mosquitosidal terpenoid

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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: [email protected]

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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: [email protected]

Navneet Kishore et al. 336

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].

Mosquitosidal natural products 337

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.

Navneet Kishore et al. 338

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

Mosquitosidal natural products 339

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

Mosquitosidal natural products 341

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].

Mosquitosidal natural products 347

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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