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Opportunity, Challenge and Scope of Natural Products in Medicinal Chemistry, 2011: 335-365 ISBN: 978-81-308-0448-4
11. A review on natural products with mosquitosidal potentials
Navneet Kishore, Bhuwan B. Mishra, Vinod K. Tiwari and Vyasji Tripathi
Department of Chemistry, Faculty of Science, Banaras Hindu University Varanasi-221005, India
Abstract. Mosquito, a flying insect of family Culicidae, serves as crucial vector for a number of arboviruses (arthropod-borne viruses) and parasites that are maintained in nature through biological transmission between susceptible vertebrate hosts by blood feeding arthropods (mosquitoes, psychodids, ceratopogonids, and ticks) responsible for inflammation/encephalitis, dengue, malaria, rift valley fever, yellow fever and others. Despite of a direct human affliction, they are also known to transmit several diseases and parasites that are lethal to dogs and horses, i.e., dog heartworm (Dirofilaria immitis), West Nile virus (WNV) and Eastern equine encephalitis (EEE) with ability to affect the central nervous system and cause severe complications and death. Vector control is by far the most successful method for reducing the incidences of diseases, but the emergence of widespread insecticide resistance and the potential environmental issues associated with some synthetic insecticides (such as DDT) has indicated that additional approaches to control the proliferation of mosquito population would be an urgent priority research. In concern to quality & safety of life on controlling mosquito vectors has shifted steadily from the use of conventional chemicals toward alternative insecticides that are target-specific, biodegradable, environmentally safe, and botanicals in origin. In present article, we have discussed
Correspondence/Reprint request: Dr. Vyasji Tripathi, Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-221005, India. E-mail: [email protected]
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the local and traditional uses of plants in mosquito control and have reviewed 185 phytochemicals of paramount importance for the development of efficient chemical entities to control mosquito population by direct as well as indirect inhibitions. In order to highlight any possible mechanism based action for promising mosquitosides, the review has been organized according to chemical structural classes. 1. Introduction Mosquito serves as crucial vector for a number of arboviruses (arthropod-borne viruses) and parasites that are maintained in nature through biological transmission between susceptible vertebrate hosts by blood feeding arthropods responsible for inflammation/encephalitis, dengue, malaria, rift valley fever, yellow fever and others. The Word Health Organization (WHO) estimates that each year 300-500 million cases of malaria occur and more than 1 million people die of malaria. About 1,300 cases of malaria are diagnosed in the United States each year. In addition, some 2500 million people (two fifth of the world's population) are now at risk from dengue [1]. One can imagine the dangers of these mosquitoes with all the other diseases that it can transmit. Vector control is by far the most successful method for reducing incidences of mosquito born diseases, but the emergence of widespread insecticide resistance and the potential environmental issues associated with some synthetic insecticides (such as DDT) has indicated that additional approaches to control the proliferation of mosquito population would be an urgent priority research. Currently, numerous products of botanical origin, especially the secondary metabolites, have received considerable renewed attention as potentially bioactive agents used in insect vector management. However, there is a little other than anecdotal, traditional or cultural evidence on this topic [2]. The Greek natural philosopher Pliny the Elder (1’st century AD) recorded all the known pest control methods in ‘‘Natural History’’. The use of powdered chrysanthemum as an insecticide comes from Chinese record. The other natural products like pyrethrum, derris, quassia, nicotine, hellebore, anabasine, azadirachtin, d-limonene, camphor and turpentine were among some important phytochemical insecticides widely used in developed countries [3]. The discovery of DDT’s and the subsequent development of organochlorines, organophosphates and pyrethroids suppressed natural product research as the problem for insect control were thought be solved. However, high cost of synthetic pyrethroids, environment and food safety concerns, the unacceptability and toxicity of many organophosphates and organochlorines, and increasing insecticide resistance on a global scale argued for stimulated research towards potential botanicals [4].
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Mosquitoes in the larval stage are attractive targets for pesticides because they breed in water and, thus, are easy to deal with them in this habitat. Some of new significant larvicidal insect growth regulators such as methoprene, pyriproxyfen, diflubenzuron and endotoxins obtained from Bacillus thuringiensis israelensis and B. sphaericus have been developed. The plant Azardichita indica has gained wide acceptance in some countries as an antifeedant [5] while many essential oils from plant origin such as citronella, calamus, thymus, and eucalyptus are reportedly promising mosquito larvicides [6-10]. The use of herbal products is one of the best alternatives for mosquito control. The search for herbal preparations that do not produce any adverse effects in the non-target organisms and are easily biodegradable remains a top research issue for scientists associated with alternative vector control [11]. Many plant species are known to possess biological activity that is frequently assigned to the secondary metabolites. Among these, essential oils and their constituents have received considerable attention in the search for new biopesticides. Many of them have been found to possess an array of properties, including insecticidal activity, repellency, feeding deterrence, reproduction retardation and insect growth regulation against various mosquito species [12-16]. 2. Traditional mosquito repellents and usage custom There are several reports particularly in Africa describing about the burned plant materials effective to drive away mosquitoes. Thirteen percent of rural Zimbabweans use plants and 15% using coils [17] while 39% of Malawians burn wood dung or leaves [18]. Up to 100% of Kenyans burned plants to repel mosquitoes [19], and in Guinea Bissau 55% of people burned plants or hung them in the home to repel mosquitoes [20]. The local communities adapt various methods to repel the insects/ mosquitoes. Application of smoke by burning the plant parts is one of the most common practices among the local inhabitants. Other types of applications are spraying the extracts by crushing and grinding the repellent plant parts, hanging and sprinkling the repellent plant leaves on the floor etc. The leaf of repellent plant is one of the commonly and extensively used plant parts to repel the insects and mosquitoes, followed by root, flower and remaining parts of repellent plants [21]. Various traditional repellent plants used by the local inhabitants in order to avoid mosquito bites have been listed in Table 1.
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Table 1. Traditional plants as mosquito repellents [21].
Traditional Names Scientific Names Family Tinjut Ostostegia integrifolia Lamiaceae Woira Olea europaea Oleaceae Neem Azadirachta indica Meliaceae Wogert Silene macroserene Caryophyllaceae Kebercho Echinops sp. Asteraceae Waginos Brucea antidysenterica Simaroubaceae Eucalyptus Eucalyptus camaldulensis Myrtaceae Ades Myrtus communis Myrtaceae Gemmero Capparis tomentosa Capparidaceae Tej-sar Cymbopogen citrates Rutaceae Ats-faris Datura stramonium Solanaceae Endode Phytolacca dodecandra Phytolaccaceae Azo-hareg Clematis hirsuta Ranunculaceae Berberra Millettia ferruginea Fabaceae Gullo Ricinus communis Euphorbiaceae
3. Natural products as potential antimosquito agents The plant world comprises a rich untapped pool of phytochemicals that may be widely used in the place of synthetic insecticides. Plant-based products have been used to control domestic pests for a very long time. The search for and investigation of natural and environmentally friendly insecticidal substances are ongoing worldwide [22-24]. Insecticidal effects of plant extracts vary not only according to plant species, mosquito species and plant parts, but also to extraction methodology [25]. A brief delve into the literature reveals many laboratory and applied investigations [26-28] into the biological activity of many plant derived components against a large number of pathogens and arthropods but the lack of reviews in this area is somewhat surprising since much effort been invested in locating mosquitocidal phytochemicals from edible crops, ornamental plants, herbs, grasses, tropical and subtropical trees and marine angiosperms. A review by Roark, 1947 [29] highlights about 1200 plant species with a wide spectrum of bioactive insecticides. A relevant effort to present context comes from a review by Sukumar et al., 1991 [30] who listed 344 insecticidal botanical agents. Reviews by Schmutterer, 1990 [31] and Mulla & Su, 1999 [32] did not cover significant topics such as structure-activity relationship based activity, mode and site of action and joint action of botanical extracts with other phytochemicals and synthetic insecticides. This review is focused to cover the entire formal and constant research on mosquitocidal natural
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products from the 1947 to early 2010 with special attention on structure-activity relationship (SAR) based activity and mechanism of action for most of natural products, in addition to a number of bioassay procedures and toxicities of crude plant extracts on different species of mosquitoes reported in literature Table 2. Table 2. Mosquitocidal activity of crude plant extracts against different mosquito larvae as well as adults.
Plant Family Plant species Parts Mosquitoes
Acoraceae
Acorus calamus [91,92]
Rhizome Cx. quinquefasciatus Ae. aegypti Ae. albopictus An. tessellates An. subpictus Cx. fatigans
Agavaceae Agave sisalana [93] Fiber Cx. pipiens Alliaceae Allium sativa [94] Bulb Cx. pipiens
Annona squamosa [95]
Leaf Ae. aegypti Cx. quinquefasciatus
Mkilua fragrans [96] Aerial Part An. gambiae Xylopia caudata [96] Leaf Ae. aegypti
Annonaceae
Xylopia ferruginea [96] Leaf Ae. aegypti Calotropis procera [97] Root An. labranchiae Apocynaceae Catharanthus roseus [98] Whole Cx. quinquefasciatus
Apiaceae Daucus carota [92] Seed Ae. Aegypti, Cx. fatigans
Rhinocanthus nasutus [99]
Leaf
Ae. aegypti An. Stephensi Cx. quinquefasciatus
Hygrophila auriculata [98] Shoot Cx. quinquefasciatus
Acanthaceae
Justicia adhatoda [98] Leaf Cx. quinquefasciatus Anthemis nobilis [100] Flower Cx. pipiens Baccharis spartioides [101] Aerial Part Ae. aegypti Cotula cinerea [97] Whole Plant An. labranchiae Sassurea lappa [92] Leaf
Ae. Aegypti Cx. fatigans
Asteraceae
Tagetes minuta [102] Whole Plant Ae. aegypti An. stephensi
Araceae Homalomena propinqua [92] Rhizome Aedes aegypti Betulaceae Alnus glutinosa [103]
Old Litter Cx. pipiens
Ae. rusticus Ae. albopictus Ae. aegypti
Cucurbiataceae Bryonopsis laciniosa [104] Whole Plant Cx. quinquefasciatus Caesalpinaceae Cassia tora [105]
Seed Ae. aegypti,
Cx. pipiens pallens
Navneet Kishore et al. 340
Table 2. Continued
Cupressaceae Callitris glaucophylla [106] Wood Ae. aegypti, Cx. annulirostris
Clusiaceae
Calophyllum inophyllum [99]
Leaf and Seed
Cx. quinquefasciatus,An. Stephensi Ae. aegypti
Cannabaceae Cannabis sativa [107]
Leaf An. Stephensi, Cx. quinquefasciatus Ae. aegypti
Caulerpaceae Caulerpa scalpelliformis
[108] Whole Plant Ae. aegypti
Capparidaceae Cleome viscosa [109] Whole Plant Cx. quinquefasciatus Caryophyllaceae Dictyota caryophyllum [110] Flower Ae. aegypti Dictyotaceae Dictyota dichotoma [109] Whole Plant Ae. aegypti
Codiaeum variegatum [95] Leaf Ae. Aegypti, Cx. quinquefasciatus
Jatropha curcus [111] Leaf Cx. quinquefasciatus
Euphorbiaceae
Ricinus communis [112] Whole Plant An. stephensi Abrus precatorius [98] Shoot Cx. quinquefasciatus Cassia obtusifolia [105]
Seed Ae. aegypti, Cx. pipiens pallens
Croton bonplandianum [98] Shoot Cx. quinquefasciatus
Fabaceae
Vicia tetrasperma [105] Seed Ae. Aegypti, Geraniaceae Pelargonium citrosum [96] Whole Plant Ae. aegypti
Endostemon tereticaulis [113] Aerial Parts An. gambiae Lavandula afficinalis [112] Whole Plant An. stephensi Leucas aspera [98] Whole Cx. quinquefasciatus Mentha arvensis [112] Whole Plant An. stephensi Mentha piperita [114]
Aerial Parts Ae. aegypti An. Tessellatus Cx. quinquefasciatus
Minthostachys setosa [115] Whole Plant Ae. Aegypti An. Tessellatus
Moschosma polystachyum
[96] Leaf Cx. quinquefasciatus
Ocimum basilicum [116] Aerial Parts An. stephensi Origanum majoranal [100] Leaf Cx. pipiens Plectranthus longipes [116] Aerial Parts An. gambiae Pogostemon cablin [117] Leaf Ae. aegypti
Labiatae
Rosmarinus officinalis [118] Shoot An. stephensi Thymus capitatus [119] Whole Plant Cx. Pipiens
Cinnamomum iners [96] Leaf Ae. aegypti Cinnamomum kuntsleri [96] Leaf Ae. aegypti Cinnamomum pubescens [96] Leaf, Bark and
Twig Ae. aegypti
Cinnamomum scortechinii
[96] Bark Ae. aegypti
Lauraceae
Cinnamomum sintoc [96] Bark and Leaf Ae. aegypti
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Table 2. Continued
Cinnamomum zeylanicum
[118]
Bark and Leaf An. stephensi Ae. aegypti Cx. quinquefasciatus
Liliaceae Gloriosa superb [98] Whole Cx. quinquefasciatus Lythraceae Pemphis acidula [120] leaf Cx. quinquefasciatus
Ae. aegypti Menispermaceae Abuta grandifolia [115] Fruit Ae. aegypti
Azadirachta indica [95]
Leaf and Seed Ae. aegypti Cx. quinquefasciatus
Khaya senegalensis [106] Seed Cx. annulirostris Lansium domesticum [95] Leaf Ae. Aegypti
Cx. quinquefasciatus Melia azadirachta [112]
Whole Plant An. stephensi Cx. pipiens molestus
Meliaceae
Melia volkensii [121]
Seed and Fruit Cx. pipiens molestus Ae. aegypti An. arabiensis
Eucalyptus camaldulensis
[122] Fruit Cx. pipiens
Eugenia caryophyllus [112] Whole Plant An. stephensi Eucalyptus globules [100]
Whole Plant An. stephensi Cx. pipiens Ae. albopictus
Myrtaceae
Syzygium aromaticum [117]
Leaf Ae. aegypti Cx. quinquefasciatus An. dirus
Oleaceae Jasminum fructicans [100] Leaf Cx. pipiens Papaveraceae Argemone mexicana [111] Leaf Cx. quinquefasciatus Pinaceae Cedrus deodara [112] Whole Plant An. stephensi
Piper longum [123] Fruit Cx. pipiens pallens Piperaceae
Piper nigrum [124] Fruit Cx. pipiens pallens Ae. aegypti Ae. togoi
Plumbago dawei [125] Root An.gambiae
Plumbago stenophylla [125] Root An.gambiae
Plumbaginaceae
Plumbago zeylanica [125] Root An.gambiae Cymbopogon citratus [96] Whole Plant Cx. quinquefasciatus Cymbopogon flexuosus [112] Whole Plant An. stephensi Cymbopogon martini [112] Whole Plant An. stephensi Sorghum bicolour [126] Seedling Cx. pipiens
Poaceae
Vetiveria zizanioides [100] Rhizome Cx. pipiens Rubiaceae
Spermacoce hispida [98]
Whole
Cx.quinquefasciatus
Citrus limon [94] Peel Cx. pipiens Rutaceae Zanthoxyllum acanthopodium
[96] Stem Ae. aegypti
Navneet Kishore et al. 342
Table 2. Continued
Solanum elaeagnifolium [97] Berry An. labranchiae Solanum indicum [98] Shoot Cx. quinquefasciatus Solanum sodomaeum [97] Seed An. labranchiae Withania somnifera [111] Leaf Cx. quinquefasciatus
Solanaceae
Solanum xanthocarpum [127] Leaf Cx. quinquefasciatus Simaroubaceae Quassia amara [128] Whole Plant Cx. quinquefasciatus
Aquilaria malaccensis [96] Wood Ae. aegypti Thymelaeaceae Dirca palustris [129] Seed Ae. aegypti
Angelico glauca [92]
Aerial Parts Ae. aegypti Cx. fatigans
Umbelliferae
Pimpinella anisum [122] Seed Cx. pipiens Valerianaceae Valarian wallichii [92] Rhizome Ae. Aegypti
Aloysia citriodora [101] Whole Plant Ae. aegypti Clerodendrun inerme [98] Leaf Cx. quinquefasciatus Stachytarpheta jamaicensis
[98] Shoot Cx. quinquefasciatus
Verbenaceae
Vitex nequrdo [109] Whole Plant Cx. quinquefasciatus Curcuma domestica [91] Rhizome An. culicifacies Kaempferia galangal [98] Whole Cx. quinquefasciatus
Zingiberaceae
Zingiber officinalis [130] Tubers Cx. quinquefasciatus 4. Alkanes, alkenes, alkynes and simple aromatics The hydrocarbon, octacosane (1) isolated from Moschosma polystachyum shows significant larvicidal activity against Culex quinquefasciatus mosquito with LC50 value of 7.2±1.7 mg/L [33]. The (E)-6-hydroxy-4,6-dimethyl-3-heptene-2-one (2) isolated from Ocimum sanctum exhibit toxicity against fourth-instar larvae of Aedes aegyptii with LD100 value of 6.25 μg/mL in 24 h [34]. Among the acetylenic compounds, falcarinol (3) and falcarindiol (4) isolated from Cryptotaenia canadensis display strong activity against Culex pipiens larvae [35,36]. The more lipophilic 3 with LC50 values of 3.5 and 2.9 ppm in 24 h and 48 h, respectively exert strong toxicity than the more polar acetylene 4 with LC50 values of 6.5 and 4.5 ppm in 24 and 48 h, respectively [37]. The volatile aromatics, 4-ethoxymethylphenol (5), 4-butoxymethylphenol (6), vanillin (7), 4-hydroxy-2-methoxycinnamaldehyde (8), and 3,4-dihydroxyphenylacetic acid (9) isolated from Vanilla fragrans show very efficient mortality against mosquito larvae. The compunds 5-8 display 100% larval mortality at 0.5, 0.4, 2.0 and 1.0 mg/mL concentrations, respectively while 9 shows 17% larval mortality at a concentration of 1.0 mg/mL [38]. The hexane extract of Delphinium cultorum shows significant mosquitosidal activity (100% mortality at a concentration of 10 mg/mL) against Ae. aegyptii larvae at 2 h. A literature report comprising GC-EIMS
Mosquitosidal natural products 343
analysis of hexane extract of D. cultorum resulted into isolation of six volatiles, ethylmethylbenzene (10), 1-isopentyl-2,4,5-trimethylbenzene (11), 2-(hex-3-ene-2-one)phenyl methyl ketone (12), E and Z isomers of 3-butylidene-3H-isobenzofuran-1-one (13 and 14) and 2-penten-1-ylbenzoic acid (15) [39]. The trans-asarone (16) isolated from seeds of Daucus carota shows 100% mortality at a concentration of 200 μg/mL against fourth-instar larvae of Ae. Aegyptii [40]. The compound (17) isolated from rhizomes of Curcuma longa display 100% mortality against Ae. aegyptii larvae with LD100 value of 50 μg/mL in 18 h [27]. Similarly, 18 isolated from leaf and stem of Ocimum sanctum display mosquitocidal activity against fourth-instar larvae of Ae. aegyptii with LD100 value of 200 μg/mL in 24 h, respectively [34]. The 5-allyl-2-methoxyphenol (19) isolated from seeds of Apium graveolens exhibit 100% mortality on fourth-instar Ae. aegyptii larvae at 200 μg/mL
concentration [41]. The trans-anethole (20), methyl eugenol (21) and iso-methyl eugenol (22) isolated from Myrica salicifolia display 100% mortality with LD100 value of 20, 60 and 80 ppm in 24 h against 4th instar larvae of Ae. aegypti [42]. The stilbenes (23-29), isolated from the root bark of Lonchocarpus chiricanus possess larvicidal activities Ae. aegypti mosquito larvae. Among these, 27 at a concentration of 3.0 ppm exhibits highest activity while 24 and 25 with minimal concentration of 6.0 ppm each, display pronounced affect by kill all the larvae in 24 h. The compounds 23, 26, 28 and 29 with ≈50 ppm concentrations show moderate activity against larvae of Ae. aegypti [43]. 5. Lactones The lactones 30 and 31, isolated from Hortonia floribunda, H. angustifolia and H. ovalifolia, exhibit potent larvicidal activity against the second instar larvae of Ae. aegypti with LC50 values of 0.41 and 0.47 ppm, respectively [44]. The 3-n-butyl-4,5- dihydrophthalide (32) isolated from seeds of Apium graveolens show 100% mortality on fourth-instar Ae. aegyptii larvae at a concentration of 25 μg/mL [41]. The sedanolide (33) isolated from seeds of same species exhibits 100% mortality at 50 μg/mL concentrations against fourth-instar larvae of Ae. aegyptii [45]. 6. Essential oils and fatty acids The essential oils, α-phellandrene (34), limonene (35), p-cymene (36), γ-terpinene (37), terpinolene (38) and α-terpinene (39) isolated from leaves of Eucalyptus camaldulensis possess significant larvicidal activity against
Navneet Kishore et al. 344
CH3
CH3
1
H3C CH3
OCH3
OH
2
H2C
CH3OH
3 R = H4 R = OH
OH
OC2H5
OC4H9
OH
OH
OCH3
CHO
OH
OH
5 6 7 8 9
CH3
CH3
10
CH3
CH3
H3C
CH3CH3
11
CH3
CH3
O
O
12
O
O
H
H3C
13
O
O
HCH3
14
OH
CH3
O
15
CH2
O
CH3
H3C
17 18
OCH3
OCH3
H3C
H3CO
R
OH
OCH3
CHOCOOH
16
CH2
O
CH3
H3C
19
CH3
H3CO
CH2
H3CO
20
H3C
H3CO
H3CO
21
H3CO
22
OH
H3CO
CH2
OCH3
CH3H3C
OH
OCH3
CH3H3C
OH
CH3
H3C
OH
CH3
OH CH3
O
CH3H3COH
OH
23 24 25
26
OCH3
OCH3
27
OH
CH3
OCH3
CH3
H3C CH3
28
O
OH
CH3H3CHO
H3C CH3
29
Mosquitosidal natural products 345
H
O
H
HH3C
O9
H
O
HH3C
O9
H
HH
30 31
O
C4H9
O
32 33
O
C4H9
O
fourth-instar larvae of Ae. aegypti and Ae. albopictus. The compound 39 exert the strongest activity against Ae. aegypti larvae with LC50 value of 14.7 μg/mL (LC90 = 39.3 μg/mL) in 24 h, following the compounds 34 (LC50 = 16.6 μg/mL, LC90 = 36.9 μg/mL), 35 (LC50 = 18.1 μg/mL, LC90 = 41.0 μg/mL), 36 (LC50 = 19.2 μg/mL, LC90 = 41.3 μg/ mL), 38 (LC50 = 28.4 μg/mL, LC90 = 46.0 μg/mL) and 37 (LC50 = 30.7 μg/mL, LC90 > 50.0 μg/mL) [46]. Similarly, 40-49 isolated from leaves of different Cinnamomum osmophloeum exhibit strong activity against Ae. aegypti larvae.
CH3H3C
CH3
34
CH2H3C
CH3
35
CH3
H3C CH3
36
CH3
H3C CH3
37
CH3
H3C CH3
38
CH3
H3C CH3
39
CHO CHO
CHOHO
COOH
40 41 42 43
OH
44
O
CH3
H
HH2C
H3C
H3C
H2C
CH3
H H
CH3CH3
46 47
CH3
H2CCH3HO CH3
48
45
O CH3
O
49
OCOCH3
CH3
O
H2C
O
CH3
CH3OH
CH3
O
H2C
CH3
50 51
Navneet Kishore et al. 346
Among these volatiles, benzaldehyde (40) 4-hydroxybenzaldehyde (41), benzenepropanal (42), cinnamic acid (43), cinnamyl alcohol (44), bornyl acetate (45), β-caryophyllene (46), caryophyllene oxide (47) and linalool (48) possess strong activities with LD50 value of 50 μg/mL while 49 with LD50 value of 33 μg/mL produce significant larvicidal effect [47]. Likewise, among the 2,2-dimethyl-6-vinylchroman-4-one (50) and 2-senecioyl-4-vinylphenol (51) isolated from the roots of Eupatorium betonicaeforme, 50 shows efficient larvicidal potential, causing 84% larval mortality at a concentration of 12.5 μg/mL in compared to 51 exhibiting 40-100% mortality at 5-100 μg/mL concentrations [48]. The fatty acid constituents, linoleic acid (52) and oleic acid (53) isolated from Dirca palustris exhibit mosquitocidal activity against fourth instar Ae. aegyptii larvae with LD50 values of 100 μg/mL at 24 h, each [49].
H3C(H2C)4(HC CHCH2)2(CH2)5CH2COOH
52
C CCH2(CH2)5CH2COOH
H
H3C(H2C)6H2C
H
53
7. Terpenes
7.1. Monoterpenes The monoterpenoids, thymol (54), cholorothymol (55), carvacrol (56), β-citronellol (57), cinnamaldehyde (58) and eugenol (59) isolated from a number of plant species possess mosquitocidal activity against forth instar larvae of Culex pipiens with LC50 values of 37.95, 14.77, 44.38, 89.75, 58.97 and 86.22 μg/mL, respectively. The N-methyl carbamate derivatives of 54-57, i.e. 60-63 display high toxicities against forth instar larvae of Cx. pipiens with LC50 values of 7.83, 11.78, 4.54, 15.90 μg/mL, respectively. Moreover, the N-methyl carbamate derivatives of geraniol (64) and borneol (65) also exhibit significant activity against forth instar larvae of Cx. pipiens with LC50 values of 24.08 and 33.00 μg/mL, respectively [50]. Likewise, 1,8-cineole (66) isolated from leaves of Hyptis martiusii display pronounced insecticidal effect against Ae. aegypti larvae at concentrations 25 (10%), 50 (53%), 100 (100%) mg/mL [51]. Other monoterpenoids, geranial (67) and neral (68) isolated from Magnolia salicifolia show 100% mortality with LD100 value of 100 ppm in 24 h against 4th instar Ae. aegypti [42].
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CH3
OH
CH3
Cl
H3C
55
CH3
CH3
H3C
56
OH
CH2
OCH3
OH
59
OH
H3C CH3
CH3
57
H3C CH3
CH3
63
OCNHCH3
O
CH3
OCNHCH3
CH3
Cl
H3C
O
CH3
OCNHCH3
CH3
Cl
H3C
O
6160
CH3
CH3
H3C
62
OCNHCH3
O
H3C CH3
CH3
OCNHCH3
O
64
CH3
OCNHCH3
O
65
CH3
OH
CH3
H3C
54
CHO
58
CH3
CH3H3C
O
66
CH3
CH3H3C
CH3
CH3H3C
CHO
CHO
67 68 7.2. Sesquiterpenes The β-selinene (69) isolated from seeds of Apium graveolens show 100% mortality against fourth-instar larvae of Ae. aegyptii at a concentration of 50 μg/mL [41]. The pregeijerene (70), geijerene (71), and germacrene D (72) isolated from leaves of Chloroxylon swietenia possess activity against An. gambiae, Cx. quinquefasciatus and Ae. aegypti. The results of SAR indicate that 72 with LD50 values of 1.8, 2.1 and 2.8×10-3 exert highest activity followed by 70 with LD50 values of 3.0, 3.9 and 5.1×10-3 while 71 with LD50 values of 4.2, 5.4 and 6.8×10-3 display lowest activity against An. gambiae, Cx. quinquefasciatus and Ae. aegypti, respectively [52]. The sesquiterpene lactones, 73 and 74 isolated from leaves, stem bark, flowers and fruits of Magnolia salicifolia exhibit significant toxicity against Ae. aegypti larvae. The lactone 73 with LD100 value of 15 ppm kills all the mosquito larvae of Ae. aegypti in 24 h while 74 possess 100% mortality with LD100 value > 50 ppm in 24h [53]. The sesquiterpene, 74 does not show mosquitocidal activity at 50 ppm, thus suggesting the presence of a double bond rather than an epoxide at C-4 and C-5 in 73 is essential for mosquitocidal activity [42].
Navneet Kishore et al. 348
CH3
CH2
CH2
CH3
69
CH2
CH2
H3CCH2CH3
CH3
CH3
CH3CH3
CH3
70 71
72O
CH3
CH2
OCH3
73
O
CH3
CH2
O
H3C O
74
7.3. Diterpenes Among the diterpenes, 75-77 isolated from Pterodon polygalaeflorus exhibit significant larvicidal activity against fourth-instar larvae of Ae. aegypti with LC50 values of 50.08, 14.69 and 21.76 μg/mL, respectively [54]. Similarly, hugorosenone (78) isolated from the Hugonia castaneifolia display larvicidal activity against mosquito larvae An. gambiae with LC50 values of 0.3028 and 0.0986 mg/mL at 24 and 48 h, respectively [55].
O
O
H3C
CH3 H
O
CH3
HOH
75
OHOH
O
H3C
CH3 HO
CH3H
OH
76
OHOCH3
O
H3C
CH3 H
CH3H
OH
O
77
CH2
CH3
HO
CH3
OH
CH3
HH3C
78
7.4. Triterpenes The triterpenes, 3β,24,25-trihydroxycycloartane (79) and beddomeilactone (80) isolated from Dysoxylum malabaricum and D. beddomei possess strong larvicidal, pupicidal and adulticidal activity and also affect the reproductive potential of adults by acting as oviposition deterrents. Among these, the 79 at a concentration of 10 ppm kills more than 90% of pupae and 85% of adults. Similarly, 80 at the same concentration results in more than 95% of pupal and larval mortality and more than 90% mortality in case of adult An. Stephensi [56].
Mosquitosidal natural products 349
CH3
H2C
CH3H3C
OH
CH3
OH
H
CH3
H
CH3
H
HO
O CH3
O
H3C COOH
O H2C H
CH3
CH3
CH3
H
8079
H3C H3C
7.5. Tetranortriterpenoids The limonin (81), nomilin (82) and obacunone (83) isolated from the seeds of Citrus reticulate [57] exhibit mosquitocidal activity against fourth instar larvae of Cx. quinquefasciatus at 59.57, 26.61 and 6.31 ppm concentrations, respectively [58]. The limonoids 84-86, isolated from the root bark of Turraea wakefieldii exhibit activity against late third or early fourth-instar larvae of An. gambiae. In SAR, the strong larvicidal activities of 84, 85 and 86 with LD50 values of 7.83, 7.07 and 7.05 ppm, respectively indicate that the epoxidation of the C-14, C-15 double bond or de-acetylation of the 11-acetate group does not alter the larvicidal activity [59]. Other limonoids, azadirachtin (87), salannin (88), deacetylgedunin (89), 17-hydroxyazadiradione (90), gedunin (91) and deacetylnimbin (92) isolated from Azadirachta indica possess significant activity against An. stephensi larvae. Among these, 87 with EC50 value of 0.014, 0.021, 0.028 and 0.034 ppm, 88 with EC50 value of 0.023, 0.036, 0.047 and 0.061 ppm, 89 with EC50 value of 0.028, 0.041, 0.0614 and 0.078 ppm, 90 with EC50 value of 0.047, 0.054, 0.076 and 0.0104 ppm, 91 with EC50 value of 0.058, 0.073, 0.095 and 0.0117 ppm and 92 with EC50 value of 0.055, 0.067, 0.091 and 0.0113 ppm, show activity against first, second, third and fourth instar larvae of An. stephensi, respectively. The metabolite 87 exerts 100% larval mortality at 1 ppm concentration thus demonstrates that the A. indica (Neem) products may have benefits in mosquito control programs [60]. Likewise, 93-95 isolated from Turraea wakefieldii and T. floribunda exhibit toxicity against An. gambiae larvae with LD50 values of 7.1, 4.0, and 3.6 ppm, respectively and display more potency than azadirachtin (87; LD50 value of 57.1 ppm), a commonly used positive control [61].
Navneet Kishore et al. 350
O
O
OCH3
O
CH3H3C
OO
O
CH3O
CH3
O
OO
O
CH3CH3
O
81
O
OAc
CH3H3C
O
82
O
CH3
O
CH3
OO
O
CH3
O
CH3H3CO
83O
CH3
OAc
OH
CH3HH3C
CH3
OAcO
H
O
O
CH3
OAc
OH
CH3HH3C
CH3
OAcO
H
O
O
O
CH3
OAc
OH
CH3H
H3C
CH3
OHO
H
OAc
84 85 86
O
H3C
O
OH3CAcO
O
H3C
H3CO
CH3 CH3O
O
O
H3C
H3CO
OHOOAc
O
O
O
CH3OH
HOAcO
AcO OH
CH3
87 88
O
H3CO
CH3
OH
CH3
CH3O
CH3
CH3 89
H3C
O
H3CO
CH3
OAc
CH3
CH3O
CH3
CH391
CH3 CH3
OHH3C
O
OHO
C O
OCH3
O
90
OCH3
CH3H3CO
CH3 CH3
CH3
CH2
OH
OAc
92
O
CH3
O
OAc
OH OH
CH3
H3C
CH3 CH3
H
O
O
HO
OAc
H
(H3C)2HCOCOCH3
OAc
H
H3C
CH3
AcO
CH3
O
O
HO
OAc
H
(H3C)2HCOCOCH3
OH
H
H3C
CH3
AcO
CH3
O
CH3
O
93 94 95
O OCH3 O O
CH3
Mosquitosidal natural products 351
8. Alkaloids
8.1. Alkamides The alkamides, undeca-2E-4Zdien- 8,10-diynoic acid isobutylamide (96), undeca-2Z,4E-dien-8,10-diynoic acid isobutylamide (97), dodeca-2E,4Z-dien-8,10-diynoic acid isobutylamide (98), undeca-2E,4Z-dien-8,10-diynoic acid 2-methylbutylamide (99), dodeca-2E,4Z-dien-8,10-diynoic acid 2-ethylbutylamide (100), and a mixture of dodeca-2E,4E,8Z,10E-tetraenoic acid isobutylamide (101) and dodeca-2E,4Z,8Z,10Z-tetraenoic acid isobutylamide (102) isolated from the dried roots of Echinacea purpurea and other plant species of family Asteraceae [62] display significant mosquitocidal activity against Ae. aegyptii. The mixture of 101 and 102 exert most effective mosquitocidal activity at 100 μg/mL concentration with 87.5% mortality of mosquito larvae in 15 min while 96 display 100% mortality at same concentration in 2 h. The alkamides, 97 and 98 exhibit 50% mortality at the end of 9 h with 100 μg/mL while 99 and 100 show least activity with 10% mortality at a concentration of 100 μg/mL in 24 h [63]. Among isobutyl amides, pellitorine (103), guineensine (104), pipercide (105), and retrofractamide-A (106) isolated from fruits of Piper nigrum exhibit toxicity against Cx. Pipiens larvae. The toxicities against Cx. pipiens larvae falls in the order: 105 (0.004 ppm)> 106 (0.028 ppm) > 104 (0.17 ppm) > 103 (0.86 ppm). These compounds also display larvicidal activity against Ae. aegypti larvae in which 106 exerts pronounced activity at a concentration of 0.039 ppm than 105 (0.1 ppm), 104 (0.89 ppm) and 103 (0.92 ppm). Also, the amides 105, 106 and 104 exhibit 255, 31 and 5 times more toxicity than 103, respectively. The SAR indicates that the N-isobutyl amine moiety might play a crucial role in the larvicidal activity, but the methylenedioxyphenyl moiety does not appear essential for toxicity [64].
8.2. Carbazole alkaloids Among carbazoles, mahanimbine (107), murrayanol (108) and mahanine (109) isolated from leaves of Murraya koenigii display promising mosquitocidal activity against Ae. Aegyptii [65]. The alkaloid 107 exhibits 100% mortality at a concentration of 100 μg/mL while 108 and 109 at 12.5 μg/mL concentration display 100% mortality [66,67].
Navneet Kishore et al. 352
C C C CH2C CH2
C C
C CC NH
H2C CH
CH3
CH3H
H H
H
H
O
C C C CH2C CH2
C C
C CC
HN
H2C CH
CH3
CH3
H
H
H
H H
O
96
97
C C C CH2C CH2
C C
C CC
HN
H2C CH
CH3
CH3H3C
H H
H
H
O
C C C CH2C CH2
C CC C
C NH
H2C CH
H2C
CH3
H
H
H
H H
O
98
99 CH3
C C C CH2C CH2
C C
C CC N
H
H2C CH
H2C
CH3H3C
H H
H
H
O
C CC C
H2C CH2
C CC C
CHN
H2C CH
CH3
CH3
HH
H
H
H
O
101
CH3
100
H3C H
H H
C CC C
H2C CH2
C CC C
CHN
H2C CH
CH3
CH3
H
H
H
H
H
O
H3C
H
H H
102
HNH3C
O
CH3
CH3103
Mosquitosidal natural products 353
O
OHN
O
CH3
CH3
O
OHN
O
CH3
CH3
O
OHN
O
CH3
CH3
104
105
106
NH
O CH3
CH3
R
CH3
CH3
NH
OH CH3
CH3
H3COCH3
107: R = H109: R = OH
H3C
108
8.3. Naphthylisoquinoline alkaloid The alkaloid, dioncophylline-A (110) isolated from Triphyophyllum peltatum [68] possess promising activity against different larval stages of An. stephensi with LD50 values of 0.5, 1.0 and 2.0 mg/L concentrations at 3.33, 2.66 and 1.92 h, respectively. In each instar larval stage, the LC50 values decrease as a function of time indicating that 110 continues to exert its action during at least 48 h [69].
N
H3CO
CH3
OH
H
CH3
H3CO
CH3
110
8.4. Piperidine alkaloids The alkaloid, pipernonaline (111) isolated from fruits of Piper longum exhibits activity against the fourth-instar larvae of Ae. aegypti [70] and Cx. Pipiens [71] with LC50 values of 0.25 and 0.21 mg/L, respectively in 24 h.
Navneet Kishore et al. 354
The larvicidal potential of 111 against the Ae. aegypti, is comparable to that of pirimiphos-methyl, a commonly used insecticide and may be useful for development of new mosquito larvicides [70]. Similarly, N-methyl-6β-(deca-l',3',5'-trienyl)-3-β-methoxy-2-β-methylpiperidine (112) isolated from stem bark of Microcos paniculata shows significant insecticidal activity against second instar larvae of Ae. aegypti with MC50 value of 1.0 ppm and LC50 value of 2.1 ppm at 24 h against second instar larvae of Ae. aegypti [72].
N
O
O
O111
H3CN
O
CH3
CH3
112
CH3
Insecticidal activity evaluation of piperidine derivatives (113-145) against female adults of Ae. aegypti, along with the structure-activity relationships (SAR) using piperine (E,E)-1-piperoyl-piperidine as standard insecticide (LD50 value of 8.13 μg per mosquito) reveals that different moieties (ethyl-, methyl-, and benzyl-) attached to the piperidine ring are responsible for different toxicities (i.e. 113, 1.77; 114, 2.74; 115, 8.76; 116, 1.20; 117, 1.09; 118, 1.13; 119, 4.14; 120, 1.92; 121, 2.07; 122, 1.80; 123, 4.90; 124, 4.25; 125, 2.63; 126, 6.71; 127, 1.22; 128, 1.67; 129, 0.94; 130, 1.56; 131, 1.83; 132, 0.84; 133, 29.20; 134, 14.72; 135, 19.22; 136, 12.89; 137, 0.80; 138, 1.38; 139, 3.59; 140, 1.32; 141, 2.07; 142, 7.43; 143, 1.54; 144, 2.72 and 145, 14.72 μg) against Ae. aegypti. The 3-methylpiperidines (119-122) exhibit slightly lower toxicities than that of 2-methyl-piperidines (113-118) with LD50 values ranging from 1.80 to 4.14 μg. However, there is no significant difference found between the toxicities of 3-methyl piperidines (119-122) and 4-methyl piperidines (123-127), whose LD50 values range from 1.22 to 6.71 μg while the saturated long chain derivatives of 4-methyl-piperidine (123 and 126) show lower toxicity than others with LD50 values of 4.90 and 6.71 μg, respectively [73]. Further, SAR among the piperidines with two different moieties (ethyl- and benzyl-) attached to the carbons of the piperidine ring against Ae. aegypti establishes that 2-ethyl-piperidines (128-132) show higher toxicity than the benzyl-piperidines (133-136) with LD50 values ranging from 0.84-1.83 and 12.89-29.20 μg, respectively. The results of SAR suggest that ethyl-piperidines
Mosquitosidal natural products 355
O
N
H3C
NR
O
H3C113
H3C
N
O
H3C
N
H3C
O
O
N
CH3
CH3N
O
CH3
NC6H13
CH3
O O
N
CH3
117 118
119 120 121 122
114 R = C9H19115 R = C11H23116 R = C6H13
NR
O
CH3
N
O
CH3
O
N
CH3123 R = C9H19126 R = C11H23
124 125
(H2C)2 N
O
CH3127
N
O
N
O
CH3CH3
N
CH3
H3CO
N
CH3
O
C8H17 N
CH3
O
128 129 131130 132
H3C N
O
N
O
133 134
NH2C
O
N
O
135 136
H2C
H3C
N
OH2C
N
O
R137 R = CH3 139 R = C6H5
138
H2CN
OH2C
N
O
CH3CH3
140 141
H2CN
O
H2CN
O
H2CN
O
CH3
CH3
144
143
H2CN
O
145
142
Navneet Kishore et al. 356
generally exhibit higher toxicities than methyl-piperidines, followed by benzyl-piperidines whose toxicities are lowest. Among the three 1-undec-10-enoyl-piperidines (134-139) with the three different moieties at the second carbon of the piperidine ring, the 137 displays highest toxicity with LD50 value of 0.80 μg, in compared to 138 (LD50 value of 1.38 μg) and 139 (LD50 value of 3.59 μg). Similarly, among the three 1-undec-10-enoyl-piperidines (140-142) with the three different moieties attached to the third carbon of the piperidine ring, the 140 exhibit highest toxicity (LD50 value of 1.32 μg), followed by the 141 and 142 with LD50 values of 2.07 and 7.43 μg, respectively. Likewise, among the three 1-undec-10-enoyl-piperidines (143-145) with the three different moieties attached to the fourth carbon of the piperidine ring, the 143 shows highest toxicity (LD50 value of 1.54 μg), following 144 (LD50 value of 2.72 μg) and 145 (LD50 value of 14.72 μg). 8.5. Stemona alkaloids The Stemona alkaloids, stemocurtisine (146), stemocurtisinol (147) and oxyprotostemonine (148) isolated from roots of Stemona curtisii exhibit potency against mosquito larvae An. minimus with LC50 values of 18, 39 and 4 ppm, respectively. Among these, 148 display highest potency with LC50 value of 4 ppm [74].
N
OO
HO
H
H HH3COCH3
H3C
O
N
OO
OH
H HH3COCH3
H3C
O
OH
CH3
146 147
N
OO
HHH3COCH3
H3C
O
OO
H
H
O
CH3
148
Mosquitosidal natural products 357
9. Phenolic derivatives 9.1. Naphthoquinones The cordiaquinones (149-152), isolated from the roots of Cordia curassavica show toxic properties against larvae of the yellow fever-transmitting Ae. aegypti. The quinones 149 and 151 with 25.0 μg/mL concentration result in 100% larval mortality while 150 and 152 with 12.5 μg/mL concentrations kill all the Ae. aegypti larvae in 24 h [75]. Likewise, the alkaloids 153-155 isolated from the roots of Cordia linnaei exhibit larvicidal potency against Ae. aegypti at 12.5, 50.0 and 25.0 μg/mL concentrations, respectively [76]. The naphthoquinone, plumbagin (156) isolated from Plumbago zeylanica [77] and other plant species [78,79] exhibit mosquito larvicidal activity against An. gambiae with LC50 value of 1.9 μg/mL [80,81]. Some of natural and synthetic naphthoquinones e.g. lapachol (157) and its synthetic derivatives (158-160) possess toxicity against fourth instar larvae of Ae. aegypti. The quinone 159 with LC50 value of 15.24 μM exerts higher activity in compared to 160 (19.45 μM), 158 (33.94 μM) and 157 (108.7 μM). Likewise, juglone (161) and its synthetic derivatives (162-170) display significant toxicity against fourth instar larvae of Ae. aegypti. The bromo-naphthoquinone 167 with LC50 value of 3.46 μM exhibits the best larval toxicity in compared to 164 (4.64 μM), 165 (3.98 μM), 166 (36.48 μM), 167 (3.46 μM), 168 (24.79 μM) and 169 (21.62 μM) while 161 and derivatives 162, 163 and 170 display relatively weak toxicity with LC50 values of 20.61, 21.08, 42.12 and 86.93 μM, respectively [82]. The shikonin (171), alkannin (172) and shikalkin (173) isolated from root of Lithospermum erythrorhizon [83], Alkanna tinctoria [84] and young leaves and stems of L. officinale [85] exhibit toxicities against mosquito larvae. The quinone 171 at a concentration of 3.9 mg/L show high toxicity against mosquito larvae followed by 173 and 172 with 8.73 and 12.35 mg/L concentrations, respectively. Results of SAR indicate that naphthoquinones, compared with other natural compounds with larvicidal activity, are very toxic against mosquito larvae and would be a potential source of natural larvicidal substances [86]. 9.2. Coumarins Coumarin, pachyrrhizine (174), isolated from Neorautanenia mitis exhibits activity against An. gambiae adults with LC50 value 0.007 mg/mL. The marmesin (175), isolated from Aegle marmelos exhibits toxicity against An. gambiae adults with LC50 and LC90 values of 0.082 and 0.152 mg/L, respectively [87].
Navneet Kishore et al. 358
H3C
CH3 OCH3
O
O
OH
O
O
CH3H3C
CH3
150149O
O
OH2C
CH3
CH3
152
CH3
CH3OH3CO
O 151
CH3 CH3
OH3C
O
O 153
CH3CH3
H3C
O
O
OH
OH
154CH3 CH3
OHH3C
O
O
OH
155
O
O OH
H3C
156
OHO
OCH3
CH3
157
OAcO
O
CH3
CH3
158
OO
O
CH3
CH3
159
Li
OH
CH3
CH3O
O
160
O
OOH161
O
OOAc162
O
OOCH3163
O
OOH
Br
164
O
OOAc
Br
165
O
OOCH3
BrO
OOH
166
Br
167
O
OOCH3
O
OOAc
Br
168
O
O
CH3
Br
169
170
CH3
OHO
O
CH3
OH
OH
CH3
O
O
CH3
OH
OH
CH3
OHO
O
CH3
OH
OH
OH
171 172 173
Mosquitosidal natural products 359
O OOCH3
O
O
O
174
OO
H3C
HOH3C
O
175
9.3. Isoflavonoids The isoflavonoids neotenone (176), neorautanone (177) isolated from Neorautanenia mitis display activity against adult An. gambiae mosquitoes with LD50 values of 0.008 and 0.009 mg/mL, respectively [88].
OOCH3
OO
O
O
176
O O
OCH3OCH3
OCH3
O
177
9.4. Pterocarpans The pterocarpans, neoduline (178), 4-methoxyneoduline (179), and nepseudin (180) isolated from tubers of Neorautanenia mitis exhibit mosquitocidal activity against An. gambiae and Cx. quinquefaciatus larvae with LD50 values 0.005, 0.011 and 0.003 mg/mL, respectively [87,89].
OO
O O
O
H
H
178
O O
O
OO
OCH3
179
O
O
OO
OCH3
H3CO
180
Navneet Kishore et al. 360
9.5. Lignans The lignans, conocarpan (181), eupomatenoid-5 (182), eupomatenoid-6 (183) and decurrenal (184) isolated from Piper decurrens possess significant mortality at 10 μg/mL concentrations against mosquito larvae [90].
O
CH3
H
H
OH
H3C
O
CH3
H
HC
OH
O
H3CCH3
OCH3
OH
O
H3CCH3
OH
181
183
182
184O
H
10. Conclusive remarks Our ancestors exclusively depended on the use of plant-derived products to repel or kill mosquitoes and other blood sucking insects. Modern synthetic chemicals could provide immediate results for the control of insects/mosquitoes; on the contrary they bring irreversible environmental hazard, severe side effects and pernicious toxicity to human being and beneficial organisms. In concern to the quality and safety of life and the environment, the emphasis on controlling mosquito vectors has shifted steadily from the use of conventional chemicals toward alternative insecticides that are target-specific, biodegradable, and environmentally safe, and these are generally botanicals in origin. Therefore, right now use of eco-friendly and cost-free plant based products for the control of insects/mosquitoes is inevitable. Efforts should be made to promote the use of easy accessible and affordable traditional insect/mosquito repellent plants. Acknowledgement The author sincerely acknowledged Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi, India, for infrastructural facilities.
Mosquitosidal natural products 361
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