Research Signpost 37/661 (2), Fort P.O.

Trivandrum-695 023 Kerala, India

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: vyas_45@rediffmail.com

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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 (1st 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 DDTs 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 Tinjut Woira Neem Wogert Kebercho Waginos Eucalyptus Ades Gemmero Tej-sar Ats-faris Endode Azo-hareg Berberra Gullo Scientific Names Ostostegia integrifolia Olea europaea Azadirachta indica Silene macroserene Echinops sp. Brucea antidysenterica Eucalyptus camaldulensis Myrtus communis Capparis tomentosa Cymbopogen citrates Datura stramonium Phytolacca dodecandra Clematis hirsuta Millettia ferruginea Ricinus communis Family Lamiaceae Oleaceae Meliaceae Caryophyllaceae Asteraceae Simaroubaceae Myrtaceae Myrtaceae Capparidaceae Rutaceae Solanaceae Phytolaccaceae Ranunculaceae Fabaceae 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 structureactivity 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 Acoraceae Plant species Acorus calamus [91,92] Parts Rhizome Mosquitoes Cx. quinquefasciatus Ae. aegypti Ae. albopictus An. tessellates An. subpictus Cx. fatigans Cx. pipiens Cx. pipiens Ae. aegypti Cx. quinquefasciatus An. gambiae Ae. aegypti Ae. aegypti An. labranchiae Cx. quinquefasciatus Ae. Aegypti, Cx. fatigans Ae. aegypti An. Stephensi Cx. quinquefasciatus Cx. quinquefasciatus Cx. quinquefasciatus Cx. pipiens Ae. aegypti An. labranchiae Ae. Aegypti Cx. fatigans Ae. aegypti An. stephensi Aedes aegypti Cx. pipiens Ae. rusticus Ae. albopictus Ae. aegypti Cx. quinquefasciatus Ae. aegypti, Cx. pipiens pallens

Agavaceae Alliaceae Annonaceae

Agave sisalana [93] Allium sativa [94] Annona squamosa [95] Mkilua fragrans [96] Xylopia caudata [96] Xylopia ferruginea [96] Calotropis procera [97] Catharanthus roseus [98] Daucus carota [92] Rhinocanthus nasutus [99] Hygrophila auriculata [98]

Fiber Bulb Leaf Aerial Part Leaf Leaf Root Whole Seed Leaf Shoot Leaf Flower Aerial Part Whole Plant Leaf Whole Plant Rhizome Old Litter

Apocynaceae Apiaceae Acanthaceae

Asteraceae

Justicia adhatoda [98] Anthemis nobilis [100] Baccharis spartioides [101] Cotula cinerea [97] Sassurea lappa [92] Tagetes minuta [102]

Araceae Betulaceae

Homalomena propinqua [92] Alnus glutinosa [103]

Cucurbiataceae Caesalpinaceae

Bryonopsis laciniosa [104] Cassia tora [105]

Whole Plant Seed

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Table 2. Continued
Cupressaceae Clusiaceae Cannabaceae Caulerpaceae Capparidaceae Caryophyllaceae Dictyotaceae Euphorbiaceae Callitris glaucophylla [106] Calophyllum inophyllum [99] Cannabis sativa [107] Caulerpa scalpelliformis [108] Cleome viscosa [109] Dictyota caryophyllum [110] Dictyota dichotoma [109] Codiaeum variegatum [95] Jatropha curcus [111] Ricinus communis [112] Abrus precatorius [98] Cassia obtusifolia [105] Croton bonplandianum [98] Vicia tetrasperma [105] Pelargonium citrosum [96] Endostemon tereticaulis [113] Lavandula afficinalis [112] Leucas aspera [98] Mentha arvensis [112] Mentha piperita [114] Minthostachys setosa [115] Moschosma polystachyum [96] Ocimum basilicum [116] Origanum majoranal [100] Plectranthus longipes [116] Pogostemon cablin [117] Rosmarinus officinalis [118] Thymus capitatus [119] Cinnamomum iners [96] Cinnamomum kuntsleri [96] Cinnamomum pubescens [96] Cinnamomum scortechinii [96] Cinnamomum sintoc [96] Wood Leaf and Seed Leaf Whole Plant Whole Plant Flower Whole Plant Leaf Leaf Whole Plant Shoot Seed Shoot Seed Whole Plant Aerial Parts Whole Plant Whole Whole Plant Aerial Parts Whole Plant Leaf Aerial Parts Leaf Aerial Parts Leaf Shoot Whole Plant Leaf Leaf Leaf, Bark and Twig Bark Bark and Leaf Ae. aegypti, Cx. annulirostris Cx. quinquefasciatus, An. Stephensi Ae. aegypti An. Stephensi, Cx. quinquefasciatus Ae. aegypti Ae. aegypti Cx. quinquefasciatus Ae. aegypti Ae. aegypti Ae. Aegypti, Cx. quinquefasciatus Cx. quinquefasciatus An. stephensi Cx. quinquefasciatus Ae. aegypti, Cx. pipiens pallens Cx. quinquefasciatus Ae. Aegypti, Ae. aegypti An. gambiae An. stephensi Cx. quinquefasciatus An. stephensi Ae. aegypti An. Tessellatus Cx. quinquefasciatus Ae. Aegypti An. Tessellatus Cx. quinquefasciatus An. stephensi Cx. pipiens An. gambiae Ae. aegypti An. stephensi Cx. Pipiens Ae. aegypti Ae. aegypti Ae. aegypti Ae. aegypti Ae. aegypti

Fabaceae

Geraniaceae Labiatae

Lauraceae

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Table 2. Continued
Cinnamomum zeylanicum [118] Liliaceae Lythraceae Menispermaceae Meliaceae Gloriosa superb [98] Pemphis acidula [120] Abuta grandifolia [115] Azadirachta indica [95] Khaya senegalensis [106] Lansium domesticum [95] Melia azadirachta [112] Melia volkensii [121] Myrtaceae Eucalyptus camaldulensis [122] Eugenia caryophyllus [112] Eucalyptus globules [100] Syzygium aromaticum [117] Oleaceae Papaveraceae Pinaceae Piperaceae Jasminum fructicans [100] Argemone mexicana [111] Cedrus deodara [112] Piper longum [123] Piper nigrum [124] Bark and Leaf Whole leaf Fruit Leaf and Seed Seed Leaf Whole Plant Seed and Fruit Fruit Whole Plant Whole Plant Leaf Leaf Leaf Whole Plant Fruit Fruit An. stephensi Ae. aegypti Cx. quinquefasciatus Cx. quinquefasciatus Cx. quinquefasciatus Ae. aegypti Ae. aegypti Ae. aegypti Cx. quinquefasciatus Cx. annulirostris Ae. Aegypti Cx. quinquefasciatus An. stephensi Cx. pipiens molestus Cx. pipiens molestus Ae. aegypti An. arabiensis Cx. pipiens An. stephensi An. stephensi Cx. pipiens Ae. albopictus Ae. aegypti Cx. quinquefasciatus An. dirus Cx. pipiens Cx. quinquefasciatus An. stephensi Cx. pipiens pallens Cx. pipiens pallens Ae. aegypti Ae. togoi An.gambiae An.gambiae An.gambiae Cx. quinquefasciatus An. stephensi An. stephensi Cx. pipiens Cx. pipiens Cx.quinquefasciatus Cx. pipiens Ae. aegypti

Plumbaginaceae

Plumbago dawei [125] Plumbago stenophylla [125] Plumbago zeylanica [125] Cymbopogon citratus [96] Cymbopogon flexuosus [112] Cymbopogon martini [112] Sorghum bicolour [126] Vetiveria zizanioides [100] Spermacoce hispida [98] Citrus limon [94] Zanthoxyllum acanthopodium [96]

Root Root Root Whole Plant Whole Plant Whole Plant Seedling Rhizome Whole Peel Stem

Poaceae

Rubiaceae Rutaceae

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Table 2. Continued
Solanaceae Solanum elaeagnifolium [97] Solanum indicum [98] Solanum sodomaeum [97] Withania somnifera [111] Solanum xanthocarpum [127] Quassia amara [128] Aquilaria malaccensis [96] Dirca palustris [129] Angelico glauca [92] Pimpinella anisum [122] Valarian wallichii [92] Aloysia citriodora [101] Clerodendrun inerme [98] Stachytarpheta jamaicensis [98] Vitex nequrdo [109] Curcuma domestica [91] Kaempferia galangal [98] Zingiber officinalis [130] Berry Shoot Seed Leaf Leaf Whole Plant Wood Seed Aerial Parts Seed Rhizome Whole Plant Leaf Shoot Whole Plant Rhizome Whole Tubers An. labranchiae Cx. quinquefasciatus An. labranchiae Cx. quinquefasciatus Cx. quinquefasciatus Cx. quinquefasciatus Ae. aegypti Ae. aegypti Ae. aegypti Cx. fatigans Cx. pipiens Ae. Aegypti Ae. aegypti Cx. quinquefasciatus Cx. quinquefasciatus Cx. quinquefasciatus An. culicifacies Cx. quinquefasciatus Cx. quinquefasciatus

Simaroubaceae Thymelaeaceae Umbelliferae

Valerianaceae Verbenaceae

Zingiberaceae

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 7.21.7 mg/L [33]. The (E)-6-hydroxy-4,6-dimethyl-3heptene-2-one (2) isolated from Ocimum sanctum exhibit toxicity against fourthinstar larvae of Aedes aegyptii with LD100 value of 6.25 g/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 3,4dihydroxyphenylacetic 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

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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 g/mL against fourthinstar 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 g/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 g/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 g/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 g/mL [41]. The sedanolide (33) isolated from seeds of same species exhibits 100% mortality at 50 g/mL concentrations against fourth-instar larvae of Ae. aegyptii [45].

6. Essential oils and fatty acids

The essential oils, -phellandrene (34), limonene (35), p-cymene (36), -terpinene (37), terpinolene (38) and -terpinene (39) isolated from leaves of Eucalyptus camaldulensis possess significant larvicidal activity against

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CH3 OH CH3

H2C OH R CH3

H 3C

CH3 CH3

1
OH OH

2
CHO

3R=H 4 R = OH
COOH CHO OCH3 CH3 OCH3

OH OH OH CH3

C2 H5 O O

C4H9

OH

6
CH3

8
O

10

CH3

CH3 CH3 H3 C CH3 O

CH3 O O

H H 3C

CH3

11
CH3

12
H3CO OCH3

13
CH3

14
CH 3

OH OCH3 O H3 C H 3C CH2 O H3 C CH2 O

15
OH

16

17

18

H3CO H3CO H3CO CH 3 CH2 H3CO H3CO CH2

H3CO

H 3C

19

20

21

22

CH3 OH H3C OH OH OCH3 OCH3 OH H3C 23 H3C O CH3 OH OCH3 CH3 H3C 24 CH3 25 CH3 CH3

OH

OCH3

26 CH3 H3C OCH3 CH3 CH3 OH

27 H3C HO CH3 O

OH

H3C 28 29

CH3

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H3C H3C O O C4H9 32 33 O

345

H O H H 9 H

H O O

O C4H9

9 H 30

31

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 g/mL (LC90 = 39.3 g/mL) in 24 h, following the compounds 34 (LC50 = 16.6 g/mL, LC90 = 36.9 g/mL), 35 (LC50 = 18.1 g/mL, LC90 = 41.0 g/mL), 36 (LC50 = 19.2 g/mL, LC90 = 41.3 g/ mL), 38 (LC50 = 28.4 g/mL, LC90 = 46.0 g/mL) and 37 (LC50 = 30.7 g/mL, LC90 > 50.0 g/mL) [46]. Similarly, 40-49 isolated from leaves of different Cinnamomum osmophloeum exhibit strong activity against Ae. aegypti larvae.
CH3 CH3 CH3 CH3 CH3 CH3

H3C 34

CH3

H3C 35

CH2

H3C 36

CH3

H3C 37

CH3

H3C 38

CH3

H3C 39

CH3

CHO

CHO OH CHO COOH 43 CH3 OCOCH3 H2C H3C H H CH3 CH3 H3C H H2C 47 O H2C CH3 O CH3 51 OH CH3 CH3 H 44 CH3 O

HO 40 41 O O CH3 42 CH3

49 CH3 H2C CH3 48

45 O

46

HO H2C

CH3

50

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Among these volatiles, benzaldehyde (40) 4-hydroxybenzaldehyde (41), benzenepropanal (42), cinnamic acid (43), cinnamyl alcohol (44), bornyl acetate (45), -caryophyllene (46), caryophyllene oxide (47) and linalool (48) possess strong activities with LD50 value of 50 g/mL while 49 with LD50 value of 33 g/mL produce significant larvicidal effect [47]. Likewise, among the 2,2-dimethyl-6-vinylchroman-4-one (50) and 2-senecioyl-4vinylphenol (51) isolated from the roots of Eupatorium betonicaeforme, 50 shows efficient larvicidal potential, causing 84% larval mortality at a concentration of 12.5 g/mL in compared to 51 exhibiting 40-100% mortality at 5-100 g/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 g/mL at 24 h, each [49].
H3C(H2C)6H2C H3C(H2C)4(HC 52 CHCH2)2(CH2)5CH2COOH C H 53 C H CH2(CH2)5CH2COOH

7. Terpenes
7.1. Monoterpenes
The monoterpenoids, thymol (54), cholorothymol (55), carvacrol (56), -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 g/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 g/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 g/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 Cl CH3 CH3 OH CH3 OH CHO OH OCH3

347

OH H3C 54 CH3 Cl O OCNHCH3 H3C 60 CH3 O OCNHCH3 CH3 H3C Cl CH3 H3C 55

OH CH2 CH3 H3C 56 CH3 CH3 H3C 57 CH3 O OCNHCH3 O OCNHCH3 CH3 61 H3C 62 CH3 CH3 O OCNHCH3 O CHO CH3 CHO CH3 H3C 63 CH3 CH3 CH3 58 CH3 O OCNHCH3 59

H3C 64

CH3 65

H3C 66

CH3

H3C 67

CH3

H3C 68

CH3

7.2. Sesquiterpenes
The -selinene (69) isolated from seeds of Apium graveolens show 100% mortality against fourth-instar larvae of Ae. aegyptii at a concentration of 50 g/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 2.810-3 exert highest activity followed by 70 with LD50 values of 3.0, 3.9 and 5.110-3 while 71 with LD50 values of 4.2, 5.4 and 6.810-3 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].

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CH3 CH2 CH2 69 CH3 CH3 CH3 72 CH2 CH3 73 O O CH2 H3C O 74 CH3 CH3 70 CH3 CH3 CH3 CH2 CH2 CH3 71

Navneet Kishore et al.

H3C

CH2 O O

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 g/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 O H CH3 H CH3 78 CH2 CH3

CH3

H O O

CH3

O OH OH H3C

CH3

O OH

OCH3 HO H3C

H3C

H CH3 OH 75

H3C

H CH3 OH 76

H CH3 OH 77

7.4. Triterpenes
The triterpenes, 3,24,25-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

OH H3C CH3 H2C H H CH3 HO H3C H CH3 79 CH3 OH CH3 O O H COOH 80 H2C H CH3 H3C CH3 O

349

CH3 CH3

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 deacetylation 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].

350
O O O CH3 CH3 O O CH3 81 O H O H3C O H3C H3C AcO AcO OH O 87 OCH3 CO CH3 CH3 O OH CH3 90 O H3C CH3 91 O HO CH3 CH3 CH3 CH3 OAc CH3 O O H3C CH3 O H O AcO H3C 88 O O O O H CH3 OAc OAc CH 3 CH3 H O H3C 84 OAc CH3 OH O CH3 H O H CH3 O OH H3C H3C O O H 3C O H O H 3C 85 H3C O O O O O O O H3C CH3 OAc CH3 O CH3 CH3 O O 82 O O O O O H3C

Navneet Kishore et al.

O CH3 CH3 CH3 O CH3 O 83 O O O

O H3C

OAc OAc CH 3 CH3 O H O

OAc OH CH3 CH3 H

H CH3

OAc 86 O CH3 CH3 CH3 CH3 OH CH3 89 CH3OH CH3 CH3 OAc 92

CH3

H3C O CH3

O CH2

O H3C

O CH3 OAc CH3 O O CH3 H3C H H OH O HO H3C H O O CH3 (H3C)2HCOCO AcO OAc CH3 H CH3

O (H3C)2HCOCO CH3 AcO OAc CH3 CH3 H HO H3C O H O OH CH3 O

CH3 O OAc CH3 94

93

95

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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), dodeca2E,4Z-dien-8,10-diynoic acid isobutylamide (98), undeca-2E,4Z-dien8,10-diynoic acid 2-methylbutylamide (99), dodeca-2E,4Z-dien-8,10diynoic acid 2-ethylbutylamide (100), and a mixture of dodeca2E,4E,8Z,10E-tetraenoic acid isobutylamide (101) and dodeca2E,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 g/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 g/mL while 99 and 100 show least activity with 10% mortality at a concentration of 100 g/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 g/mL while 108 and 109 at 12.5 g/mL concentration display 100% mortality [66,67].

352
O 96 H C C C C H2 C CH2 C H 97 H C C C C H2 C CH2 C H H H C C H H C C H H C C H H C C H H 102 H3C C H C H H H C C H2C CH2 C C C C C H H H N H C C O H H N C H C H O 100 H3C C C C C H2 C CH2 C H H3C 101 H H C C C H H2C C H H CH2 C C N H O C N H H2 C C H C C C H O 98 H3C C C C C H2 C CH2 C H 99 H C C C C H2 C CH2 C H C H N H C C H H O C C H C NH

Navneet Kishore et al.

CH3 CH3

H2 C CH

H N

H2 C CH

CH3 CH3 CH3 CH3

H2 C CH

H2C CH CH3 H2C H2 C CH

CH3

CH3

CH3

H2 C CH

CH3 CH3

H2 C CH

CH3 CH3

103

H3C O

H N

O CH3 CH3

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O 104 O O 105 O O O 106 O O CH3 R N H O H3C H3CO CH3 N H 108 OH CH3 CH3 CH3 H N CH3 CH3 H N O CH3 CH3 H N

353
CH3 CH3

CH3 CH3

107: R = H 109: R = OH

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].
CH3 CH3 N OH H3CO H3CO
110

CH3

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.

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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-6-(decal',3',5'-trienyl)-3--methoxy-2--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].
O O 111 O O CH3 112 H3C N CH3 CH3 N

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 g 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 g) 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 g. However, there is no significant difference found between the toxicities of 3-methyl piperidines (119-122) and 4-methyl piperidines (123127), whose LD50 values range from 1.22 to 6.71 g 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 g, 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 benzylpiperidines (133-136) with LD50 values ranging from 0.84-1.83 and 12.8929.20 g, respectively. The results of SAR suggest that ethyl-piperidines

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O N H3C
113

355
O R H3C
114 R = C9H19 115 R = C11H23 116 R = C6H13

O N H3C
117

O N H3C H3C
118

O CH3 N CH3

O N CH3 O C6H13

O N CH3 O N CH3 CH3

125

O N CH3

O R

119

120

121

122

N CH3
123 R = C9H19 126 R = C11H23 124

O N (H2C)2

N CH3
127

O N CH3
128 129

O N H3C

O N

O N CH3
131

O C8H17 N CH3
132

CH3

CH3
130

O H3C
133

O N
134

N O

O N

H2C

135

136

O H2C
137 R = CH3 139 R = C6H5

O N H2C
138

N H3C O

R O N H2C

H2C
140

N
141

O H2C N

CH3 H2C

O N

CH3

142

CH3
143

O H2C
144

O N H2C CH3
145

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Navneet Kishore et al.

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 g, in compared to 138 (LD50 value of 1.38 g) and 139 (LD50 value of 3.59 g). 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 g), followed by the 141 and 142 with LD50 values of 2.07 and 7.43 g, 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 g), following 144 (LD50 value of 2.72 g) and 145 (LD50 value of 14.72 g).

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].
H O H N H3C O O O 147 CH3 H HC OCH3 3 H3C O O O 148 H H O N O O OCH3H3C HH

H OCH3 H3C O O 146 H3C H H

O N OH

CH3

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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 g/mL concentration result in 100% larval mortality while 150 and 152 with 12.5 g/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 g/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 g/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 M exerts higher activity in compared to 160 (19.45 M), 158 (33.94 M) and 157 (108.7 M). Likewise, juglone (161) and its synthetic derivatives (162-170) display significant toxicity against fourth instar larvae of Ae. aegypti. The bromonaphthoquinone 167 with LC50 value of 3.46 M exhibits the best larval toxicity in compared to 164 (4.64 M), 165 (3.98 M), 166 (36.48 M), 167 (3.46 M), 168 (24.79 M) and 169 (21.62 M) 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 M, 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].

358
O H3C O O
149

Navneet Kishore et al.

CH3 O O CH3 H3C CH3 OH CH3 O H3C O CH3 CH3 H2C O O H3C O O
151 150

O CH3 CH3

O CH3 CH3 O O CH3 OH OH O

152

OH CH3 CH
3

H3C

OH

153

CH3 H3C

154

H3C

O O
155

O OH CH3 O CH3 O CH3 O CH3 OH O

161

156

OAc CH3

OH O

OLi CH3

O
158

CH3 O O

O
159

CH3 O Br

157

OH

OAc O
162

OCH3O
163

OH O
164

160

O Br

O Br

Br OAc O 165 O CH3 CH3 O 170 OH CH3 OH 172 O OH CH3 CH3 OH OCH3 O 166 O OH 167 OH O O OAc O

Br OCH3 O 169 OH O

Br

168

CH3 OH CH3

OH

O 171

OH

O 173

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O O

359

H3C O O 174 O OCH3 H3C HO O 175 O O

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].
O O OCH3 O OCH3 OCH3 OCH3 O O
176

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].
O O H O O H O O O OCH3 178 179 H3CO O OCH3 180 O O O O O O

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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 g/mL concentrations against mosquito larvae [90].
O H3C 181 O H C O H OH H H OH H 183 CH3 H3C 184 CH3 CH3 H3C 182 O OH CH3 O OCH3 OH

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.

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