molecules Review Antiviral Activities of Oleanolic Acid and Its Analogues Vuyolwethu Khwaza, Opeoluwa O. Oyedeji and Blessing A. Aderibigbe * Department of Chemistry, University of Fort Hare, Alice Campus, Alice 5700, Eastern Cape, South Africa; [email protected] (V.K.); [email protected] (O.O.O) * Correspondence: [email protected]; Tel.: +27-406022266; Fax: +08-67301846 Academic Editors: Patrizia Ciminiello, Alfonso Mangoni, Marialuisa Menna and Orazio Taglialatela-Scafati Received: 27 July 2018; Accepted: 5 September 2018; Published: 9 September 2018 Abstract: Viral diseases, such as human immune deficiency virus (HIV), influenza, hepatitis, and herpes, are the leading causes of human death in the world. The shortage of effective vaccines or therapeutics for the prevention and treatment of the numerous viral infections, and the great increase in the number of new drug-resistant viruses, indicate that there is a great need for the development of novel and potent antiviral drugs. Natural products are one of the most valuable sources for drug discovery. Most natural triterpenoids, such as oleanolic acid (OA), possess notable antiviral activity. Therefore, it is important to validate how plant isolates, such as OA and its analogues, can improve and produce potent drugs for the treatment of viral disease. This article reports a review of the analogues of oleanolic acid and their selected pathogenic antiviral activities, which include HIV, the influenza virus, hepatitis B and C viruses, and herpes viruses. Keywords: HIV; influenza virus; HBV/HCV; natural product; triterpenoids; medicinal plant 1. Introduction Viral diseases remain a major problem for humankind. It has been reported in some reviews that there is an increase in the number of viral diseases responsible for death and morbidity around the world [1,2]. According to the recent release from the National Health Laboratory Service (NHLS), influenza kills approximately 6000–11,000 South Africans every year [3]. Although other treatments eradicate some pathogens, such as polio, mumps and smallpox, other viral diseases, such as the hepatitis C virus (HCV) and the human immunodeficiency virus (HIV), have proven difficult to combat using the conventional treatment approach. In addition, the increase in viral resistance to drugs, as well as the serious adverse effects of antiviral drugs, results in serious medical problems, particularly when drugs are administered in combination over a prolonged treatment period [4]. Thus, there is a great need to develop novel potential antiviral agents from different sources, such as medicinal plants or natural products, which have been used in many regions as antiviral agents for many years [5–7]. Natural products have been proven as the main source of biologically active compounds, and they are potentially useful for drug development [8]. Pentacyclic triterpenes (PTs) are the most significant group of phytochemicals synthesized from plants through cyclization of squalene, and are known as a large class of secondary plant metabolites that are constructed by isoprene (2-methylbutadiene) (C5H8) units [9]. Structurally, they contain 5- and 6-membered rings (A, B, C, D, and E). The carbon skeleton of PTs is divided into six different subgroups: Oleanane (1), ursane (2), friedelane (3), hopane (4), lupine (5), and gammacerane (6) (Figure1)[ 10]. It has been reported that approximately 20,000 triterpenoids exist in nature [11,12]. Molecules 2018, 23, 2300; doi:10.3390/molecules23092300 www.mdpi.com/journal/molecules Molecules 2018, 23, 2300 2 of 14 Molecules 2018, 23, x 2 of 14 Molecules 2018, 23, x 2 of 14 E E E E E E C D C D C D C D C D C D B A A B A B B A A B A B 1 2 1 3 2 3 E E E E C E E D C D C D C C C B D D D A B B B A A A A B A B 4 5 6 4 5 6 FigureFigure 1. 1.Types Types ofof pentacyclicpentacyclic triterpenes structures. structures. Figure 1. Types of pentacyclic triterpenes structures. AntiviralsAntivirals are are compounds compounds which which preventprevent viralviral development. Some Some of of these these antivirals antivirals can can be be isolatedisolatedAntivirals from from sources, sources, are compounds such such as as plants, plants,which animals,preventanimals, viral bacteria development. or or fungi, fungi, whileSome while othersof others these can canantivirals be beobtained obtained can beby by chemicalisolatedchemical synthesis from synthesis sources, [13 [13,14 ,14such].] Antiviral. Antivi as plants,ral mechanisms mechanisms animals, bacteria identifiedidentified or fromfungi, from natural naturalwhile productsothers products can have havebe shedobtained shed light light byon on howchemicalhow they they interact synthesis interact with with[13 the,14 the] viral. Antivi viral life rallife cycle, mechanisms cycle, such such as as viralidentified viral entry, entry, from replication, replication, natural products assembly, assembly, have and and shed release, release, light as on as well as targetinghowwell theyas targeting ofinteract virus–host-specific withof virus the viral–host‑specific life interactions cycle, interactionssuch [5 ,as6]. viral The [5,6] entry, antiviral. The replication, propertiesantiviral assembly, properties of PTs haveand of r attractedelease,PTs have as the attentionwellattracted as of targeting the many attention researchers. of virus of many–host‑specific Pompei researchers. and interactions colleaguesPompei and [5,6] extracted colleagues. The glycyrrhizica extractedntiviral properties glycyrrhizic acid (Figure of acid PTs2)( (figure have7) from attracted the attention of many researchers. Pompei and colleagues extracted glycyrrhizic acid (figure the2) crude (7) from extract the crude of Glycyrrha extract of glabra Glycyrrharoots, glabra and roots it was, and found it was to found be active to be against active against the herpes the herpes simplex 2) (7) from the crude extract of Glycyrrha glabra roots, and it was found to be active against the herpes virussimplex [15]. Chenvirus et[15] al.,. alsoChen isolated et al., analso oleanane-type isolated an oleanane triterpene-type derivative triterpene known derivative as salaspermic known as acid simplexsalaspermic virus acid [15] (F.igure Chen 2) et(8 ) al.from, also Tripterygium isolated anwilfordii oleanane, which-type blocked triterpene the replication derivative of knownHIV in H9as (Figure2)( 8) from Tripterygium wilfordii, which blocked the replication of HIV in H9 lymphocytes (IC50: salaspermiclymphocytes acid (IC (50F:igure 10 μM) 2) ([16]8) from. Toshihiro Tripterygium et al. wilfordiialso isolated, which betulinic blocked acid the replication(BA) (Figure of 2)HIV (9 )in from H9 10 µM) [16]. Toshihiro et al. also isolated betulinic acid (BA) (Figure2)( 9) from the bark and leaves of 50 lymphocytesthe bark and (ICleaves: 10 of μ SyzigiumM) [16]. Toshihiroclaviflorum et, which al. also showed isolated a significantbetulinic acid effect (BA against) (Figure HIV 2) (EC(9) 50from: 1.4 Syzigium claviflorum, which showed a significant effect against HIV (EC : 1.4 µM) [17]. Since then, theμM) bark [17] and. Since leaves then, of many Syzigium natural claviflorum PTs have, which been reportedshowed a to significant have antiviral effect50 activities against .HIV (EC50: 1.4 manyμM) natural [17]. Since PTs then, have many been natural reported PTs to ha haveve been antiviral reported activities. to have antiviral activities. X X O O H HOOC H HOHOOC O HO O HOHOC O HO OO HOOC O OO HHOO 7 HO OH 7 OH X X H H H H H H X H H H O H X H HO O HO H HO 8 H 8 HO 9 H 9 X-COOH X-COOH Figure 2. Isolated antiviral compounds from plants. FigureFigure 2. 2.Isolated Isolated antiviral compounds compounds from from plants. plants. Molecules 2018, 23, 2300 3 of 14 Molecules 2018, 23, x 3 of 14 One natural natural PT PT is Oleanolic is Oleanolic acid acid(OA) (OA)(Figure (Figure 3), which3), whichpossess possesseses many interesting many interesting biological biologicalactivities, such activities, as antiviral such as [18] antiviral, anti-inflammatory, [18], anti-inflammatory, analgesic [18,19] analgesic, antibacterial [18,19], antibacterial [20,21], anti- [cancer20,21], anti-cancer[22–26], anti [-22oxidation–26], anti-oxidation [27,28], antimicrobial [27,28], antimicrobial [29–31], and [ 29cardioprotective–31], and cardioprotective activities [32] activities. Chen et [32 al].. Chenreported et al.that reported OA provides that OAextraordinary provides extraordinaryprotection against protection acute and against chronic acute liver and injury, chronic and liver can injury,be used and as an can oral be usedmedication as an oralfor the medication treatment for of the human treatment liver disorders of human [33] liver. OA disorders is isolated [33]. from OA ismore isolated than 1600 from different more than plant 1600 species different [33– plant37], and species is non [33-toxic–37], and and moderately is non-toxic water and-soluble moderately [19]. water-solubleTable 1 below [19 shows]. Table some1 below medicinal shows some plants medicinal contain plantsing OA containing as an active OA asconstituent an active constituent,, and their andbiological their biological activities. activities. In this study In this we study review we reviewmodifications modifications of the basic of the oleanolic basic oleanolic acid structure acid structure that thathave have been been made. made. 30 29 19 20 21 12 18 22 17 11 OH 25 26 13 28 1 9 14 16 2 O 10 8 15 3 7 5 HO 27 4 6 10 24 23 Figure 3. Structure of oleanolic acid (OA). Table 1. Several plants where OA was reported, the plant parts used, and their biological activities. Table 1. Several plants where OA was reported, the plant parts used, and their biological activities. Plant Species (Family) Biological Activity Plant Parts Used References Plant Species (Family) Biological Activity Plant Parts Used References Oleaeuropaea L. (Oleaceae) Anticancer, antimicrobial, anti-diabetic Fruits and leaves [22,28,37,38] Oleaeuropaea L. (Oleaceae) Anticancer, antimicrobial, anti-diabetic Fruits and leaves [22,28,37,38] Fabiana imbricata R.