The Chemistry and Biological Activities of Natural Products from Northern African Plant Families: From Taccaceae to Zygophyllaceae

Abstract Traditional medicinal practices have a profound influence on the daily lives of people living in developing countries, particularly in Africa, since the populations cannot generally afford the cost of Western medicines. We have undertaken to investigate the correlation between the uses of plants in Traditional African medicine and the biological activities of the derived natural products, with the aim to validate the use of traditional medicine in Northern African communities. The literature is covered for the period 1959–2015 and part III of this review series focuses on plant families with names beginning with letters T to Z. The authors have focused on curating data from journals in natural products and phytomedicine. Within each journal home page, a query search based on country name was conducted. All articles “hits” were then verified, one at a time, that the species was harvested within the Northern African geographical regions. The current data partly constitutes the bases for the development of the Northern African natural compounds database. The review discusses 284 plant-based natural compounds from 34 species and 11 families. It was observed that the ethnobotanical uses of less than 40 % of the plant species surveyed correlated with the bioactivities of compounds identified. Graphical Abstract Electronic supplementary material The online version of this article (doi:10.1007/s13659-016-0091-9) contains supplementary material, which is available to authorized users.


Introduction
Northern Africa includes the countries Algeria, Egypt, Libya, Morocco, North Sudan, South Sudan, Tunisia and Western Sahara, covering a land surface of about 8935659 km 2 [1]. This region is mostly covered by the Sahara desert (a surface area of [50 % of the total area of the region), the rest of the region being oases and grasslands, with a total of 343 vascular plant species from 69 families non-native to this region [2]. The use of these plants for the treatment of disease ailments is known and documented from the Ancient Egyptian civilization [3]. Till today, diverse plant parts (roots, rhizomes, flowers, leaves, fruits, seeds and oils; in the form of powders, pills, suppositories, creams, pastes, and ointments, or sometimes combinations of these) are often used locally in traditional medicine within this region and the herbal material is commonly commercialized in the local markets. Urbanization and desertification however represent constant threats to some of the plant species [4][5][6]. Although Arabic traditional medicine is in danger of disappearing as a result of the influence of Western medicine [7], the use of plantbased medicines in Africa, as a whole, dates back to several centuries and several attempts have been made by government authorities to ensure its continuity [8]. Additionally, scientists have attempted to record and study the old recipes with the view of identifying the active principles in the herbal preparations and understanding the modes of action of the bioactive principles, with the ultimate goal of developing phytomedicines and/or drugs from these preparations [6]. It should be noted that traditional medicine is not just commonly practised in Northern Africa, but in the entire continent, to the extent that traditional medicine has been included as one of the hubs of the African Network for Drugs and Diagnostics Innovation (ANDI) [9][10][11].
The assertion that natural products represent a huge potential for drugs and drug leads cannot be disputed [12]. This is because nature uses exquisite enzyme reaction sequences, conducts many chemical transformations with high regio-and stereospecificity, leading to the formation of secondary metabolites [13]. These secondary metabolites (originally designed by plants for their own defence mechanism and survival) could be used directly as drugs or further chemically modified to give drug molecules. A quick search of the literature (the main stream natural products journals and PhD theses from university libraries in Northern Africa) could give an estimate of [3000 unique compounds which have been previously isolated from Northern African flora, algae and fauna. Although the database of natural compounds from Northern African sources is still under construction, a recent survey has been undertaken by two of us to investigate the correlation that exists between the biological activities of the isolated metabolites from Northern African floral matter and the use of the respective plant species in local traditional medicine [14,15]. The current review paper represents a continuation of this survey, with plants belonging to families having names beginning with letters T to Z (34 species and 11 families). As in the two previous reviews, the plant families have been presented in alphabetical order. Wherever the biological activities of the isolated metabolites correlate with the ethnobotanical uses of the plant species, these are highlighted in bold in the Tables.
Nawwar et al. have also recently isolated twenty phenolic compounds from the aerial parts of Reaumuria vermiculata (Tamaricaceae) [49], a plant whose decoction is used externally or taken internally to cure fromitch and bruises [50]. The isolates included four metabolites which had not been reported previously to occur as natural products, namely; tamarixetin 3,7-disulphate (82), 3-methoxyellagic acid 4,4 0 -disulphate (83), 2-O-dehydrodigallic acid monocarboxyloyl-3-O-galloyl-(a/b)-glucose (84) and the ellagitannin dimer, vermaculitin (85) [49,50], meanwhile kaempferol-3,7-disulphate (86) is known to have been isolated for the first time from the Northern African species [51]. Compounds 84 and 85 were shown to be cytotoxic ellagitannins, which demonstrated radical scavenging capacity using both the DPPH method and the ORAC assay. Additionally, both compounds were cytotoxic against prostate cancer cell lines (PC-3), with IC 50 values of 1.5 and 0.45 lM respectively [49,50]. Plants of the Tamaricaceae, particularly T. nilotica, have been investigated for their anticancer properties [52]. It is also recorded in ancient Egyptian papyri that this plant was used to expel fever, relieve headache, draw out inflammation and as an aphrodisiac, in addition to its use in Egyptian traditional medicine as an antiseptic agent [53]. In Egypt, different parts of Tamarix are used in traditional medicine. For example, the leaves and young branches are cooked for oedema of spleen and mixed with ginger for uterine infections, while the bark, when boiled in water with vinegar is used as lotion against lice [54]. The above uses clearly correlate with some of the aforementioned biological activities of the isolates.
From the aerial parts of T. lythroides, Kabbaj et al. successfully isolated eight secondary metabolites, including the depsipeptide bassiatin (96); the coumarins daphenone (97) and daphnelone (98), the dicoumarin daphnoretin (99), the lignans; d-sesamin (100) and wikstromol (101), the flavonoid glucoside trans-tiliroside (102), and the dicoumarin rutarensin (103) [59]. Although the isolated compounds were not tested by the authors of the aforementioned paper, it was suggested that d-sesamin (100) Among the isolated compounds, daphnoretin (87) is known to be a cancer chemopreventive agent by inhibiting tyrosine-specific protein kinase, with insignificant cytotoxicity against human cell lines [56], while the hirseins (93 and 94) were shown to be inhibitors of melanogenesis in B16 murine melanoma cells [58]. Some of the 12-hydroxy-daphnane esters are known to activate protein kinase C (the tumour-promoting receptor site) [60] and are further claimed to possess anti-tumour activities in vivo against P-388 leukemia in mice [61,62]. Furthermore, the mechanism of antiproliferative activity of daphnoretin has been recently explored, showing that the compound causes death of human osteosarcoma (HOS) by blocking cells successively in G2/M phases and activating the caspase-3 pathway [63]. It has recently been shown that this compound displays antiviral activity [64], induces respiratory burst in rat neutrophils through protein kinase C activation [65,66] and is a well known antineoplastic agent (inhibits or prevents the proliferation of neoplasms) [67].
Plants from the genus Thymelaea are known to be used to treat a wide range of diseases, including; prostate inflammation, diabetes, rheumatism, otitis and cancer of the uterus (particularly T. lythroides) [68]. This has been confirmed by a recent ethnopharmacological survey of traditional plants used for cancer treatment in Morocco [69]. In Tunisia, T. hirsuta is used traditionally as an antiseptic and anti-inflammatory agent and for the treatment of hypertension by external application [58]. The anticancer properties of the aforementioned compounds could justify the use of Thymelaea species for the treatment of uterine cancer, prostate inflammation and other related infirmities.
Meanwhile, the Tribulaceae are known for steroids (steroidal saponins and steroidal glycosides). From the Northern African Tribulaceae, the remarkable species investigated are of the genus Tribulus (T. pentandrus, T. terrestris, T. megistopterus subsp. pterocarpus and T. parvispinus), harvested in Egypt [70][71][72][73]. Traditionally, T. terrestris is known for diverse uses [74], including the ability to increase appetite, increase sexual desire in humans, regulate heart rate, blood pressure and cholesterol levels, treatment of prostatic hyperplasia, reducing the symptoms and prostate volume, etc. [75], while the organic and aqueous extracts from the fruits, leaves and roots have shown antimicrobial properties [76]. The plant is also claimed to possess anticancer [77], anticholinergic [78], The Chemistry and Biological Activities of Natural Products 77 antifilarial [79], anti-malarial [80], CNS depressant and stimulant [81], hypoglycemic effect [82], immunologic effect [83], smooth muscle relaxant and stimulant activity [84] and other important activities [85]. Kostova and Dinchev have previously published a review on the chemical diversity of saponins isolated from this species [86]. From the Northern African species from this genus, Saleh et al. detected twenty five flavonoid glycosides from extracts of T. pentandrus and T. terrestris, belonging to the common flavonols; kaempferol, quercetin and isorhamnetin, together with the 3-gentiobiosides as the major compounds [70]. The authors also found traces of a flavone (tricin) glycoside in T. pentandrus. The above study permitted the authors to separate the Tribulaceae as a distinct family from Zygophyllaceae [70]. Ulvaceae contain polyunsaturated fatty acids with algicidal activities, phenolic compounds with antioxidant activities, sterols, terpenss and polyphenolic compounds [88][89][90]. A summary of the medicinal uses and biological activities of the compounds of the above plant families are indicated in Table 3. Marine algae (Ulvaceae) are known for their wide variety of uses as food, in industry and in medicine [91]. Additionally, their bioactive components have a broad range of pharmacological functions [88][89][90][91][92][93][94][95]. Ulva lactuca (commonly known as sea lettuce), for example can be used in salads and soups, ice cream, other food products, and medicine [96]. The species is also used to monitor environmental pollution, since the plant thrives in moderate levels of nutrient pollution [96]. Awad isolated the steroid 3-O-b-D-glucopyranosyl-stigmasta-5,25-dien (124), which exhibited topical anti-inflammatory activity in the mouse ear oedema assay [95]. Compound 124 as well showed antimicrobial activity against a broad range of Gram-positive and Gram-negative bacteria, fungi and yeast strains [95]. This proves that the consumption of the plant as food may be of both dietary and medicinal importance. El Ashry et al. also carried out phytochemical investigations of the same species, leading to the isolation of two new compounds; (E)-6-heptacosen-5-one (125) and (E)-6- The Umbelliferae (apiaceous plants) are known for the presence of saponins, sesquiterpene lactones, coumarins, flavone glucosides, tanins and a broad range of volatiles. The family has been previously discussed in this review series under the Apiaceae [14], but we further highlight herein some species that were not included in the previous review and provide a more in-depth discussion of this family. Plants of the genus Daucus have been used by natives of some Northern African countries as diuretics, emollient, vermifuge, carminative and against stomach ache [98,99], some of the species having edible roots, e.g.  [103]. The isolated compounds also included the polyacetylene falcarindiol (145) and the sesquiterpene coumarin ferulenol (146). The assessment of the antimicrobial activities of these compounds showed that the MIC values for 141 and 142 were \2 mg/mL against Staphylococcus aureus, Streptomyces scabies, Bacillus subtilis, Bacillus cereus as well as the gram negative species Pseudomonas aeroginosa. Meanwhile, compound 146 had an estimated MIC \ 2.5 mg/mL against S. aureus, S. scabies, B. subtilis, B. cereus and P. aeroginosa and within the range 5 mg/mL \ MIC \ 4.5 mg/mL against E. coli, F. oxysporum and A. niger. Compounds 144 and 145 had MIC values \2.5 mg/mL against all the above tested microorganisms but showed no antibacterial effect against F. oxysporum and E. coli [103]. These results are in accordance with the use of wild carrots in traditional medicine; extract of the plant are used traditionally for the treatment of hepatic and renal insufficiency as well as for skin disorders (microbial infections) [104], while the extracts of the wild plants are also known to exhibit antioxidative and iron-chelative properties. They could also be suggested for venereal diseases, skin diseases like scabies and eczema as well as the treatment of stomach ache.
Plants of the genus Carum (Umbelliferae) have a wide range of industrial and pharmacological uses, e.g. C. carvi (also known as Caraway) has been used in Europe for flavouring bread, sauerkraut, candies, meat products, sauces, cheese and alcoholic liqueurs [141,142]. Moreover, the seeds of this plant have been used traditionally for the treatment of colic, appetite loss, anti-malarial preparations, as a vermifuge and for digestive disorders, etc. [142]. Laouer et al. have investigated the essential oil of the aerial parts (leaves and flowers) of the sister species, C. montanum (a plant commonly grazed by livestock), harvested from the Megress Mountain in Algeria, although no medicinal applications are known for the Algerian species locally [142]. This study led to the isolation of phenylpropanoids with antimicrobial properties [142]. These include; nothoapiole (212), myristicin (213), apiole (214) and dillapiole (215) [142]. Meanwhile, Benahmed et al. had previously isolated the new furanocoumarin glucoside, xanthotoxin-5-O-b-D-glucoside named carumoside (216), together with the known coumarin xanthotoxin (217), from aerial parts of the Algerian species, but did not test the isolated compounds [143]. It should be noted that although coumarins are common in apiaceous plants (particularly within the genera Apium, Ammi and Magydaris) [144][145][146][147][148], the presence of the coumarin xanthotoxin (217) in both species (C. carvi [146] and C. montanum [143]) and the concurrent absence of its 5-glucosides in C. carvi may be an indication that the biosynthesis of 5-glucosides of furanocoumarins is a distinctive characteristic of the Algerian species, C. montanum [143].
From the Urticaceae, Urtica dioica (or nettle) is widely used as a food supplement (with salad) in the East of Morocco [153]. The plant is also known in Eastern Moroccan traditional medicine for its antihypotensive and antidiabetic properties [154,155], meanwhile its extracts have displayed hypoglycemic [153,156], antioxidant, antimicrobial, antiulcer and analgesic [157], antiproliferative [158,159] antirheumatic [160] and hepatoprotective [161] effects. It has also been demonstrated that a preparation containing several medicinal plants, including U. dioica exhibited antidiabetic activity [162] and could also be used to treat allergic rhinitis [163]. Bnouham [164,165]. The compounds were tested for their affinity to human sex hormone binding globulin (SHBG) and results showed that all lignans except (-)pinoresinol developed a binding affinity to SHBG in the in vitro assay, with the affinity of (-)-3,4-divanillyltetrahydrofuran proving to be significantly high, when compared with those of the other isolates [164]. These results could suggest the further examination of these compounds (225-228 and 230) and plant lignans in general for the development of drugs against benign prostatic hyperplasia (BPH).

Verbenaceae and Vitaceae
Verbenaceae contain triterpenoids, flavonoids, chromomoric acid derivatives, quinones, apocarotenoids and lignans [166], while Vitaceae are known to be rich in flavonoids, terpenes, organic acids, vitamins, carbohydrats, lipids and enzymes [167]. A summary of the medicinal uses and biological activities of the compounds of the plant families above are indicated in Table 4. Flowering plants of the genus Clerodendrum (formerly Verbenaceae, now Lamiaceae) are currently classified in the subfamily Ajugoideae [168,169]. The species have diverse uses in folk medicine, e.g. the aqueous leaf extract of C. glandulosum is traditionally used by people of North-East India to alleviate symptoms of diabetes, obesity and hypertension, while the plant is used to prepare a staple diet among the Zomi tribes (North East India) [170]. The leaf juice of the sister species C. inerme (commonly used as a hedge plant) is reportedly used as a remedy to bring down fever [171]. Phytochemical investigation of the leaf extracts of C. inerme from Giza in Egypt led to the identification of five novel complex iridoid glycosides; inerminosides A and B (231 and 232) [172], as well as inerminosides A1, C and D (233-235) [173], although the compounds were not tested. Therefore, the validation of the ethnobotanical uses of Clerodendrum species from Northern Africa is still under investigation. Verbena officinalis (Verbenaceae) is a herb that has been used in traditional Austrian medicine (as tea or liqueur) for the treatment of infections and fever [174]. Vebena, a common food supplement derived from this plant, is used for sore throats and respiratory tract diseases such as asthma and whooping cough, and for heart conditions such as chest pain (angina) and fluid retention due to heart failure [175]. An investigation of V. officinalis and the sister species V. supina collected in Egypt, led to the identification of several flavonoid glycosides which permitted to chemically distinguish between the two species [176,177]. Although the compounds were not tested, the favonoid profiles of the species indicated that luteolin-7neohesperidoside (236) and diosmetin-7-neohesperidoside (237) are major components in V. officinalis while the major component of V. supina was tuteolin-7-glucoside (238). Both species contained luteolin-7-galactoside (239) and diosmetin-7-galactoside, together with apigenin-7glucoside and chrysoeriol-7-galactoside in minor quantities [176,177].

Discussion and Conclusions
This review paper is not an attempt to present an exhaustive overview of compounds from Northern African plant species and their biological activities, the reason being that such an attempt is not feasible in a journal article. The main goal of this review series has been to establish a baseline for further investigations of North African flora. Data on plant sources, geographical collection sites and chemical structures of pure compounds have been retrieved from literature sources (mainly from the major international journals on natural products and some available PhD theses, spanning the period 1959-2015). From Taccaceae to Zygophyllaceae, we have discussed 284 metabolites which have been isolated from 34 plant species belonging to 11 Northern African plant families. From Tables 1 to 5, it appears as though the correlation between the application of plant materials (e.g. in traditional medicines) and the biological activities of the isolated plant metabolites is relatively weak (with the exception of a few correlations marked in bold), when compared with our previous reviews from Central Africa [247,248], West Africa [249][250][251][252], Southern Africa [253,254] and the previously discussed families from the region [14,15]. One could easily explain off this weak correlation by the fact that traditional methods like boiling, the use of total extracts as mixtures, steam baths, etc. do not match the typical chemical extraction methods employed in a NP laboratory. The survey however portrays the importance of traditional medicine in drug discovery programs. Previous surveys have also demonstrated that NPs from African flora have shown a great diversity of chemical classes with a broad range of biological activities; including [500 compounds with antimalarial activties [255,256], *100 compounds with potential anti-mycobacterial activities [257], [400 compounds with potential anticancer activities [258,259] and *100 compounds with anti-trypanosomal activities [260,261]. This leaves us with a huge repository for drug discovery. It should be noted that the tested compounds only represent a small proportion of NPs from the region which have been isolated. The chemical scaffolds from the untested NPs still remain to be explored. From this data and the previously presented reviews, we are currently building a searchable database for compounds isolated from Northern African flora, in order to assist in drug discovery programs on the continent of Africa.