leek is usually localized in semi-arid regions and can tolerate sub-zero freezing winters [116]. It occurs as a weed in oases and span across Afghanistan, Iran, Pakistan, Turkmenistan, Tajikistan, and central and Eastern Asian regions [116]. As a representative circumboreal plant, A. victorialis has a wide altitudinal climatic tolerance [117]. It is predominantly located in lowland deciduous forest and subalpine birch forest, but seldom found in the subalpine meadows [117]. This species is scattered distribution on the island stretches of Japan, Russia, and Northern China [117,118]. Although practically grown throughout the world, A. ascalonicum, also called shallot, is native to the Middle East, and the name is derived from the Syrian city Ascalon. These shallots are distributed on the main islands of Indonesia, in Bangladesh, Japan, Korea, Malaysia, Taiwan, and Thailand [119]. A. chinense (locally referred to as Chinese/Japan onion or scallion, Kiangski scallion, oriental onion, Rakkyo) is an uncommon Allium species found mainly in the tropical and sub-tropical regions of China, Japan, Vietnam, and eastern areas of India [111,120]. A. tuberosum is an indigenous species native to southeastern Asia and regarded as a lateseasonal bloomer. During the initial growth phases, A. tuberosum is evergreen in hot climates but succumbs to cold climatic conditions. However, the Chinese chive becomes tolerant to all seasonal variations [121,122]. A. griffithianum and A. oreoprasum are geographically skewed towards the mountainous regions of Pakistan, Afghanistan, Kyrgyzstan, Uzbekistan, and Tajikistan [123], whereas A. oschaninii are located in the Darvaz mountains of Central Tajikistan [124].

Phytochemistry of Allium
Owing to the numerous traditional uses of these species, it is not surprising that the genus contains several phytoconstituents which may be responsible for their observed activity. Table 10 outlines various phytochemicals isolated, their geographic location and their biological activity.
Anti-ADP-aggregation activity in human blood platelets. Inhibition of human platelet aggregation. Cytotoxic activity against murine melanoma B16 and sarcoma XC.
Pigmented scales of red onion, bulbs, red onion skin waste  Antifungal activity against Sclerotium cepivorum. Antimicrobial activity. Strong inhibitory effect on human platelet aggregation generated by 2 µM ADP in both primary and secondary waves (adenosine).
Strong inhibitory effect on human platelet aggregation generated by 2 µM ADP in both primary and secondary waves (adenosine).
Antimicrobial activity against Aspergillus fumigatus and C. albicans. [197] NR: not reported. Molecules The chemical structures of compounds from the genus Allium are shown in Figure 4.
The chemical structures of compounds from the genus Allium are shown in Figure 4.

Pharmacological Effects of Allium
There are several species within Allium whose biological activities have been well established [198]. This section focuses on the pharmacological activities associated with these species.

Pharmacological Effects of Allium
There are several species within Allium whose biological activities have been well established [198]. This section focuses on the pharmacological activities associated with these species.
Previous studies have shown that garlic extract inhibit the growth of Blastocystis species in vivo and this effect was attributed to the several phytochemicals contained in garlic extracts. Examples of these phytochemicals are thiosulfinates and allicin which have been investigated to possess antibacterial and antiprotozoal effects [204,207]. Garlic extracts have been evaluated for antiviral effects against influenza B, human rhinovirus type 2, human cytomegalovirus (HCMV), parainfluenza virus type 3, Herpes simplex type 1 and -2, vaccinia virus, and vesicular stomatitis virus [208]. Danquah et al. again reported the antitubercular effects of analogues of disulfides from A. stipitatum as well as their antibiofilm and anti-efflux effects [209].

Antioxidant Properties
It has been reported that frequent garlic intake promotes internal antioxidant activities and reduces oxidative adverse effects either by increasing the endogenous antioxidant synthesis or reducing the production of oxidizing agents such as oxygen-free radical species (ORS) [210]. It has also been demonstrated that garlic possesses protective properties against gentamycin as well as acetaminophen-induced hepatotoxicity by improving antioxidant status, and regulating oxidative stress [200]. Garlic extract was found to elevate the activities of selected antioxidant enzymes (e.g., superoxide dismutase (SOD)) and decrease glutathione peroxidase (GSH-Px) in rats' hepatic tissues [13,118,211]. Saponins extracted from garlic were reported to scavenge intracellular ROS and protect mouse-derived C 2 C 12 myoblasts towards growth inhibition and H 2 O 2 -induced DNA damage [13,212]. A. ursinum aqueous extract also demonstrated antioxidant effect which lasted approximately 16 h [213]. A. hirtifolium was reported to possess antioxidant capacity by neutralizing the free radical species in a system [214].

Anti-Inflammatory Properties
It has been reported widely that garlic extracts and its related phytochemicals possess anti-inflammatory activity. A study by Ahmad et al. revealed that garlic extracts significantly impaired liver inflammation and damage caused by Eimeria papillata infections [215]. The mechanism underlying the anti-inflammatory effects of garlic was attributed to the inhibition of emigration of neutrophilic granulocytes into epithelia as described by Hobauer et al. [216] and Gu et al. [217]. The chloroform extract of aged black garlic acts by reducing NF-κB activation in human umbilical vein endothelial cells caused by tumor necrosis factor-α (TNF-α) and the methanolic extract also reported to prevent the cyclooxygenase-2 (COX-2) and prostaglandin E 2 (PGE 2 ) production by NF-κB inactivation [218]. A report by Jin et al. confirmed that thiacremonone (a sulfur compound isolated from garlic) prevents neuroinflammation and amyloidogenesis by blocking the NF-κB activity, and therefore makes it an ideal remedy to manage neurodegenerative disorders (e.g., Alzheimer's disease) related to inflammation [219]. Krejčová et al. reported that pyrithione and related sulfur-containing pyridine Noxides from Persian shallot possessed anti-inflammatory and neurological activity [220]. The extracts of A. stipitatum were reported to exhibit antibacterial effect in vivo against methicillin-resistant S. aureus [221]. Anti-inflammatory effect of A. hookeri on carrageenaninduced air pouch mouse model was also established by Kim et al. [222].

Anticancer Activity
Comparison of the anticancer effect of raw garlic extracts against other extracts from different plants found garlic to be the most effective and highly specific anticancer agent [223]. The anticancer mechanisms of garlic extracts were reported to be mediated via inhibition of cell growth and proliferation, regulation of carcinogen metabolism, stimulation of apoptosis, prevention of angiogenesis, invasion, and migration; and thus affording the anticancer agent with minimal negative effects [13]. Chabria et al. reported that allicin isolated from garlic suppresses colorectal cancer metastasis through enhancing immune function and preventing the formation of tumor vessels as well as surviving gene expression to enhance the cancer cell's apoptosis [224]. Fleischauer and Arab [225] reported that continuous garlic intake could decrease different kinds of cancer propagation such as cancer of the lung, colon, stomach, breast, and prostate. Piscitelli et al. reported that garlic reduced the plasma concentrations of saquinavir by approximately 50% in healthy participants after a 3-week garlic supplement intake. In addition to this, many researchers evaluated the antitumor and cytotoxic actions of garlic and its related constituents in vitro and in vivo [226].

Other Pharmacological Effects of Allium Species
Investigations on extracts of A. sativum (garlic) revealed anticholinesterase effects, which could be further developed and utilized in the management of Alzheimer's disease [227][228][229]. Garlic is known to possess hypolipidemic effects by reducing the total glycosaminoglycans concentration in heart and aorta [230]. Garlic is also known to reduce the level of cholesterol either by acid stimulation and excretion of neutral steroids or by reducing the cholesterogenic and lipogenic effects of fatty acid synthase, 3-hydroxy-3methyl-glutaryl-CoA reductase, malic acid, and glucose-6 phosphate dehydrogenase in hepatocytes [231]. Garlic tablets formulated by Ashraf et al. and administered at a dose of 600 mg/day for 12 weeks in diabetic patients with dyslipidemia resulted in high HDL, low LDL and TC levels [232].
Allicin, a constituent in garlic, was found to reduce diabetes mellitus in rats, which was similar to that demonstrated by glibenclamide and insulin [233]. Garlic extracts reduce body weight, adipose tissue mass and improved plasma lipid profiles in mice with high-fat diet-induced obesity [234]. The mechanism of these activities is downregulation of multiple gene expression such as adipogenesis along with upregulation of the mitochondrial inner membrane proteins expression [234]. Garlic extract is widely known to significantly control blood pressure by reducing both systolic and diastolic pressures [235]. Moreover, several reports have confirmed the antihypertensive effects of garlic [236]. Extracts of A. stipitatum were also assessed and established to possess significant wound healing properties [237].

Geographical Distribution of Crinum
Crinum, which also belongs to the Amaryllidaceae family, comprises approximately 160 beautiful lilies that grow naturally in coastal areas of the tropics and subtropics. They are widely distributed in Africa, Asia, Australia and America [238][239][240][241]

Traditional Uses of Crinum
Plants of the genus Crinum have been used to treat various diseases across the world [242]. In China and Vietnam, Crinum plants in traditional medicine are believed to possess antiviral and immune-stimulatory properties. A hot aqueous extract of Crinum latifolium (C. latifolium) is used as an antitumor agent. Crinum asiaticum (C. asiaticum) is used in Malaysia to treat rheumatism and to relieve local pain [239]. Crinum amabile Donn. (C. amabile) is used in Vietnam to induce emesis, as well as for rheumatism and earache [241].
The bulbs of C. asiaticum L. are used as a tonic, laxative and expectorant in Indian traditional medicine, as well as for treating urinary tract diseases [241]. The seeds are used as purgatives, diuretics, and tonics, while the raw roots are used as an emetic. The leaves are also very useful in the management of skin problems, inflammation and cough [241]. C. latifolium L. is also used to treat rheumatism, abscesses, earaches, and as a tonic. Crinum pratense (C. pratense) and Crinum longifolium (C. longifolium) are also used as bitter tonics, laxatives and in the management of chest illnesses [243].
Crinum zeylanicum (C. zeylanicum) L. is used in Sri Lanka to treat abscesses and fevers; the bulbs are also used as rubefacient in rheumatism and against snake bites; and the juice from the leaves used to treat earaches [244].
The roots of Crinum species have been used in African traditional medicine to cure urinary infections, coughs and colds, renal and hepatic disorders, ulcers, sexually transmitted infections, and backache, as well as enhance breastfeeding in both animal and human mothers [241]. Crinum kirkii Bak. (C. kirkii), a widespread East African grassland plant, is used to heal wounds in Kenya. In Tanzania, the fruit and inner part of the bulbs are used as purgatives, and the outer scales employed as rat poison [245,246]. Extracts of Crinum delagoense (C. delagoense) Verdoorn is utilized in Zulu and Xhosa traditional medicine in South Africa to treat urinary tract infections and body oedema [247][248][249]. Rheumatism, aching joints, septic sores, varicose veins, and kidney and bladder infections have all been treated using the South African Crinum bulbispermum (C. bulbispermum) [250]. In Cameroon, Crinum pupurascens (C. pupurascens) Herb is used to treat sexual asthenia and spleen disorders.
Crinum species (C. defixum Keraudren et Gawl., C. firmifolium Baker, C. modestum Baker) are as well used in Madagascar to treat abscesses, anthrax, and otitis. It is also employed as an emetic, diaphoretic, and emollient. Externally, Crinum firmifolium (C. firmifolium) is used to treat a variety of parasite skin afflictions [40,243].
sinicum. Inhibitory activity against LPS-induced nitric oxide production. Anticancer activity (against cervical cancer SiHa cells). Inhibition of platelet aggregation. Promotion of hair growth through dermal papilla proliferation. Inhibition of the growth of HepG2 tumor cells. Anti-AChE activity, cytotoxic activity. Cytotoxic against Meth-A (mouse sarcoma) and Lewis lung carcinoma (mouse lung carcinoma). Inhibition of the activity of hypoxia inducible factor-1 (crinamine). Cytotoxicity.
Antibacterial activity [287] NR: not reported. Chemical structures of common compounds from Crinum are shown in Figure 5. activity.

Anti-Inflammatory and Analgesic Effects
The anti-inflammatory and the analgesic properties of various Crinum species have been investigated by several authors. The anti-inflammatory effect of C. asiaticum as well as its effect on bradykinin-induced contractions on isolated uterus has been reported [288][289][290][291]. The ethanolic extract of C. asiaticum demonstrated significant analgesic effect in an aceticacid-induced writhing test [292]. Antipyretic and anti-inflammatory properties of C. jagus were recently reported by Minkah and Danquah [291]. Leaf extract of C. bulbispermum has also been established to possess antinociceptive effects [293,294].

Anticancer and Cytotoxicity Effects
The cytotoxic effects of C. asiaticum extract was investigated and was shown to exert toxic effect on brine shrimps and murine P388 D1 cells [294][295][296][297][298]. Yui et al. demonstrated that hot water extracts of C. asiaticum exhibited potent inhibition of calprotectin-induced cytotoxicity in MM46 mouse mammary carcinoma cells. This activity whi1ch was later attributed to lycorine, an active compound in C. asiaticum [297]. Some alkaloids isolated from the bulbs of C. asiaticum have been reported to show remarkable inhibition against tumor cell lines A549, LOVO, HL-60, and 6T-CEM [261].
The extract of C. asiaticum exhibited antiproliferative and chemosensitizing effects against multi-drug-resistant cancer cells [298,299]. The antiangiogenic activity of the methanolic leaf extract of C. asiaticum was evaluated and established by Yusoff [300]. The cytotoxic effect of the essential oil extracted from C. asiaticum was as well established in MCF-7 cells [301]. A recent work done by Yu et al. reported the inhibition of the growth of HepG 2 cells in a dose-dependent manner by polysaccharide CAL-n, an isolate from C. asiaticum [262]. Also, the neuroprotection and anti-neuroinflammatory effects in Neuronal Cell Lines were reported by Lim et al. [279,302]. Alkaloids from C. bulbispermum have also been reported to possess cytotoxic activities [284]. Evaluation of the cytoprotective potential of C. bulbispermum, after induction of toxicity using rotenone, in SH-SY5Y neuroblastoma cells proved that, the plant has such effect as reported [303]. Aboul-Ela et al. [279] tested the cytotoxic effect of C. bulbispermum bulbs using the brine shrimp bioassay.

Antimicrobial Properties
The in vitro antitubercular effects of C. asiaticum on Mycobacterium tuberculosis (M. tuberculosis) surrogate, Mycobacterium smegmatis (M. smegmatis), were reported [291,304]. C. asiaticum was shown to possess a broad-spectrum antimicrobial activity against Grampositive, Gram-negative bacteria and fungal pathogens [291,299]. Antifungal activities of the essential oil and extracts of C. asiaticum against pathogenic fungi have also been established [305,306]. It is reported that the methanolic root extract of C. asiaticum exerts significant anti-HIV-1 activity [307]. The ethanolic extract of C. asiaticum significantly inhibited selected bacteria as evaluated by Naira et al. [308]. Dichloromethane extract of C. asiaticum was found to be the most effective against selected oral and vaginal Candida species [309]. Minkah and Danquah again demonstrated the antimicrobial activity of extracts of C. jagus against clinically significant microorganisms in the High-throughput spot culture growth inhibition (HT-SPOTi) assay [291]. Water/Ethanol extract of C. jagus was observed to be active on Shigella flexneri-induced diarrhea in rats [310]. The antimicrobial and antioxidant properties of C. jagus make it suitable as a wound healing agent [311]. The crude methanolic extract of C. jagus was investigated to have effect on Mycobacterium tuberculosis [312,313]. The crude alkaloid of C. jagus inhibited Dengue virus infection [314]. C. macowanii has also been shown to possess biological effects such as antifungal, antiviral and antiplasmodial activities [315].

Antioxidant Properties
There antioxidant effects of C. asiaticum have been studied extensively. The ethanolic extract exhibited protective effects on human erythrocyte [316]. C. asiaticum bulbs also exerted remarkable free radical scavenging ability [317]. The antioxidant activity of the ethanolic extract of C. asiaticum leaves in alloxan-induced diabetic rats was well demonstrated [318]. More recent work on the methanolic extract of C. asiaticum showed antioxidant effects [319]. Potent DPPH radical scavenging activity was also observed for the aqueous C. asiaticum leaf extract [304]. Both the leaves and bulbs of C. jagus are important sources of antioxidant compounds [320]. A methanolic bulb extract of C. bulbispermum showed mild radical scavenging activity [321]. The leaf extracts of C. bulbispermum also showed modest antioxidant activity in a thiobarbituric acid reactive substances assay [297].

Other Pharmacological Properties
Kumar reported the wound healing activities of the ethanolic C. asiaticum extract. The extract was found to possess pro-healing effects when topically applied on animal models by influencing various stages of healing process [322]. C asiaticum extract and norgalanthamine potentially influenced hair growth via inhibition of 5α-reductase activity and TGF-β1-induced canonical pathway [39,314]. There is a report on the inhibitory effects of three C. asiaticum genotypes against key enzymes implicated in the pathogenesis of Alzheimer's disease and diabetes [319].
The anti-obesity effect of the C. asiaticum extract on a high-fat diet-induced obesity in monogenic mice has been reported [323,324]. An active fraction of C. jagus was shown to possess anticonvulsant activities in experimental rats [325].
Ethyl acetate and methanol extracts of C. bulbispermum have also been shown to exhibit acetylcholinesterase inhibitory properties [321]. The alkaloid galanthamine isolated from C. bulbispermum and other genera of Amaryllidaceae, has been approved for the treatment of Alzheimer's disease [326]. Cognitive enhancing effect of a hydroethanolic extract of C. macowanii against memory impairment induced by aluminum chloride in balb/c mice has as well been reported [327].

Botanical Description
Another large genus of the family Amaryllidaceae is Cyrtanthus. Cyrtanthus is derived from a Greek word for curved flower [6]. Species of this genus have numerous, black, winged seeds and give off a strong onion smell [6]. They possess a rhizome or bulb, flowers and a loculicidal capsule fruit [6]. They have leaves that are linear to lorate [6]. Flowers are funnel shaped with their stamens fixed in the corolla tube [6]. Species that belong to this genus include Cyrtanthus elatus (C. elatus) (Jacq.) Traub, Cyrtanthus obliquus (C. obliquus) (L.f.) Aiton, and Cyrtanthus mackenii (C. mackenii) Hook [44].

Geographical Distribution
Cyrtanthus is diverse and is a large sub-Saharan Africa genus consisting of approximately 55 species found mostly in South Africa. Cyrtanthus extends from the summer-dry southwest to the summer rainfall northeast [328]. The genus displays diverse floral morphology. The three major lineages show varying biogeographic affinities.
Clade A comprises taxa located in Southern African Grassland Biome with a few outliers in the Savanna Biome to the east and north, the Indian Ocean Coastal Belt Biome to the extreme east and the Fynbos Biome to the south [328]. Hence, it falls in the Afrotemperate Phytogeographical Region [329] that encompasses Afromontane phytochorion in the north and the Cape Floristic Region in the south [328]. Most existing species in the Afrotemperate lineage (Cyrtanthus attenuatus (C. attenuatus), Cyrtanthus macowanii (C. macowanii), Cyrtanthus epiphyticus (C. epiphyticus), C. mackenii subsp. cooperi, Cyrtanthus huttonii (C. huttonii), Cyrtanthus macmasteri (C. macmasteri), Cyrtanthus suaveolens (C. suaveolens), Cyrtanthus stenanthus (C. stenanthus var. stenanthus) and Cyrtanthus flanaganii (C. flanaganii) occur currently in the south-eastern African temperate grasslands. Cyrtanthus tuckii var. transvaalensis (C. tuckii) is the only species found in the grassland of the Highveld in the northern parts of South Africa. Few species are found outside this grassland area and includes Cyrtanthus angustifolius (C. angustifolius), Cyrtanthus fergusoniae (C. fergusoniae) and Cyrtanthus aureolinus (C. aureolinus) in the Cape Region together with C. mackenii subsp. Mackenii and Cyrtanthus brachyscyphus (C. brachyscyphus) that occupies drainage lines on the subtropical Indian Ocean Coastal Belt [330]. Southern Africa is the area where Cyrtanthus breviflorus (C. breviflorus) is found extending northwards in a series of disjunct populations along mountain corridors to East Africa and Angola.
Clade B is limited to the Fynbos and Succulent Karoo Biomes which constitute the Greater Cape Region, referred to hereafter as 'the Cape' [331]. Cyrtanthus labiatus (C. labiatus) and Cyrtanthus montanus (C. montanus) from the Baviaansklo of Mountains and Eastern Cape are found at the interface of the Fynbos and Albany Thicket Biomes. The Richtersveld species, Cyrtanthus herrei (C. herrei) is found in the semi-arid Succulent Karoo [328]. Most species found in 'the Cape' lineage are located on the summer-dry, southeast coast forelands with half the number in the Fynbos of the nonseasonal rainfall Eastern Cape. Cyrtanthus carneus (C. carneus, C. elatus, Cyrtanthus guthrieae (C. guthrieae, C. labiatus, Cyrtanthus leptosiphon (C. leptosiphon), Cyrtanthus leucanthus (C. leucanthus, Cyrtanthus montanus (C. montanus), and Cyrtanthus odorus (C. odorus) are found in specific vegetation types and soils.
Only two species of this taxon, namely Cyrtanthus collinus (C. collinus) and Cyrtanthus ventricosus (C. ventricosus) are well known, inhabiting the same soils and aspect in habitats on the continuous Cape Fold mountain ranges [328]. Cyrtanthus collinus is found on the coastal and inland mountains of the southern Cape and C. ventricosus extends from the Cape Peninsula into the Eastern Cape [328].
Most species of Clade C are found in the eastern lowlands and midlands of southern Africa, where they are concentrated in the subtropical biomes, Albany Thicket and Savanna [330,332]. This lineage constitutes Cyrtanthus flammosus (C. flammosus) and Cyrtanthus spiralis (C. spiralis), which are narrowly widespread to the Albany Thicket Biome. Confined to the Savanna Biome are Cyrtanthus eucallus (C. eucallus) and Cyrtanthus galpinii (C. galpinii) in the Lowveld. Other species span the Albany Thicket and Savanna Biomes: the Eastern Cape Cyrtanthus helictus (C. helictus) and, extending northwards from the Albany region through South Africa, Zimbabwe, western Mozambique and East Africa into Sudan, is Cyrtanthus sanguineus (C. sanguineus) [328]. Cyrtanthus obliquus, adapted to nutrient-poor soils, occupies rocky habitats in east-west tending valleys. A summary of their geographic distribution is presented in Table 12.

Traditional Uses
Cyrtanthus obliquus, locally known as umathunga in South Africa, is used traditionally in the management of chronic coughs, headaches and scrofula [43,44]. C. obliquus root infusions are also employed in the management of stomach aches [333] while the crushed roots have been reported to find use in the management of leprosy [334]. Cyrtanthus species are also employed in the management of ailments associated with pregnancy, as well as cystitis, age-related dementia and leprosy [43,44]. Bulbs of C. contractus extracted in May and September is widely used locally in the management of mental illness, infections, inflammation, and cancer [335]. Infusions from species such as C. breviflorus, C. contractus, C. mackenii, C. sanguineus, C. stenanthus and C. tuckii are used by the Zulu in South Africa as protective sprinkling charms against storms and evil spirits [336]. Extracts of C. breviflorus Harv. are used as an anti-emetic agent and in the management of worm infestations such as tapeworm and roundworm. Extracts of C. elatus also finds use in the management of cough, headache and in labour induction [337].
The presence of lycorine, tazettine and 11-hydroxyvittatine in dried bulb ethanol extract of Cyrtanthus mackenii (Hook f.) has been demonstrated by Masi et al. [340]. Fresh bulb methanol extracts of C. contractus also contains a phenanthridone alkaloid called narciclasine [335]. Furthermore, two crinine alkaloids; haemanthamine and haemanthidine have been isolated from fresh bulb ethanol extracts of C. elatus. Further studies on the alcoholic extracts of the fresh bulbs also yielded the alkaloids zephyranthine, galanthamine and 1,2-O-diacetylzephyranthine [43,44]. Tazettine, maritidine, O-methylmaritidine, and papyramine are all phytochemicals that have been identified in fresh bulb methanol extracts of C. falcatus [337].
Chemical structure of compounds isolated from Cyrtanthus have been shown in Figure 6.

Anti-Inflammatory Activity
The methanol extract of the bulbs of C. contractus has been investigated and shown to possess significant anti-inflammatory activity. The extract exhibited dose-dependent inhibition of E-selectin, a proinflammatory agent, when tested on endothelial cells. Further studies of the methanol extract on human umbilical vein endothelial cells revealed a concentration-dependent reduction in THP-1 adhesion via blockade of the expression of endothelial adhesion molecule ICAM-1. Narciclasine was identified as the main anti-inflammatory compound in the methanol extract of the bulbs of C. contractus [335].
The dichloromethane (DCM) extracts of C. falcatus (roots) and C. mackenii (leaves) were shown to interfere with the activity of cyclooxygenase 2 (COX-2) by at least 90%. DCM extract of C. suaveolens also blocked prostaglandin synthesis via antagonizing COX-2 activity by 81.6 %. Moderate inhibition (approximately 70%) of COX-2 activity was also observed with the methanol extracts of the roots and leaves of C. falcatus [341,342]. Selective inhibition of COX-2 by these extracts makes them suitable candidates for development for clinical use.

Anti-Inflammatory Activity
The methanol extract of the bulbs of C. contractus has been investigated and shown to possess significant anti-inflammatory activity. The extract exhibited dose-dependent inhibition of E-selectin, a proinflammatory agent, when tested on endothelial cells. Further studies of the methanol extract on human umbilical vein endothelial cells revealed a concentration-dependent reduction in THP-1 adhesion via blockade of the expression of endothelial adhesion molecule ICAM-1. Narciclasine was identified as the main antiinflammatory compound in the methanol extract of the bulbs of C. contractus [335].
The dichloromethane (DCM) extracts of C. falcatus (roots) and C. mackenii (leaves) were shown to interfere with the activity of cyclooxygenase 2 (COX-2) by at least 90%. DCM extract of C. suaveolens also blocked prostaglandin synthesis via antagonizing COX-2 activity by 81.6 %. Moderate inhibition (approximately 70%) of COX-2 activity was also observed with the methanol extracts of the roots and leaves of C. falcatus [341,342]. Selective inhibition of COX-2 by these extracts makes them suitable candidates for development for clinical use.

Inhibition of Acetylcholinesterase
The phenanthridone alkaloid nacriprimine, isolated from the ethanolic bulb extract of C. contractus has been shown to possess mild acetylcholinesterase inhibition property with an IC 50 of 78.9 µg/mL compared to the 40-fold more potent standard galanthamine with an IC 50 of 1.9 µg/mL [11].

Antimicrobial Activity
Cyrtanthus species and their isolated compounds have demonstrated noteworthy antimicrobial activity against a panel of microorganisms. C. suaveolens bulbs/roots and leaves isolated with DCM demonstrated broad-spectrum antimicrobial activity against B. subtilis, E. coli, K. pneumoniae, M. luteus and S. aureus with zones of inhibition ranging between 0.13-0.91 mm. DCM extracts of C. falcatus also inhibited the growth of B. subtilis S. aureus and E. coli. C. mackenii bulb/root extracts also inhibited the growth M. luteus and S. aureus [337].
Haemanthamine and haemanthidine isolated from the bulbs of C. elatus have been investigated for their activity against parasitic protozoans [43]. Haemanthamine showed activity against trophozoite stage of Entamoeba histolytica (E. histolytica) HK9 with an IC 50 of 0.75 µg/mL and mild activity against Plasmodium falciparum (P. falciparum) NF54 with an IC 50 of 0.67 µg/mL. The activity against E. histolytica was compared to ornidazole with an IC 50 0.28 µg/mL whiles the activity against P. falciparum was compared to chloroquine with an IC 50 of 0.004 µg/mL and artemisinin with an IC 50 of 0.002 µg/mL [43].

Cytotoxic Activity
Haemanthamine isolated from C. elatus was shown to possess cytotoxic activity which was mediated via the apoptotic pathway as depicted in rat hepatoma cell (5123tc). The ED 50 was determined at 15 µM and this result was of particular interest due to its selectivity; haemanthamine demonstrated insignificant activity in normal human embryo kidney (293t) cells [337].
Alkaloids isolated from C. obliquus tested for cytotoxic activity against Chinese Hamster ovarian and human hepatoma (hepG2) cells showed no cytotoxic activity up to a concentration of 100 µg/mL [339].
Tazettine isolated from C. falcatus and other members of Amaryllidaceae has been reported to possess cytotoxic activity on colon cell line murine alveolar non-tumoral fibroblast [343,344]. Papyramine, also extracted from C. falcatus showed cytotoxic activity against murine alveolar non-tumoral fibroblast and human lymphoid neoplasm as well [343,344].

Miscellaneous Pharmacological Activities
Roots of C. falcatus and C. surveolens extracted with DCM exhibited mutagenicity in Salmonella strain TA98 which was higher than that observed in the leaves of these plants. Mutagenicity was, however, not observed in the methanol extracts of these plants [337]. The mutagenicity of C. suaveolens has been attributed to the compound captan isolated from the bulbs/roots using DCM [344].
A summary of the traditional uses, phytochemicals and pharmacological activities of Cyrtanthus species have been highlighted in Table 13.

Conclusions
The discovery of new drugs in response to the growing burden of infectious and non-communicable diseases is of utmost necessity in this era. The genera Tulbaghia, Allium, Crinum, and Cyrtanthus of the Amaryllidaceae family have been well presented and shown to be a source of promising medicinal compounds with varying biological properties. Further research is therefore necessary to propel these compounds through clinical trials for possible usage in therapeutics. Although natural products have been attributed with high safety profiles, the presence of mutagenic compounds in crude extracts of these plants underscores the importance of pharmacological studies prior to their use in traditional medicine. These findings are relevant in light of augmenting the lean pipeline of drug discovery.

Conflicts of Interest:
The authors declare no conflict of interest.