Insecticidal Triterpenes in Meliaceae III: Plant Species, Molecules, and Activities in Munronia–Xylocarpus

Plants of the Meliaceae family have long attracted researchers’ interest due to their various insecticidal activities, with triterpenes being the main active ingredients. In this paper, we discuss 93 triterpenoids with insecticidal activity from 37 insecticidal plant species of 15 genera (Munronia, Neobeguea, Pseudocedrela, Nymania, Quivisia, Ruagea, Dysoxylum, Soymida, Lansium, Sandoricum, Walsura, Trichilia, Swietenia, Turraea, and Xylocarpus) in the family Meliaceae. Among these genera, Trichilia deserves further research, with twelve species possessing insecticidal activity. The 93 insecticidal molecules included 27 ring-seco limonoids (comprising 1 ring A-seco group chemical, 1 ring B-seco group chemical, 5 ring D-seco group chemicals, 14 rings A,B-seco group chemicals, 5 rings B,D-seco group chemicals, and 1 rings A,B,D-seco group chemical), 22 ring-intact limonoids (comprising 5 cedrelone-class chemicals, 6 trichilin-class chemicals, 7 havanensin-class chemicals, 2 azadirone-class chemicals, 1 vilasinin-class chemical, and 1 other chemical), 33 2,30-linkage chemicals (comprising 25 mexicanolide-class chemicals and 8 phragmalin-class chemicals), 3 1,n-linkage-group chemicals, 3 onoceranoid-type triterpenoids, 2 apotirucallane-type terpenoids, 2 kokosanolide-type tetranortriterpenoids, and 1 cycloartane triterpene. In particular, 59 molecules showed antifeedant activity, 30 molecules exhibited poisonous effects, and 9 molecules possessed growth regulatory activity. Particularly, khayasin, beddomei lactone, 3β,24,25-trihydroxycycloartane, humilinolides A–E and methyl-2-hydroxy-3β-isobutyroxy-1-oxomeliac-8(30)-enate showed excellent insecticidal activities, which were comparable to that of azadirachtin and thus deserved more attention. Moreover, it was noteworthy that various chemicals (such as 12α-diacetoxywalsuranolide, 11β,12α-diacetoxycedrelone, 1α,7α,12α-triacetoxy-4α-carbomethoxy-11β-hydroxy-14β,15β-epoxyhavanensin, and 11-epi-21-hydroxytoonacilide, etc.) from Turraea showed excellent insecticidal activity. Specially, the insecticidal activity of khayasin from Neobeguea against the coconut leaf beetle were similar to that of rotenone. Therefore, it was a promising candidate insecticide for the control of the coconut leaf beetle.


Introduction
The severe damage to the ecology, environment, and human health that occurs due to the usage of synthetic pesticides has necessitated a shift to natural-product-based agrochemicals that are biodegradable, eco-friendly, and safe for the environment [1].Plants produce a diverse range of secondary metabolites, such as limonoids, alkaloids, flavonoids, and quinones, as part of their defense mechanisms against insect pests.Among these chemicals, limonoids and their precursors have attracted the attention of researchers globally because of their obvious effects on insect pests [2][3][4].The Meliaceous plants have been proven to produce various antifeedant limonoids.Azadirachtin from the neem tree is the best example, showing strong insecticidal activities against a broad spectrum of insect species, with favorable non-toxicity toward mammalian organisms [5,6].In general, Meliaceae, with approximately 1400 species, is a rich source of structurally diverse limonoids [3,7].Limonoids from this family have drawn great interest among scientists due to their diverse properties [8].Researchers have also considered these limonoids in the search for eco-friendly pesticides [9].
In our first two reviews, we discussed 218 triterpenoid molecules with insecticidal activity from 41 plant species of 13 genera (Aglaia, Aphanamixis, Azadirachta, Cabralea, Carapa, Cedrela, Chisocheton, Chukrasia, Cipadessa, Entandrophragma, Guarea, Khaya, and Melia) in Meliaceae [10,11].As a continuation of these two reviews and the last part of our series of reviews of insecticidal Meliaceae species, our attention in this paper is focused on the species from 15 genera (Munronia, Neobeguea, Pseudocedrela, Nymania, Quivisia, Ruagea, Dysoxylum, Soymida, Lansium, Sandoricum, Walsura, Trichilia, Swietenia, Turraea, and Xylocarpus) in Meliaceae.Herein, we present a summary of the insecticidal plant species, the insecticidal molecules and their structures, the diverse insecticidal activities, the structure-activity relationship (SAR), the insecticidal mechanism of action, and the environmental toxicity of the active insecticidal molecules, to provide some meaningful hints for the exploration of these chemicals as possible lead compounds in the development of novel insecticides.with a mortality rate of 40% against the larvae of the fall armyworm, Spodoptera frugiperda (J.E.Smith), indicating that it was less active than the positive control gedunin (63.3%) [27].
Particularly, khayasin exhibited marked insecticidal activity toward the fifth-instar larvae of the coconut leaf beetle, Brontispa longissimi (Gestro), with an LC 50 value of 7.28 µg/mL at 24 h [28].Wu et al. (2003) also confirmed the insecticidal activity of khayasin against the coconut leaf beetle at 10 µg/mL [29].The insecticidal activity of khayasin against the coconut leaf beetle was more potent than that of azadirachtin and toosendanin, and was similar to that of rotenone.Therefore, khayasin was a promising candidate insecticide for the control of the coconut leaf beetle [28].

Nymania
The genus Nymania is endemic to South Africa [45,46].In this genus, Nymania capensis (Thunb.)Lindb.has been reported to be an insecticidal species [46].Generally, it is used as a garden plant and a source of forage for goats [47].

Quivisia
Quivisia papinae Baillon ex.Grandidier is an endemic Madagascan species.It is currently the sole species of the genus Quivisia.Azadiradione, swietenolide, and melianone have been isolated from this plant [51,52].

Ruagea
Ruagea comprises 15 species in Guatemala, Costa Rica, and Panama and throughout Andean South America from Venezuela to Bolivia.All Ruagea species are treelets or medium-to-large trees up to 35 m high and 130 cm in dbh (diameter at breast height).The bark slash is usually pinkish and fragrant [56,57].In this genus, Ruagea glabra Triana and Planch. is reported to show insecticidal activity [58].
Dysoxylumins A-C, dysoxylumolides A-C and dysoxylumic acid D showed antifeeding activity against the cabbage butterfly.The AR values (24 h) of dysoxylumic acids A-C at 500 µg/mL ranged from 59.4% to 78.7%, which was lower than that of azadirachtin (100%), while the AR values (24 h) of dysoxylumins A-C at 1000 µg/mL ranged from 73.8% to 77.4%, which was also lower than that of azadirachtin (100%) [65].
Interestingly, beddomei lactone and 3β,24,25-trihydroxycycloartane exhibited strong poisonous activity, antifeedant activity, growth inhibitory activity and oviposition deterrence activity against the rice leaf-folder, C. medinalis.The LC 50 values (48 h) of the two triterpenes were 6.66 and 5.79 µg/mL, respectively, while the LC 90 values (48 h) were 14.65 and 13.93 µg/mL, respectively [68,69].Further studies also revealed that these two chemicals have strong larvicidal, pupicidal, and adulticidal activity against the mature and immature stages of the malarial vector Anopheles stephensi Liston [70].They also affected the reproductive potential of adults by acting as oviposition deterrents against the mature and immature stages of A. stephensi.The highest tested concentration of both compounds (10 µg/mL) evoked more than 90% mortality and oviposition deterrence (24 h).The LC 50 and LC 90 values for the fourth-instar larvae, pupae, and adults of A. stephensi exposed to beddomei lactone and 3β,24,25-trihydroxycycloartane were less than 10 µg/mL (24 h) [62].Therefore, beddomei lactone and 3β,24,25-trihydroxycycloartane could be used as active principles during the preparation of botanical insecticides for insect pest, like rice leaf-folder and mosquitoes.

Soymida
In this genus, Soymida febrifuga (Roxb.) A. Juss. is reported to show insecticidal activity.S. febrifuga is a well-known Indian medicinal plant that mainly grows in tropical areas of Asia, such as India, Malaysia, Myanmar, and southern China [71,72].This plant has been used therapeutically for centuries in Indian traditional medicine systems for many medical purposes, including for its wound-healing properties [72][73][74].
Mexicanolide-type fissinolide and prieurianin-type swietenitin O were obtained from this species, and they showed antifeedant activity against the castor semilooper, Achaea janata Linnaeus, with AI values of 76.46 and 66.61, respectively, which were lower than that of azadirachtin (100).For S. litura, the AI values of these two chemicals were 61.69 and 51.93, respectively, which were also lower than that of azadirachtin (100).In addition, swietenitin O also showed insecticidal activity on the castor semilooper and the tobacco caterpillar, with LC 50 values of 0.65 and 0.75 µg/cm 2 , respectively.However, the LC 50 values of azadirachtin were 0.024 and 0.013 µg/cm 2 , respectively.Therefore, the insecticidal activity of fissinolide and swietenitin O was lower than that of azadirachtin [2].

Lansium
The duku (Lansium domesticum Corr.), also known as the langsat or the kokosan, is a tropical lowland fruit tree native to western Southeast Asia, from Borneo to Thailand.It occurs in the wild and in cultivated forms and is one of the most widely cultivated fruits [75][76][77][78][79]. L. domesticum cv kokossan is a higher tree commonly called "kokosan" in Indonesia and widely distributed in Southeast Asian countries [80].This plant is reported to produce fruits that contain a bitter seed substance with antifeedant activity [81].
The methanol extract of L. domesticum showed strong antifeedant activity against the fourth instar larvae of the twenty-eight-spotted lady beetle, Epilachna vigintioctopunctata Fabricius [82].The methanol extract of the leaves of this tree also caused the death of A. aegypti larvae [83].
Antifeedant-activity-directed fractionation of the seed extract, with larvae of S. frugiperda and the European corn borer, Ostrina nubilalis (Hübner), resulted in the isolation of two new limonoids, sandoricin and 6-hydroxysandoricin, as the primary active constituents [92].Sandoricin and 6-hydroxysandoricin showed antifeedant activity against European corn borer larvae at 200 µg/mL.At the same concentration, these two chemicals resulted in nearly 100% mortality before pupation.They also showed similar activity against fall armyworm larvae at 25 µg/mL [92].

Walsura
The genus Walsura comprises approximately 40 evergreen tree species widely distributed in Southeast Asia [93].Triterpenoids and limonoids are, so far, the most abundant metabolites in this genus and have been shown to possess a wide range of biological activities, including insecticidal properties [94][95][96].
Among these species, Walsura trifoliata (A.Juss.)Harms.(synonym: Walsura piscidia Roxb.) is one of the most important.Recently, it has been reported to be an insecticidal plant.The bark of this plant has been commonly used in India to treat skin allergies, astringency, and diarrhea [96][97][98].Previous chemical investigations on this plant revealed a series of tirucallane and apotirucallane triterpenoids (proto-limonoids) [96,99,100].The apotirucallane-type terpenoids piscidinols I and L showed insecticidal activity against A. Janata and S. litura.The LC 50 values of piscidinol I against the two insects were 40.83 and 46.55 mg/cm 2 , respectively, while those of piscidinol L were 20.00 and 22.02 mg/cm 2 , respectively.The activities of both of piscidinol I and L were quite lower than that of azadirachtin (0.024 and 0.013 mg/cm 2 , respectively) [96].

Trichilia
In the genus Trichilia, twelve species-Trichilia elegans A. Juss., Trichilia catigua A. The acetone extract of seeds of T. havanensis in solid state (resin) and its supernatant oil affected the viability and development of neonate larvae of the beet armyworm, Spodoptera exigua (Hübner) [101].The aqueous extracts of leaves and twigs from Trichilia species (T.casaretti, T. catigua, T. clausenii, T. elegans, T. pallens, and T. pallida) reduced the larval weight and survival of the beet armyworm [108].Dichloromethane extracts of the leaf and fruit of T. pallida showed insecticidal activity against the tomato leaf-miner, Tuta absoluta Meyrick [112].
Trisinlin A at 20 µg/mL showed a comparable insecticidal activity to that of azadiranchtin against the newly hatched larvae of S. litura, with corrected mortality rates of 96.67% (14 d).As a contrast, that of azadirachtin was 100.00% [111].
The ring D-seco chemical gedunin possessed various activities toward insects.Photogedunin at 100 µg/mL was active against A. sexdens rubropilosa and the S 50 value was 9 d [44].More information can be obtained from reviews by Lin (2021) and Michel (2021), where these chemicals' activities are summarized [10,118].
In a conventional leaf disk assay, xyloccensins P and Q at 500 µg/mL showed potent antifeedant activity against the third instar larvae of the armyworm, Mythimna separata (Walker), while xyloccensins O, R, S, T, U, and V showed weak activity [149].Xyloccensin L at 1000 µg/mL showed antifeedant activity against the cabbage butterfly, Piece brassicae (Linnaeus) [3].

Structure-Activity Relationship (SAR) of the Insecticidal Chemicals
Structure-activity relationship (SAR) or quantitative structure-activity relation (QSAR) analysis can be used for the rational design of novel pesticides and d [11,113,122,151].For the reported 93 chemicals from the 15 genera examined he QSAR studies of ring-intact limonoids (including those of the cedrelone class trichilin class) and rearranged limonoids (those of the 1,n-linkage-group and the m The 36 rearranged limonoids comprise 3 chemicals of the 1,n-linkage-group and 33 chemicals of the 2,30-linkage-group.Specifically, the 33 chemicals of the 2,30-linkagegroup comprise 25 mexicanolide-class chemicals and 8 phragmalin-type chemicals.

Structure-Activity Relationship (SAR) of the Insecticidal Chemicals
Structure-activity relationship (SAR) or quantitative structure-activity relationship (QSAR) analysis can be used for the rational design of novel pesticides and drugs [11,113,122,151].For the reported 93 chemicals from the 15 genera examined herein, QSAR studies of ringintact limonoids (including those of the cedrelone class and trichilin class) and rearranged limonoids (those of the 1,n-linkage-group and the mexicanolide-class limonoids of the 2,30-linkage group) have been reported.

Insecticidal Mechanism of Action
Plants of these fifteen genera in family Meliaceae contains insect growth regulators and antifeedants against various insect pests.However, studies on the insecticidal mechanism of action (MOA) of triterpenoids from these fifteen genera are still scarce.Relevant studies in the literature have mainly focused on the MOAs of beddomei lactone, azadirone, 3β,24,25trihydroxycycloartane, 3,7-diacetylhavanensin, and 1,3-diacetylhavanensin.
Presently, it is known that beddomei lactone and 3β,24,25-trihydroxycycloartane inhibit gut enzymes including the acid phosphatase, alkaline phosphatase, and adenosine triphosphatase of the rice leaf-folder.Further work was needed to elucidate the effect of these triterpenoids on midgut enzymes, especially midgut alkaline phosphatase and acid phosphatase, as they are the primary hydrolytic enzymes found in the gut of many lepidopteran insects.
Meanwhile, it was reported that a mixture of 3,7-diacetylhavanensin and 1,3-diacetylhavanensin applied at 300 µg/mL caused a reduction in protease and esterase activities during the treatment period.The activities of glutathione S-transferase and poly-substrate mono-oxygenases significantly increased in the treatment.However, azadirone decreased esterase activity and increased glutathione S-transferase activity during the treatment period when applied at 1000 µg/mL, whereas protease and poly-substrate mono-oxygenases activities were not affected [118,120].
Generally, the majority of triterpenoids tested showed antifeedant activity to some extent.The triterpenoids affected the digestion and absorption of ingested food.These responses may also be explained because of the disruption in the neuroendocrine center of molting in insects [70].Until now, it has been clear that triterpenoids have different MOA depending on the test insect species and that they can exhibit both antifeedant and toxic modes of action, e.g., azadirachtin, which could reduce relative growth rate, relative consumption rate, digestibility, and efficiency of conversion of digested food, and so on.It can also act as a chronic toxin.Therefore, the MOA of these triterpenoids is quite complicated and thus more research should be conducted on the MOA of these triterpenoids.

Environmental Toxicity
In practice, various extracts from plants in Meliaceae have been used as traditional medicines.The ethno-medical uses of the plants are as varied as the different cultures and geographical locations of the people who use them.For example, T. emetica, a plant native to Africa, is used in traditional medicine to treat various ailments, such as abdominal pains, dermatitis, hemorrhoids, jaundice, and chest pain.This species is also known as Natal Mahogany and is used for its emetic, diuretic, and purgative properties and for the induction of labor [152,153].Many plants in Dysoxylum are traditional medicines in Fiji, Papua New Guinea, and New Zealand for the treatment of fever, spasm, facial deformation, and limb numbness [154,155].In addition to medicinal uses, the plants are also used in horticulture (for ornamental purposes and shade), as food, and for making wooden items and implements.
Generally, these extracts or chemicals are comparatively safe for the environment, human beings, and entomophagous predators.
There are some references in the literature concerning the environmental toxicity of extracts or certain isolated chemicals from these 15 genera.
For example, a crude aqueous extract from T. emetica root did not show toxicity (LC 50 > 1000 µg/mL) in a brine shrimp bioassay.Trichilins from T. emetica have attracted much attention for their various bioactivities including insect growth regulatory, antifeedant, bactericidal, antifungal and antiviral activity.The aqueous extract by decoction of root of T. emetica has been used as a traditional drug for respiratory infections.It is noteworthy that this fraction was effective at the same concentration as ampicillin against some strains of Staphylococcus aureus.In the rat in vivo model, the treatment with T. emetica extracts was effective in protecting against CCl4-induced liver damage [156].
A low cytotoxicity was observed for the humilinolides against three human cell lines.Particularly, the cytotoxic activity of humilinolides A-D was determined against three human solid tumor cell lines, lung carcinoma (A-549), breast carcinoma (MCF-7), and colon adenocarcinoma (HT-29).They showed low but measurable cytotoxic effects at concentrations several orders of magnitude higher than Adriamycin [123].
In a brine shrimp assay, extracts from the bark and leaves (1 mg/mL) of N. capensis, T. floribunda, and T. obtusifolia demonstrated minimal to no toxicity.T. floribunda was found to have the least effect on the brine shrimp with zero percentage mortality recorded at both 24 and 48 h.All percentage mortality rates observed were below 50%, hence all the plant extracts investigated were considered non-toxic.The relatively low toxicity of these plant extracts was also reported using African monkey kidney (Vero cells), mouse breast cancer cells (4T1) and liver carcinoma cell line (Hep2 cells) cells.Further, in the brine shrimp assay, all dichloromethane extracts of the studied parts of the plant species demonstrated minimal to no toxicity levels.These results also provided credence to the medicinal usage of these plants [46].
However, further studies are still needed to elucidate the environmental toxicity of the important insecticidal chemicals from these genera for their future application in the field.

Future Outlook
The comparative safety of botanical insecticides from Meliaceae for humans, animals, the environment, and entomophagous predators has created a good opportunity for the development and utilization of these plant-derived pesticidal molecules.
The systemic azadirachtin is a world-recognized and excellent botanical insecticide [157,158].However, there are some chemicals with excellent activities from these fifteen genera, as they were shown in Tables 2-4.For examples: The insecticidal activities of khayasin from Neobeguea against the coconut leaf beetle were similar to those of rotenone.Therefore, it was a promising candidate insecticide for the control of the coconut leaf beetle.Moreover, beddomei lactone and 3β,24,25trihydroxycycloartane could be used as an active principle during the preparation of botanical insecticides for insect pest; like rice leaf-folder and mosquitoes.Moreover, the insecticidal activity of trisinlin A against newly hatched larvae of S. litura was comparable to azadirachtin, while the insecticidal activity of humilinolides A-E and methyl-2-hydroxy-3β-isobutyroxy-1-oxomeliac-8(30)-enate on the European corn borer was comparable to toosendanin.
Overall, the above-mentioned triterpenoids may be good candidates as lead compounds in the development of new insecticides for pest management.Still, other active compounds, such as nymania-3, trichilin, azadirone, and prieurianin obtainable from these 15 genera of the family Meliaceae, are still in the infant stage of their research and development.These chemicals also have good activity and deserve further studies.The activity of these compounds against insects should be systematically evaluated, and their effects on non-target organisms and the environment should be further evaluated.Moreover, the mechanisms of action, structure-activity relationship, and biosynthetic pathways of these chemicals are also worthy of further research.
Still, there are some other factors hindering the practical use of the botanical active ingredients, including a short period of persistence of effectiveness, lack of plant material, insufficient information on effectiveness on target and non-target organisms, etc.Therefore, for the really highly effective chemicals, such as khayasin and beddomei lactone, research on the persistence and degradation, biosynthesis and the environmental toxicity should be systematically carried out in the future.

Figure 16 .
Figure 16.Structures of rings A,B,D-seco group chemicals.

Table 2 .
Antifeedant activity of insecticidal triterpenoids of plants from 15 genera in Meliaceae.

Table 3 .
Poisonous activity of insecticidal triterpenoids of plants from 15 genera in Meliaceae.

Table 4 .
Growth regulatory activity of insecticidal triterpenoids of plants from 15 genera in Meliaceae.