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  • Research article
  • Open Access

In vitro and in silico studies of terpenes, terpenoids and related compounds with larvicidal and pupaecidal activity against Culex quinquefasciatus Say (Diptera: Culicidae)

Chemistry Central Journal201812:53

https://doi.org/10.1186/s13065-018-0425-2

  • Received: 19 May 2017
  • Accepted: 30 April 2018
  • Published:

Abstract

Background

In order to develop new larvicidal agents derived from phytochemicals, the larvicidal activity of fifty molecules that are constituent of essential oils was evaluated against Culex quinquefasciatus Say. Terpenes, terpenoids and phenylpropanoids molecules were included in the in vitro evaluation, and QSAR models using genetic algorithms were built to identify molecular and structural properties of biological interest. Further, to obtain structural details on the possible mechanism of action, selected compounds were submitted to docking studies on sterol carrier protein-2 (SCP-2) as possible target.

Results

Results showed high larvicidal activity of carvacrol and thymol on the third and fourth larval stage with a median lethal concentration (LC50) of 5.5 and 11.1 µg/mL respectively. Myrcene and carvacrol were highly toxic for pupae, with LC50 values of 31.8 and 53.2 µg/mL. Structure–activity models showed that the structural property π-bonds is the largest contributor of larvicidal activity while ketone groups should be avoided. Similarly, property–activity models attributed to the molecular descriptor LogP the most contribution to larvicidal activity, followed by the absolute total charge (Qtot) and molar refractivity (AMR). The models were statistically significant; thus the information contributes to the design of new larvicidal agents. Docking studies show that all molecules tested have the ability to interact with the SCP-2 protein, wherein α-humulene and β-caryophyllene were the compounds with higher binding energy.

Conclusions

The description of the molecular properties and the structural characteristics responsible for larvicidal activity of the tested compounds were used for the development of mathematical models of structure–activity relationship. The identification of molecular and structural descriptors, as well as studies of molecular docking on the SCP-2 protein, provide insight on the mechanism of action of the active molecules, and the information can be used for the design of new structures for synthesis as potential new larvicidal agents.

Keywords

  • QSAR
  • Essential oils
  • Larvicidal activity
  • Sterol carrier protein-2
  • Terpenes

Introduction

More than half of the global human population is exposed to the risk of infection spread by mosquitoes; including Culex spp., Anopheles spp. and Aedes spp. that are considered a public health problem, sin are vectors of pathogenic parasites. Lymphatic filariasis uses Culex quinquefasciatus Say (Diptera: Culicidae) as vector; it is one of the leading causes of global morbidity, with close to 150 million infected, especially in tropical climates [1]. Culex quinquefasciatus is present in most tropical regions of the world; it is commonly found in many urban areas and has been reported as resistant to registered insecticides [2].

The control of mosquito larvae and pupae currently relies on the use of synthetic chemical insecticides [3]. However, prolonged use of these synthetic pesticides has caused numerous problems, such as the development of resistance [4], undesirable effects on non-target organisms, effects on wildlife, damage to human health and other negative impacts on the environment [57]. Several studies have searched for natural products derived from plants as possible mosquito control environmentally-friendly strategy; reports include the larvicidal action of essential oils (EOs) and their constituents [8, 9]. EOs can be alternative pest control agents, because some of their compounds have proven to be highly selective, easily removable, biodegradable, with low or no toxicity against mammals and are effective against a full spectrum of mosquito pests [10, 11]. Also EOs are characterized by reduced effects on non target organisms and minimal environmental persistence [12]. With few exceptions, some of the purified terpenoid constituents of EOs are moderately toxic to mammals, but the oils themselves or their compounds are mostly non toxic to mammals, birds, and fish [12].

EOs are heterogeneous mixtures of organic chemical compounds [13] mainly terpenoids and phenylpropanes, but low molecular weight aliphatic compounds, acyclic esters or lactones may also be present [14]. The EOs chemical composition is affected by diverse factors, including plant species and subspecies, geographical location, harvested time, the part of the plant used and the extraction methods employed to obtain the EO [15]. In spite of several studies on the larvicidal activity of EOs and their constituents, little is known on the mechanism of action exerted by terpenoids and phenylpropanoids on mosquito larvae. This has motivated the study of the molecular properties, reactivity or structural modulation of essential oil chemical components in order to minimize synthetic and biological evaluation effort for the development of new compounds with potential larvicidal activity.

Computer assisted prediction of the biological activity of specific chemical compounds considering their chemical structure is now a common technique used in drug discovery [16, 17]. Quantitative structure–activity relationship (QSAR) and quantitative property–activity relationship (QPAR) studies can provide information to understand the relationship between molecule’s chemical structure and biological activity [18]. Also, molecular docking is an in silico technique used to estimate the strength of the protein–ligand interaction, to determine biding poses and free energy values [19]. Docking describe ligand binding to a receptor through noncovalent interactions which is commonly used to explore the ligand recognition on targets for new drug development [20].

This article describes the larvicidal activity of fifty compounds against larvae and pupae of Culex quinquefasciatus (Diptera: Culicidae). Terpenes, terpenoids and others related compounds constituents of different EOs were evaluated in this work. Likewise, the present work reports the theoretical characterization of the molecular and electronic properties of experimentally tested molecules. QSAR/QPAR models and docking studies are also included to emphasize the molecular and structural properties that are essential in the larvicidal activity.

Materials and methods

Compounds tested

Fifty compounds were evaluated to determine their larvicidal activity against larvae (stair III and IV) and pupae of Culex quinquefasciatus Say (Diptera: Culicidae). Compounds were purchased from a Sigma-Aldrich (St. Louis, MI, USA) distributor, and its chemical structure is shown in Fig. 1.
Fig. 1
Fig. 1

(1) p-Anisaldehyde, (2) Canphor, (3) (3) Carene, (4) Carvacrol, (5) Carveol, (6) Carvomenthol, (7) Carvone, (8) Carvotanacetol, (9) β-Caryophyllene, (10) Citronellal, (11) β-Citronellol, (12) m-Cresol, (13) o-Cresol, (14) Cuminaldehyde, (15) p-Cimene, (16) t-Dihydrocarvone, (17) 3,4-Dimethylcumene, (18) Eucalyptol, (19) Geranial, (20) Geraniol, (21) Germacrene-D, (22) α-Humulene, (23) Hydrocarvone, (24) Hydrodihydrocarvone, (25) 3-Isopropylphenol, (26) Isoborneol, (27) Isopulegol, (28) t-Isopulegone, (29) Lavandullol, (30) Limonene, (31) Linalool, (32) Menthol, (33) Menthone, (34) Myrcene, (35) Neoisopulegol, (36) Perillaldehyde, (37) β-Phellandrene, (38) α-Pinene, (39) β-Pinene, (40) Pulegone, (41) Rotundifolone, (42) Sabinene (43) α-Terpinene, (44) γ-Terpinene, (45) 4-Terpineol, (46) α-Terpineol, 47) β-Terpineol, 48) γ-Terpineol, (49) Terpinolene, (50) Thymol

Insect cultures and rearing conditions

Larvae of Cx. quinquefasciatus were collected from water tanks in the Sanctorum Cemetery in Mexico City, Mexico (19°27′17″N, 99°12′47″W) and identified using Harwood and James descriptions [21]. Groups of 50 individuals of first and second instar larvae were placed in glass bottles with purified water, maintained at 26 ± 2° C with a natural photoperiod and supplied with 3:1 powdered mixture of dog food and baking powder. The third instar emerging larvae were then separated by groups of 10 individuals in 100 mL tubes with distilled water [22].

Larvicidal activity bioassays and statistical analysis

Bioassays were done according to the World Health Organization (WHO) protocol with few modifications [23]. Third and fourth instar larvae as well as pupae, were used for testing. Five groups of 20 larvae were isolated in beakers of 250 mL, exposed to different concentrations of the tested compounds and maintained in starvation throughout the experimental period; the surviving larvae were counted in order to record larval mortality. The compounds were diluted in dimethyl sulfoxide (DMSO) (Sigma, 472301) before being added to the aqueous medium which contained the larvae. Temephos H at 0.1 ppm (commercial concentration) was used as a standard for comparison. Larvae were considered dead if they were immobile and unable to reach the water surface [24]. Lethal concentrations (LC50) was calculated using Probit analysis. Data were processed using MS Excel 2010 and SAS v. 9 (Proc Probit) computer programs.

DFT study and descriptors calculations

Computational studies were carried out using the Spartan 03 [25] and Gaussian 09 quantum chemistry computer programs [26]. The molecular structures were analyzed by a conformational analysis of each molecule in gas phase using the mechanics force field SYBYL [27]. The minimum energy conformation was selected in order to obtain the geometry optimization using the density functional theory (DFT). The equilibrium geometries of the molecules in the electronic ground state were determined with the Becke three-parameter hybrid functional combined with Lee–Yang–Parr correlation functional (B3LYP) [28, 29]. The basis set 6-311G(d,p) was used for the geometry optimization and vibrational frequency calculations and the 6-311+G(d,p) was applied for vertical excitation energy calculations [3032]. Analytical frequency calculations were carried out, where the absence of imaginary frequencies confirmed that the stationary points correspond to the global minima of the potential energy hypersurfaces.

The Koopmans theorem [33] was applied for calculations of the chemical reactivity descriptors such as: the ionization potential (I), electron affinity (A), electronegativity (χ), chemical potential (μ), hardness (ɳ), softness (σ), global electrophilicity (ω), as well as the electronic parameters of, EHOMO (energy of highest occupied molecular orbital), ELUMO (energy of the lowest unoccupied molecular orbital) and band gap (GAPE) were calculated. All molecules were analyzed in the gas and aqueous phase. The polarizable continuum model (PCM) was used to model the solvent effects [34].

Structure, constitutional, physicochemical and topological descriptors were generated using Dragon 5.0 software [35] using the optimized structure in the aqueous phase.

Structure–property–larvicidal activity models

QSAR/QPAR studies was carried out using all biological activities obtained in vitro and the calculated theoretical descriptors; the analysis was carried out using genetic algorithms with the Mobydigs Software [36]. The quality of the model was considered statistically satisfactory based on the determination coefficient (R2), leave-one-out cross-validated explained variance (Q2), standard deviation (s) and the ANOVA (F) of the model.

Molecular docking studies on protein SCP-2

The sequence of sterol carrier protein (SCP-2) of Cx. quinquefasciatus (GenBank: AAO43438.1) was obtained from the database of the National Center for Biotechnology Information (NCBI). The protein was modeled through Swiss-Model server [37, 38], using as template the sterol carrier protein of Aedes aegypti (PDB: 1PZ4) [39] reported in the RCSB Protein Data Bank. The final model was subjected to Ramachandran analysis using the Rampage server [40]. Docking analysis was done using the AutoDock4 software [41]. For the docking the active site was defined considering the residues within a grid of 60 A° × 60 A° × 60 A° centered in the active site, with an initial population of 100 randomly placed individuals and a maximum number of 1.0 × 107 energy evaluations. Active site was determined under the description made by Dyer et al. [39]. Compounds for docking were drawn in Gauss view before docking, the compounds were subjected to energy minimization using the hybrid functional B3LYP with a 6, 311G(d,p) basis set. The Kd and ΔG (Kcal/mol) values were obtained from the conformation with the lowest minimum free energy of the ligand coupled on the protein targets. The figures were prepared with ChemBioOffice [42] for the structures and Chimera [43] for the proteins and ligands.

Results and discusion

Larvicidal activity and quantitative structure–larvicidal activity relationship

Chemical compounds known to be constituents of EOs demonstrated larvicidal activity against III and IV stairs of Cx. quinquefasciatus; activity against pupae was moderate, with higher concentrations of the compounds required to reach LC50; LC50 values as shown in Table 1. In all experiments, 100% of the larvae remained active in the negative control; DMSO larvicidal activity was also determined, and concentration of 1000 µg/mL had no larvicidal effect; therefore, larvicidal activity can be attributed entirely to the compounds, and not the solvent used.
Table 1

Larvicidal activity of the terpenes, terpenoids and related compounds against Cx. quinquefasciatus

 

Assays

Larvicidal activity (µg/mL)

III

IV

Pupaes

Molecules

Classification

LC50

LC50

LC50

1

p-Anisaldehyde

Benzaldehyde

18.0 (15.5–20.4)

18.8 (16.9–20.6)

96.4 (92.5–100.2)

2

Canphor

Bicyclic monoterpenoid

22.3 (21.6–23.9)

25.8 (23.6–27.9)

245.1 (234.6–255.5)

3

3-Carene

Bicyclic monoterpene

24.7 (23.7–25.7)

25.5 (24.3–26.7)

105.5 (101.8–109.1)

4

Carvacrol

Cyclic monoterpenoid

5.5 (5.28–5.72)

7.7 (7.3–8.1)

53.2 (51.8–54.5)

5

Carveol

Cyclic monoterpenoid

103.0 (99.4–109.9)

104.6 (102.0–107.2)

249.0 (241.8–256.1)

6

Carvomenthol

Cyclic monoterpenoid

198.2 (183.69–212.71)

219.8 (206.6–232.9)

452.2 (435.2–469.1)

7

(+)-Carvone

Cyclic monoterpenoid

150.2 (149.0–151.4)

150.2 (145.5–154.8)

500.6 (495.0–506.1)

8

Carvotanacetol

Cyclic monoterpenoid

152.3 (148.2–156.8)

198.3 (192.1–204.44)

245.1 (238.1–252.0)

9

β-Caryophyllene

Bicyclic sesquiterpene

45.6 (43.8–47.2)

47.7 (42.2–52.9)

222.3 (216.8–27.7)

10

Citronellal

Acyclic monoterpenoid

105.3 (98.3–102.3)

124.9 (123.2–125.6)

549.2 (557.35–565.5)

11

β-Citronellol

Acyclic monoterpenoid

90.4 (88.9–91.9)

94.8 (93.4–95.2)

203.1 (198.44–207.76)

12

m-Cresol

Phenolic derivative

60.0 (58.8–61.2)

60.6 (59.3–61.9)

107.7 (104.94–110.4)

13

o-Cresol

Phenolic derivative

54.8 (53.6–56.0)

54.4 (53.8–54.0)

105.6 (103.4–107.7)

14

Cuminaldehyde

Benzaldehyde

23.0 (22.0–24.0)

23.9 (22.0–25.8)

95.4 (91.1–99.6)

15

p-Cimene

Cyclic monoterpene

23.1 (22.3–24.9)

24.0 (23.8–26.2)

306.3 (298.4–314.1)

16

trans-Dihydrocarvone

Cyclic monoterpene

345.0 (340.8–350.1)

361.3 (346.2–366.4)

708.6 (698.1–719.1)

17

3,4-Dimethylcumene

Phenolic derivative

35.6 (33.5–37.7)

47.7 (46.2–49.2)

105.5 (101.9–109.1)

18

Eucalyptol

Bicyclic monoterpenoid

48.0 (47.9–49.1)

44.4 (43.3–45.5)

92.9 (86.2–99.6)

19

Geranial

Acyclic monoterpenoid

52.2 (51.1–53.3)

53.4 (49.9–56.8)

193.9 (186.8–200.9)

20

Geraniol

Acyclic monoterpenoid

20.4 (19.78–21.02)

20.4 (19.4–21.3)

104.6 (101.9–107.2)

21

Germacrene-D

Sesquiterpene

45.4 (44.3–46.6)

45.6 (46.71–47.49)

229.0 (222.7–235.2)

22

α-Humulene

Bicyclic sesquiterpene

100.5 (98.2–102.7)

101.8 (100.0–103.5)

508.3 (497.17–519.43)

23

Hydrocarvone

Cyclic monoterpene

1351.6 (1228.68–1474.5)

1470.9 (1347.9–1592.9)

> 2000

24

Hydrodihydrocarvone

Cyclic monoterpenemonoterpene

1416.5 (1152.4–1680.1)

1628.2 (1364.6–1889.3)

> 2000

25

3-Isopropylphenol

Cyclic monoterpene

21.3 (20.9–21.6)

23.1 (21.2–24.9)

100.2 (96.4–104.4)

26

Isoborneol

Bicyclic monoterpenoid

91.9 (89.7–94.0)

97.1 (94.1–100.1)

206.1 (199.7–213.5)

27

Isopulegol

Cyclic monoterpene

247.4 (234.4–250.9)

297.3 (290.2–304.3)

610.8 (604.6–616.9)

28

trans-Isopulegone

Cyclic monoterpene

529.1 (510.1–537.1)

538.8 (530.7–546.8)

908.6 (896.2–920.9)

29

Lavandullol

Acyclic monoterpenoid

52.2 (51.0–53.3)

56.5 (53.3–59.9)

238.7 (224.6–252.7)

30

Limonene

Cyclic monoterpene

24.2 (23.4–24.9)

27.3 (23.3–28.2)

98.4 (95.4–101.4)

31

Linalool

Acyclic monoterpenoid

26.8 (26.0–27.5)

30.7 (29.7–31.6)

249.0 (241.8–256.1)

32

Menthol

Cyclic monoterpenoid

443.6 (432.3–443.2)

404.1 (381.1–427.0)

529.1 (521.0–537.1)

33

Menthone

Cyclic monoterpenoid

500.6 (495.0–506.1)

508.9 (500.8–516.9)

878.5 (867.4–889.5)

34

Myrcene

Acyclic monoterpene

19.5 (18.5–20.4)

19.1 (18.0–20.2)

31.8 (30.2–33.2)

35

Neoisopulegol

Cyclic monoterpenoid

458.4 (450.2–466.6)

554.2 (545.6–562.7)

908.6 (896.2–920.9)

36

(−)-Perillaldehyde

Cyclic monoterpenoid

95.9 (94.8–97.0)

115.8 (113.0–118.6)

429.1 (422.9–435.22)

37

Phellandrene

Cyclic monoterpene

490.7 (483.1–498.2)

554.3 (545.8–563.0)

908.6 (896.3–920.9)

38

α-Pinene

Bicyclic monoterpene

24.4 (23.2–25.5)

25.5 (22.0–28.97)

98.4 (95.4–101.4)

39

β-Pinene

Bicyclic monoterpene

19.6 (18.82–20.38)

24.3 (22.8–25.7)

96.9 (89.9–103.9)

40

(+)–Pulegone

Cyclic monoterpenoid

168.7 (665.8–171.59)

188.1 (185.29–190.91)

496.2 (490.4–501.9)

41

Rotundifolone

Cyclic monoterpenoid

58.9 (57.8–59.9)

62.5 (61.5–63.5)

287.4 (279.4–295.3)

42

Sabinene

Bicyclic monoterpene

53.7 (51.9–55.4)

59.0 (58.3–60.7)

268.0 (262.5–273.0)

43

α-Terpinene

Cyclic monoterpene

13.8 (12.9–14.7)

13.6 (12.8–14.3)

209.5 (204.0–214.9)

44

γ-Terpinene

Cyclic monoterpenemonoterpene

45.4 (44.3–46.5)

56.8 (55.7–57.9)

287.4 (280.2–294.6)

45

4-Terpineol

Cyclic monoterpenoid

94.2 (91.1–97.3)

97.7(90.6–104.8)

201.8 (195.6–208.0)

46

α-Terpineol

Cyclic monoterpenoid

95.9 (93.8–98.0)

98.4 (95.3–101.4)

206.1 (198.4–213.7)

47

β-Terpineol

Cyclic monoterpenoid

101.3 (99.5–103.0)

107.4 (103.9–110.8)

508.3 (497.1–519.43)

48

γ-Terpineol

Cyclic monoterpenoid

100.5 (98.3–102.7)

103.6 (100.0–109.9)

4965.5 (4949.1–4981.9)

49

Terpinolene

Cyclic monoterpene

20.4 (19.6–21.2)

18.6 (16.9–20.2)

107.4 (103.9–110.8)

50

Thymol

Cyclic monoterpenoid

11.1 (10.28–11.9)

12.2 (11.7–12.7)

111.4 (108.5–114.2)

Tx

Temephos H

Organophosphorus

2.1 (1.8–2.5)

5.6 (4.1–6.7)

34.0 (29.1–39.0)

In parenthesis, 95% confidence intervals, compounds activity is considered significantly different when the 95% CI fail to overlap

EOs are aromatic extracts obtained from plant material that are complex mixtures of volatile secondary metabolites [44]. Some of the compounds present in EOs are terpenes (molecules formed of isoprene units) [45], terpenoids (terpenes with oxygen on its structure) [45] and phenylpropanoids [47]. In the present report, carvacrol and thymol (terpenoids found mainly in the EO of oregano) were the most active molecules with a LC50 of 7.7 and 8.4 μg/mL respectively, against larvae at fourth stage. Myrcene presented a relevant activity against pupae with a LC50 of 31.8 μg/mL. Cheng et al. reported the results of screening EOs and suggested that oils with LC50 values >  100 ppm should not be considered active, whereas those with LC50 values < 50 ppm could be regarded as highly active [48]. Our results agree with reports of the larvicidal activity of constituents of oregano EO; the reports demonstrate that these compounds have fumigant and repellent activity [4953].

In relation to chemical structure and larvicidal activity, results have been grouped considering the main chemical moiety of the tested compounds in monocyclic-terpenes, monocyclic-terpenoids, bicyclic-terpenes and bicyclic-terpenoids, and phenylpropanes. β-Caryophyllene, a bicyclic sesquiterpene, showed the lower larvicidal activity with a LC50 of 57.7 μg/mL against fourth instar and 222.3 μg/mL against pupae, Doria et al. also report low larvicidal activity of β-caryophyllene against Aedes aegypti [54]. Sabineno, a bicyclic monoterpene, also had a low activity, with LC50 values of 59.0 μg/mL for fourth instar and 258 μg/mL against pupae. β-Pinene and 3-carene presented a LC50 of 19.6 and 24.7 μg/mL respectively against the fourth stair being the most active of the bicyclic terpenes. Eucalyptol was the bicyclic terpenoid most active against pupae, the only activity lower than 100 μg/mL of all bicyclic compounds evaluated.

Table 2 include the QSAR models of larvicidal activity against the fourth instar with greater statistical significance. The models were built based on structural descriptors; models 1 and 2 describe the biological activity of the fifty molecules evaluated, and includes the number of total tertiary carbons (sp3) (nCt) and the number of non-aromatic conjugated carbons (sp2) (nCconj) as the structural descriptors that contribute the most to the biological activity, whereas the number of ketones (nRCO) and number of ethers (nROR) showed an inverse relationship with larvicidal activity. The structural descriptors that were less significant, including molecules without benzene ring (models 1 and 2, Table 2) were present in the tested molecules with the lowest biological activity. Sabinene and β-caryophyllene are examples of molecules with no benzene rings and presence of ketone groups. In fact the keto group reduces the activity of carvone more than a half as compared to limonene, which does not have keto groups in its structure.
Table 2

Summary of the statistics quantitative structure–larvicidal activity relationship models for activity against fourth instar of Cx. quinquefasciatus

Statistical parameter

IV instar

Model 1

Model 2

Model 3

Model 4

Model 5

Model 6

n

50

50

47

47

39

39

Q2

0.793

0.75.34

0.781

0.759

0.851

0.832

R2

0.828

0.78.73

0.881

0.858

0.965

0.957

F

14.5

11.1

21.8

21.3

49.2

39.4

s

0.291

0.301

0.231

0.234

0.137

0.152

Descriptors

Contributions

Model 1

Model 2

Model 3

Model 4

Model 5

Model 6

nCt

0.0679

WC

WC

WC

WC

WC

nCconj

0.0631

0.04241

0.052

0.0444

0.3304

0.3606

nR = Cp

WC

0.0803

WC

WC

WC

WC

nRCO

− 0.5006

− 0.5641

− 0.491

− 0.48

− 0.7285

− 0.6265

nROR

− 0.34331

WC

− 0.2618

− 0.2579

− 0.503

− 0.5205

nArOH

WC

0.1229

0.1518

WC

0.6552

0.6582

nOH

WC

WC

WC

0.0187

WC

WC

Intercept

− 1.5373

− 1.644

− 1.6531

− 1.6723

− 2.80322

− 2.8386

n, number of systems evaluated; Q2, the square of the coefficient of cross-validation; R2, the square of the correlation coefficient; s, standard deviation; F, Fisher statistic; WC, without contribution; nCt, number of total tertiary C (sp3); nCconj, number of non-aromatic conjugated C (sp2); nR = Cp, number of terminal primary C (sp2); nRCO, number of ketones (aliphatic); nROR, number of ethers; nArOH, number of phenolic groups; nOH, number of a hydroxyls

Models 3 and 4 (Table 2) were constructed based on the larvicidal activity of 47 evaluated molecules, excluding the sesquiterpenes β-caryophyllene (9), germacrene (21) and α-humulene (22) from the analysis. The models showed the same relationship with the nCconj, nRCO, nROR descriptors and the number of phenolic groups (nArOH) and the number of hydroxyl groups (nOH) as descriptors directly related to the biological activity. This is consistent with the most biologically-active molecules: carvacrol and thymol. In monocyclic terpenoids and monocyclic terpenes, increasing the number of double bonds also increased the larvicidal activity. Menthol has a LC50 of 38.1 μg/mL against fourth instar larvae, while thymol had an activity of 12.2 μg/mL. The structural difference between these two compounds is the phenolic group in thymol as compared to menthol that only has the hydroxyl group; p-Cymene has the benzene group without hydroxyl group with an activity of 24.0 μg/mL; this demonstrate the importance of the phenolic group in the larvicidal activity. Carvacrol, an isomer of thymol, has a LC50 of 7.7 μg/mL; therefore, the position of the hydroxyl group plays an important role in the larvicidal activity.

For acyclic terpenes and terpenoids, higher larvicidal activity was observed in compounds with a higher number of double bonds and increased lipophilicity. Ketone acyclic terpenes were the compounds with lowest larvicidal activity; substitution of the ketone group by the hydroxyl group increased the biological activity considerably. Citronellol was the alcohol terpene with lower activity against the fourth instar and pupae. Geraniol has one double bond more than citronellol, and this structural difference increase the larvicidal activity. Linalool also presents one double bond more than citronellol, and this differential structure is reflected in an increase in larvicidal activity, however the position of the hydroxyl group changes from a primary to a secondary alcohol; this difference could be responsible for the lower biological activity shown. On the other hand, myrcene, an acyclic molecule with no oxygen in its structure, has the highest larvicidal activity and is the only compund with significant activity against pupae, with a LD50 of 19.1 μg/mL against the fourth instar larvae and 31.8 μg/mL against pupae. Myrcene has three double bonds in its structure, and since the lipophilicity is increased in the absence of oxygen, these is an important trait for their potential activity. Accordingly, Lucia et al. consider that the octanol water partition coefficient (LogP) is an important molecular property in the larvicidal activity of monoterpenes [55].

In models 5 and 6, the sesquiterpenes and all acyclic monotepenes were excluded. The relations of the descriptors are maintained although their values increase considerably, demonstrating that nRCO and nROR obstruct the activity of monoterpenes, so that in order to potentiate the activity of the compounds as larvicides agents, these functional groups must be avoided. On the other hand, the nArOH excels on the nCconj as the descriptor of greatest contribution in larvicidal activity, an issue discussed previously. The values of structural descriptors for each target system are confined in Table 3. A plot of the predicted activity versus experimental activity for molecules using a training set for structure–activity relationship models is shown in Fig. 2. Experimental and predicted LogLC50 values are shown in Additional file 1: Table S1, while the constitutional descriptors can be observed in Additional file 1: Table S2.
Table 3

Structural descriptors calculated

Mol.

nCs

nCt

nCconj

nR = Cp

nR = Cs

nR = Ct

nRCO

nArOH

nOH

nHDon

nHAcc

1

0

0

1

0

0

0

0

0

0

0

2

2

3

1

0

0

0

0

1

0

0

0

1

3

2

2

0

0

1

1

0

0

0

0

0

4

0

1

0

0

0

0

0

1

0

1

1

5

3

1

0

1

1

2

0

0

1

1

1

6

4

3

0

0

0

0

0

0

1

1

1

7

2

1

3

1

1

2

1

0

0

0

1

8

3

2

0

0

1

1

0

0

1

1

1

9

4

2

0

1

1

2

0

0

0

0

0

10

3

1

0

0

1

1

0

0

0

0

1

11

3

1

0

0

1

1

0

0

1

1

1

12

0

0

0

0

0

0

0

1

0

1

1

13

0

0

0

0

0

0

0

1

0

1

1

14

0

1

1

0

0

0

0

0

0

0

1

15

0

1

0

0

0

0

0

0

0

0

0

16

3

2

0

1

0

1

1

0

0

0

1

17

0

1

0

0

0

0

0

0

0

0

0

18

4

1

0

0

0

0

0

0

0

0

0

19

2

0

3

0

2

2

0

0

0

0

1

20

2

0

0

0

2

2

0

0

1

1

1

21

4

2

4

1

3

2

0

0

0

0

0

22

4

0

0

0

4

2

0

0

0

0

0

23

2

2

3

0

1

1

1

0

1

1

2

24

3

3

0

0

0

0

1

0

1

1

2

25

0

1

0

0

0

0

0

1

0

1

1

26

4

1

0

0

0

0

0

0

1

1

1

27

4

2

0

1

0

1

0

0

1

1

1

28

3

3

0

0

0

0

1

0

0

0

1

29

2

1

0

1

1

2

0

0

1

1

1

30

3

1

0

1

1

2

0

0

0

0

0

31

2

1

0

1

2

1

0

0

1

1

1

32

4

3

0

0

0

0

0

0

0

1

1

33

3

3

0

0

0

0

1

0

0

0

1

34

2

0

4

2

2

2

0

0

0

0

0

35

4

2

0

1

0

1

0

0

1

1

1

36

3

1

3

1

1

2

0

0

0

0

1

37

2

1

4

0

2

2

0

0

0

0

0

38

2

2

0

0

1

1

0

0

0

0

0

39

3

2

0

1

0

1

0

0

0

0

0

40

3

1

3

0

0

2

1

0

0

0

1

41

3

1

3

0

0

2

1

0

0

0

2

42

3

2

0

1

0

1

0

0

0

0

0

43

2

1

4

0

2

2

0

0

0

0

0

44

2

1

0

0

2

2

0

0

0

0

0

45

3

2

0

0

1

1

0

0

1

1

1

46

3

2

0

0

1

1

0

0

1

1

1

47

4

2

0

1

0

1

0

0

1

1

1

48

4

1

0

0

0

2

0

0

1

1

1

49

3

0

0

0

1

3

0

0

0

0

0

50

0

1

0

0

0

0

0

1

0

1

1

nCs, Number of total secondary C (sp3); nCt, number of total tertiary C (sp3); nCconj, Number of non-aromatic conjugated C (sp2); nR = Cp, number of terminal primary C (sp2); nR = Cs, number of aliphatic secondary C(sp2); nR = Ct, number of aliphatic tertiary C(sp2); nRCO, number of ketones (aliphatic); nArOH, number of aromatic hydroxyls; nOH, number of a hydroxyls; nHDon, number of donor atoms for H-bonds; nHAcc, number of acceptor atoms for H-bonds

Fig. 2
Fig. 2

Predicted versus experimental larvicidal activity from structural–activity relationship models. a Model 1, b model 3, c model 5

Quantitative property–larvicidal activity relationship and DFT study

The models that describe the relationship between the molecular properties and biological activity demonstrate that the octanol–water partition coefficient (MlogP) descriptor is the largest contributor to the larvicidal activity. Lucia et al. developed a QSAR model based on six monoterpenes and they found that when vapor pressure and lipophilicity values decreased, the larvicidal activity against A. aegypti also diminished. The strong effect of the octanol–water partition coefficient can be explained considering that the main conduit for component entrance to the organism is tactile (external cuticle) [55]. Therefore, the partition occurs between the hydrophilic environment (water) and the lipophilic environment (larval epicuticle); therefore, molecule hydrophobicity plays an important role in the intoxication of the larva [56].

Table 4 includes the QPAR models of larvicidal activity against the fourth instar with greater statistical significance. Like QSAR models, QPAR models 1 and 2 were constricted based on all the evaluated compounds, in the models 3 and 4 the sesquiterpenos were excluded and the models 5 and 6 were constructed excluding sesquiterpenes and acyclic monoterpenes. The predicted activity versus experimental activity for molecules using a training set for structure–activity relationship models is shown in Fig. 3. Experimental and predicted LogLC50 values of QPAR models are shown in Additional file 1: Table S3.
Table 4

Summary of the statistics quantitative property–larvicidal activity relationship models for activity against fourth instar of Cx. quinquefasciatus

Statistical parameter

IV instar

Model 1

Model 2

Model 3

Model 4

Model 5

Model 6

n

50

50

47

47

39

39

Q2

0.759

0.630

0.761

0.751

0.840

0.818

R2

0.829

0.812

0.880

0.880

0.929

0.917

F

20.9

20.2

24.1

23.8

34.3

29.6

s

0.293

0.297

0.022

0.021

0.151

0.162

Descriptors

Contributions

Model 1

Model 2

Model 3

Model 4

Model 5

Model 6

J

− 2.3271

− 1.6812

WC

WC

− 0.0638

WC

MlogP

0.3632

0.3222

WC

WC

1.5415

1.1347

TIE

0.0843

0.0929

0.16824

0.1684

0.2377

0.0467

AMR

0.0441

WC

WC

WC

WC

WC

Qtot

WC

WC

0.4735

0.5324

WC

WC

BAC

WC

− 0.0535

WC

WC

WC

WC

Hy

WC

WC

− 0.7359

− 0.4735

WC

WC

ƞ

WC

WC

0.3068

WC

WC

WC

m

WC

WC

WC

0.0927

0.5698

0.6654

E HOMO

WC

WC

WC

WC

0.2377

0.2486

Intercept

− 0.3266

− 0.3421

− 2.3992

− 2.3891

7.8613

4.817

n, number of systems evaluated; Q2, the square of the coefficient of cross-validation; R2, the square of the correlation coefficient; s, standard deviation; F, Fisher statistic; WC, without contribution; J, Balaban-like index; MlogP, Moriguchi octanol–water partition coeff. (logP); TIE, E-state topological parameter; AMR, Ghose–Crippen molar refractivity; Qtot, total absolute charge; BAC, Balaban centric index; Hy, hydrophilic factor; η, chemical hardness; E HOMO , energy of the HOMO orbital; m, dipole moment

Fig. 3
Fig. 3

Predicted versus experimental larvicidal activity from property–activity relationship models. a Model 1, b model 3, c model 5

The lipophilic character of terpenes and their derivatives have been widely discussed as a key factor in the antimicrobial and larvicidal properties of these compounds [1416, 44, 45]; however, it does not finish describing their larvicidal behavior. Sesquiterpenes, for example, have high MlogP values and are not the most active compounds.

Some QPAR models consider molar refractivity (AMR) and absolute total charge (Qtot) as descriptors that contribute to larvicidal activity. Qtot is a measure of the weak intermolecular interactions which provides information on the electrical charges of the molecules and is considered as the driving force of electrostatic interactions, important for the interaction of the component with its biological target [57]. Myrcene, the most active acyclic terpene, is the terpene with largest number of double bonds, more MlogP and lowest Qtot, also it had the lowest AMR. Molar refractivity (AMR) descriptor is related to specific interactions with a target molecule and the electronic effects in the biological–chemical interaction, mainly for allosteric effects of interactions between the ligand-receptor [58]: therefore, it demonstrates the importance of interaction with a specific enzyme, pools of metabolites, or signaling pathways [59]. Hanch and Verma proposed a QSAR model for complex triorganotin with larvicidal activity reported by Eng et al., its models included hydrophobicity (Hy) and molar refractivity (AMR) as the most important parameters for the description of larvicidal activity [60, 61]. In these results, when MlogP was not included in the models the Hy presented in inverse relation to the larvicidal activity. The values of molecular and physicochemical descriptors for each compound are included in Table 5.
Table 5

Molecular and physicochemical descriptors calculated

Mol.

Qpos

Qneg

Qtot

Ui

Hy

AMR

TPSA (tot)

MlogP

AlogP

1

1.28

− 1.28

2.56

3

− 0.768

39.112

26.3

1.49

1.573

2

1.659

− 1.659

3.318

1

− 0.877

44.492

17.07

2.357

1.936

3

1.413

− 1.413

2.825

1

− 0.96

44.722

0

3.374

2.873

4

1.5

− 1.5

2.999

2.807

− 0.294

46.984

20.23

2.813

3.243

5

1.234

− 1.234

2.468

1.585

− 0.294

47.995

20.23

2.25

2.401

6

1.249

− 1.249

2.497

0

− 0.294

47.445

20.23

2.502

2.779

7

1.665

− 1.665

3.331

2

− 0.877

47.174

17.07

2.153

2.361

8

1.704

− 1.704

3.408

1

− 0.294

48.218

20.23

2.357

2.597

9

1.926

− 1.926

3.853

1.585

− 0.975

62.851

0

4.375

4.297

10

1.288

− 1.288

2.576

1.585

− 0.877

49.297

17.07

2.642

3.019

11

1.791

− 1.791

3.582

1

− 0.294

50.486

20.23

2.749

3.049

12

0.884

− 0.884

1.768

2.807

− 0.158

32.793

20.23

1.859

2.049

13

0.867

− 0.867

1.734

2.807

− 0.158

32.793

20.23

1.859

2.049

14

1.444

− 1.444

2.887

3

− 0.877

46.84

17.07

2.723

2.784

15

1.315

− 1.315

2.631

2.807

− 0.96

45.29

0

3.562

3.51

16

1.283

− 1.283

2.566

1.585

− 0.877

46.298

17.07

2.25

2.401

17

0.905

− 0.905

1.81

2.807

− 0.965

50.331

0

3.854

3.997

18

1.422

− 1.422

2.844

0

− 0.96

43.799

0

4.431

3.077

19

1.283

− 1.283

2.566

2

− 0.877

50.199

17.07

2.545

3.19

20

1.684

− 1.684

3.367

1.585

− 0.294

51.182

20.23

2.642

2.934

21

1.478

− 1.478

2.956

2

− 0.977

70.55

0

4.534

5.135

22

1.446

− 1.446

2.892

2

− 0.977

71.549

0

4.534

5.035

23

1.596

− 1.596

3.191

1.585

− 0.244

49.154

37.3

1.369

1.274

24

1.612

− 1.612

3.223

1

− 0.244

48.278

37.3

1.477

1.313

25

1.06

− 1.06

2.12

2.807

− 0.257

41.943

20.23

2.51

2.757

26

1.157

− 1.157

2.313

0

− 0.294

45.314

20.23

2.502

1.975

27

1.232

− 1.232

2.463

1

− 0.294

47.222

20.23

2.357

2.583

28

1.286

− 1.286

2.571

1

− 0.877

46.52

17.07

2.357

2.597

29

1.344

− 1.344

2.688

1.585

− 0.325

54.812

20.23

2.933

3.105

30

1.438

− 1.438

2.877

1.585

− 0.96

46.48

0

3.267

3.503

31

1.882

− 1.882

3.763

1.585

− 0.294

50.206

20.23

2.642

2.735

32

1.772

− 1.772

3.545

0

− 0.294

47.445

20.23

2.502

2.779

33

1.288

− 1.288

2.575

1

− 0.877

46.52

17.07

2.357

2.597

34

1.526

− 1.526

3.053

2

− 0.96

48.379

0

3.562

3.688

35

1.27

− 1.27

2.54

1

− 0.294

47.222

20.23

2.357

2.583

36

1.231

− 1.231

2.461

2

− 0.877

47.272

17.07

2.153

2.668

37

0.89

− 0.89

1.78

1.585

− 0.96

47.553

0

3.267

3.449

38

1.398

− 1.398

2.796

1

− 0.96

44.722

0

3.374

2.873

39

0.933

− 0.933

1.866

1

− 0.96

43.65

0

3.374

2.927

40

1.224

− 1.224

2.448

1.585

− 0.877

47.129

17.07

2.25

2.752

41

1.236

− 1.236

2.472

1.585

− 0.807

46.637

29.6

1.369

1.824

42

1.47

− 1.47

2.941

1

− 0.96

43.65

0

3.374

2.927

43

1.386

− 1.386

2.772

1.585

− 0.96

47.553

0

3.267

3.449

44

0.892

− 0.892

1.784

1.585

− 0.96

47.553

0

3.267

3.449

45

1.257

− 1.257

2.515

1

− 0.294

48.307

20.23

2.357

2.55

46

1.247

− 1.247

2.494

1

− 0.294

48.461

20.23

2.357

2.415

47

1.288

− 1.288

2.577

1

− 0.294

47.388

20.23

2.357

2.469

48

1.195

− 1.195

2.39

1

− 0.294

48.194

20.23

2.357

2.61

49

1.369

− 1.369

2.738

1.585

− 0.96

47.286

0

3.267

3.643

50

1.523

− 1.523

3.045

2.807

− 0.294

46.984

20.23

2.813

3.243

Qpos, total positive charge; Qneg, total negative charge; Qtot, total absolute charge (electronic charge index-ECI); Ui, unsaturation index; Hy, hydrophilic factor; AMR, Ghose–Crippen molar refractivity; TPSA, topological polar surface area; MlogP, Moriguchi octanol–water partition coeff.; AlogP, Ghose–Crippen octanol–water partition coeff

The quantum-chemical parameters, such as: chemical hardness (η), dipole moment (m) and energy of the HOMO orbital (E HOMO ), were considered as descriptors directly related to biological activity by the models. These descriptors, related to chemical reactivity, are derived from the information provided by molecular orbitals. Some authors have suggested that the presence of a free hydroxyl group and a delocalized electron system in terpenes are critical for their antibacterial activity [62]. This proposal is important when the chemical reactivity of carvacrol and thymol with respect to carvomenthol and menthol is compared. Phenolic group reduces the energy values of the frontier orbitals, whereas the hydroxyl groups by itself increase the η, making carvomenthol and menthol less reactive and also less active. However, η or chemical softness (S) cannot be determinants of biological activity, since p-cymene presents these values closer to thymol and carvacrol and yet has less activity than menthol and carvomenthol. Thus, the hydroxyl group alone is also important in the larvicidal activity, a factor considered in the QSAR models. The values of the chemical reactivity descriptors are shown in Table 6.
Table 6

Chemical reactivity descriptors calculated

Mol.

E HOMO

E LUMO

GAP E

I

A

χ

µ

n

σ

m

1

− 8.954

2.096

11.050

8.954

− 2.096

− 3.429

3.429

5.525

0.181

5.429

2

− 10.343

3.969

14.312

10.343

− 3.969

− 3.187

3.187

7.156

0.140

3.927

3

− 8.971

4.13

13.102

8.973

− 4.13

− 2.421

2.421

6.551

0.153

0.178

4

− 8.351

4.112

12.463

8.351

− 4.112

− 2.119

2.119

6.232

0.16

1.672

5

− 9.356

4.94

14.296

9.356

− 4.94

− 2.207

2.207

7.148

0.139

1.96

6

− 10.751

6.545

17.296

10.751

− 6.545

− 2.102

2.102

8.648

0.115

1.751

7

− 9.308

2.797

12.106

9.308

− 2.797

− 3.255

3.255

6.053

0.165

3.989

8

− 8.945

5.270

14.215

8.945

− 5.270

− 1.837

1.837

7.108

0.140

1.864

9

− 8.646

4.517

13.162

8.646

− 4.517

− 2.064

2.064

6.581

0.152

0.711

10

− 9.080

4.409

13.490

9.080

− 4.409

− 2.335

2.335

6.745

0.148

2.873

11

− 8.808

4.832

13.641

8.808

− 4.832

− 1.988

1.988

6.820

0.147

2.137

12

− 8.545

3.951

12.496

8.545

− 3.951

− 2.297

2.297

6.248

0.160

1.368

13

− 8.481

4.075

12.555

8.481

− 4.075

− 2.202

2.202

6.277

0.159

1.921

14

− 9.180

1.997

11.177

9.180

− 1.997

− 3.591

3.591

5.588

0.179

4.237

15

− 8.542

4.17

12.712

8.542

− 4.17

− 2.186

2.186

6.356

0.157

0.054

16

− 9.491

3.82

13.311

9.491

− 3.82

− 2.835

2.835

6.656

0.15

3.599

17

− 8.432

4.303

12.735

8.432

− 4.303

− 2.064

2.064

6.367

0.157

0.328

18

− 10.288

5.493

15.782

10.288

− 5.493

− 2.397

2.397

7.891

0.127

1.727

19

− 9.05

2.340

11.390

9.050

− 2.346

− 3.360

3.360

5.701

0.18

4.732

20

− 8.859

4.724

13.583

8.859

− 4.724

− 2.068

2.068

6.792

0.147

2.409

21

− 8.268

4.476

12.744

8.268

− 4.476

− 1.896

1.896

6.372

0.157

0.39

22

− 8.704

4.909

13.613

8.704

− 4.909

− 1.897

1.897

6.807

0.147

0.206

23

− 7.752

6.518

14.271

7.753

− 6.518

− 0.617

0.617

7.136

0.14

3.777

24

− 10.387

4.417

14.804

10.387

− 4.417

− 2.985

2.985

7.402

0.135

2.525

25

− 8.523

3.985

12.508

8.523

− 3.985

− 2.268

2.268

6.254

0.159

1.397

26

− 10.727

5.844

16.571

10.727

− 5.844

− 2.441

2.441

8.286

0.121

1.855

27

− 9.46

5.094

14.554

9.461

− 5.094

− 2.183

2.183

7.278

0.137

3.754

28

− 10.473

3.961

14.434

10.474

− 3.961

− 3.256

3.256

7.217

0.138

3.506

29

− 8.98

3.88

12.86

8.98

− 3.88

− 2.55

2.55

6.43

0.16

2.32

30

− 8.745

4.901

13.646

8.746

− 4.901

− 1.922

1.922

6.824

0.146

0.586

31

− 9.082

4.442

13.524

9.082

− 4.442

− 2.320

2.320

6.762

0.148

1.361

32

− 10.918

5.517

16.435

10.918

− 5.517

2.7

− 2.7

8.218

0.121

2.047

33

− 10.711

3.419

14.130

10.712

− 3.419

− 3.645

3.645

7.066

0.141

3.632

34

− 8.519

5.024

13.542

8.519

− 5.024

− 1.747

1.747

6.771

0.148

0.751

35

− 9.605

4.832

14.437

9.605

− 4.832

− 2.386

2.386

7.219

0.138

2.324

36

− 9.442

2.596

12.038

9.442

− 2.596

− 3.422

3.422

6.019

0.166

3.631

37

− 7.764

3.901

11.674

7.764

− 3.901

− 1.926

1.926

5.837

0.171

0.516

38

− 8.695

5.170

13.865

8.695

− 5.170

− 1.763

1.763

6.933

0.144

0.176

39

− 8.695

5.170

13.865

8.695

− 5.170

− 1.763

1.763

6.933

0.144

0.164

40

− 9.146

3.51

12.656

9.146

− 3.51

− 2.818

2.818

6.328

0.158

3.559

41

− 9.391

2.798

12.189

9.392

− 2.798

− 3.296

3.296

6.095

0.164

3.748

42

− 8.885

4.062

12.947

8.885

− 4.062

− 2.411

2.411

6.474

0.154

0.841

43

− 9.001

3.052

12.053

9.001

− 3.052

− 2.975

2.975

6.027

0.165

0.802

44

− 7.64

3.378

11.018

7.641

− 3.378

− 2.131

2.131

5.509

0.181

0.648

45

− 9.355

5.102

14.457

9.355

− 5.102

− 2.126

2.126

7.229

0.138

1.841

46

− 9.016

3.878

12.895

9.016

− 3.878

− 2.569

2.569

6.447

0.155

1.901

47

− 9.892

3.097

12.989

9.892

− 3.097

− 3.397

3.397

6.495

0.153

1.691

48

− 9.371

3.852

13.222

9.371

− 3.852

− 2.759

2.759

6.611

0.151

1.772

49

− 8.475

4.996

13.471

8.475

− 4.996

− 1.739

1.739

6.735

0.148

0.198

50

− 8.325

4.145

12.470

8.325

− 4.145

− 2.09

2.09

6.235

0.161

1.765

E HOMO , energy of the HOMO orbital; E LUMO , energy of the LUMO orbital; GapE, ELUMO–EHOMO; I, ionization potential; A, electron affinity; μ, chemical potential; χ, electronegativity; ƞ, Chemical hardness σ, chemical softness; m, dipole moment

A study conducted with sesquiterpenes found that the repellent activity of these compounds was related primarily to the vapor pressure (VP) and electronic properties as LUMO energies [63], so that in their models, repellent activity increased as polarizability decreased, while high LUMO energies maintained a relationship with activity. This relationship is consistent with results applied to monoterpenes and their derivatives. The HOMO orbital is used as an indicator of the highest electron density area, so that these zones exhibit a favorable region to be attacked by electrophiles [64]. Figures 4 and 5 shows the mapping of the HOMO orbitals on the most active molecules, while Additional file 1: Figure S1 shows the mapping of LUMO orbitals.
Fig. 4
Fig. 4

The contour plots of LUMO orbitals of the most active molecules. (1) p-Anisaldehyde, (2) Canphor, (3) 3-Carene, (4) Carvacrol, (9) β-Caryophyllene, (10) Citronellal, (11) β-Citronellol, (12) m-Cresol, (13) o-Cresol, (14) Cuminaldehyde, (15) p-Cimene, (17) 3,4-Dimethylcumene, (18) Eucalyptol, (19) Geranial, (20) Geraniol

Fig. 5
Fig. 5

The contour plots of LUMO orbitals of the most active molecules (conti…). (21) Germacrene-D, (22) α-Humulene, (25) 3-Isopropylphenol, 26) Isoborneol, (29) Lavandullol, (30) Limonene, (31) Linalool, (34) Myrcene, (38) α-Pinene, (41) Rotundifolone, (42) Sabinene, (43) α-Terpinene, (46) α-Terpineol, (48) γ-Terpineol, (49) Terpinolene, (50) Thymol

The models presented demonstrated that the lipophilic character as well as the electronic properties conferred by phenolic groups are important for the larvicidal activity. The models also propose topological descriptors as factors driving the activity, especially when comparing among isomers. The position of the hydroxyl in the thymol molecule favors higher values of the Balaban index (J), E-state topological parameter (TIE), centralization (CENT), variation (VAR) and radial centric information index (ICR), with respect to carvacrol, as observed in models that incorporate this descriptors. Raising J and TIE increases the biological activity and explains the difference in activities between carvacrol and thymol. Distance-based index, J [65], strongly reflects the molecular branch, based on the sum of the distances from one atom to another in the conformation of the molecule and its value depends on three-dimensional conformation [66], while TIE [67, 68] use electronic and topological organization to define the intrinsic atom state and the perturbations of this state induced by other atoms. The values calculated of topological descriptors are listed in Table 7.
Table 7

Topological descriptors calculated

Mol.

J

TIE

UNIP

CENT

VAR

BAC

Lop

ICR

CSI

ECC

PHI

1

2.174

10.042

21

40

14

9

1.261

1.922

100

52

2.185

2

2.396

18.594

16

70

13

17

0.845

1.322

73

36

1.135

3

2.037

10.135

17

46

12

10

0.853

1.571

84

40

1.073

4

2.396

14.877

21

73

14

18

1.16

1.868

99

52

2.3

5

2.396

18.074

21

73

14

18

1.16

1.868

99

52

2.504

6

2.396

19.928

21

73

14

18

1.16

1.868

99

52

2.941

7

2.396

18.471

21

73

14

18

1.16

1.868

99

52

2.281

8

2.396

18.314

21

73

14

18

1.16

1.868

99

52

2.717

9

2.059

19.097

29

144

20

17

0.788

1.531

148

72

2.328

10

3.1

25.28

26

102

22

29

2.187

2.231

122

70

5.82

11

3.1

24.613

26

102

22

29

2.187

2.231

122

70

6.24

12

2.231

6.729

13

18

6

5

0.875

1

54

28

1.31

13

2.279

7.081

12

24

6

5

0.875

1

54

28

1.31

14

2.243

13.72

23

71

19

14

1.273

1.936

113

59

2.425

15

2.26

9.324

18

60

14

11

1.185

1.971

88

46

2.103

16

2.396

20.345

21

73

14

18

1.16

1.868

99

52

2.483

17

2.396

11.627

21

73

14

18

1.16

1.868

99

52

2.33

18

2.369

11.204

14

48

8

10

0.853

0.722

58

28

1.068

19

3.1

21.175

26

102

22

29

2.187

2.231

122

70

5.452

20

3.1

20.675

26

102

22

29

2.187

2.231

122

70

5.858

21

2.45

24.92

38

158

22

18

1.029

1.506

171

88

4.873

22

2.453

23.917

41

103

18

17

0.769

0.918

166

85

4.379

23

2.512

28.931

23

102

18

27

1.124

1.855

110

58

2.383

24

2.512

31.085

23

102

18

27

1.124

1.855

110

58

2.573

25

2.32

11.61

17

64

12

11

1.185

1.522

80

42

2.073

26

2.396

17.859

16

70

13

17

0.845

1.322

73

36

1.258

27

2.437

20.001

20

80

16

18

1.16

1.936

95

50

2.717

28

2.437

20.893

20

80

16

18

1.16

1.936

95

50

2.695

29

3.631

30.981

25

146

24

42

1.888

1.959

118

68

5.733

30

2.26

11.025

18

60

14

11

1.185

1.971

88

46

2.311

31

3.376

29.883

24

96

18

37

1.859

1.936

109

63

4.126

32

2.437

20.222

20

80

16

18

1.16

1.936

95

50

2.941

33

2.437

20.893

20

80

16

18

1.16

1.936

95

50

2.695

34

3.033

15.472

22

72

16

28

1.922

1.971

98

57

4.649

35

2.437

20.001

20

80

16

18

1.16

1.936

95

50

2.717

36

2.243

16.093

23

71

19

14

1.273

1.936

113

59

2.641

37

2.26

10.108

18

60

14

11

1.185

1.971

88

46

2.311

38

2.156

10.238

16

44

10

10

0.853

1

74

35

1.073

39

2.156

10.914

16

44

10

10

0.853

1

74

35

1.073

40

2.437

18.381

20

80

16

18

1.16

1.936

95

50

2.483

41

2.044

19.068

23

86

16

18

1.126

1.959

114

55

1.464

42

2.106

10.81

15

64

13

11

1.185

1.571

80

39

1.073

43

2.26

10.108

18

60

14

11

1.185

1.971

88

46

2.311

44

2.26

9.965

18

60

14

11

1.185

1.971

88

46

2.311

45

2.481

20.27

19

87

18

18

1.16

1.981

97

51

2.382

46

2.394

19.231

20

84

18

18

1.16

1.936

99

52

2.382

47

2.362

20.311

22

66

14

18

1.16

1.936

99

52

2.382

48

2.362

18.58

22

66

14

18

1.16

1.936

99

52

2.382

49

2.26

9.616

18

60

14

11

1.185

1.971

88

46

2.311

50

2.437

15.124

20

80

16

18

1.16

1.936

95

50

2.3

J, Balaban-like index; TIE, E-state topological parameter; UNIP, unipolarity; CENT, centralization; VAR, variation; BAC, Balaban centric index; LOP, lopping centric index; ICR, radial centric; CSI, eccentric connectivity index; ECC, eccentricity; PHI, Kier flexibility index

Docking studies on sterol carrier protein-2 (SCP-2)

The mechanism of action of the larvicidal and repellent activity exerted by EOs and their constituents is not fully described. Inhibition of the acetylcholinesterase (AChE) enzyme has been frequently proposed, a similar neurotoxic effect produced by organophosphorus and carbamate incesticides [69, 70]. Similar results have been reported when flies and cockroaches are exposed to eugenol and α-terpineol [71]. However, some authors agree that in most cases there is no relationship between inhibition of AChE and larvicidal effects of terpenes and derivatives [72, 73].

Priestley et al. proposes that EOs and their constituents act on GABA receptors, as indicated by their results when exposing Drosophila melanogaster to thymol [74]. In addition, Kumar et al. have reported that terpenes present in Calotropis gigantea have larvicidal activity due to the ability to block the sterol carrier protein (AeSCP-2) [75], which is partially responsible for intracellular cholesterol transport in insects [76]. The larvaes during the feeding step contain high concentrations of SCP-2 because they depend on exogenous sources of cholesterol for biosynthesis of steroid derivatives [77]. Therefore, compounds that can inhibit this protein have a high potential as vector control agents.

With the purpose of estimating the interactions (theoretical affinity) of the evaluated compounds on sterol carrier protein (SCP-2) a docking study was carried out. The crystal structure of AeSCP-2 (Aedes agypti Sterol Carrier Protein ID-PBD: 1PZ4) was used for docking studies and to build its homologous enzyme from Culex quinquefasciatus. The SCP-2 sequence of Culex quinquefasciatus reported in the NCBI (GenBank: AA043438.1) presented a percentage of identity of 99.09% with AeSCP-2. Figure 6 shows the tridimensional (3D) model of SCP-2 and the corresponding Ramachandran plot used for evaluation. The analysis of the free energy values of the molecular interaction between the terpenes on SCP-2 enzyme showed that all the compounds bind strongly inside the active site with a similar binding mode; binding energies (ΔG) for each molecule are shown in Table 8.
Fig. 6
Fig. 6

Results of the construction homology of the sterol carrier protein (SCP-2). a Model of sterol carrier protein (SCP-2). b Ramachandran plot corresponding for the model of SCP-2

Table 8

Docking results by SCP-2 from Culex quinquefasciatus

 

Molecules

ΔG (kcal)

Interaction with amino acids

1

p-Anisaldehyde

− 5.72

N23, R24, Q25, V26, L102, F105

2

Canphor

− 5.86

L16, Q25,V26

3

3-Carene

− 6.17

I19, N23, R24, Q25, V26

4

Carvacrol

− 6.88

I19, R24, Q25, V26, L48, L102, F105

5

Carveol

− 5.22

R24, Q25, V26, L102, F105

6

Carvomenthol

− 5.69

I19, R24, Q25, V26, Q25

7

(+)-Carvone

− 6.62

R15, I19, D20, R24, N23, Q25, V26

8

Carvotanacetol

− 5.32

I19, R24, Q25, V26, Q25

9

β-Caryophyllene

− 7.87

R15, L16, I19, V26, L48, L102, F105

10

Citronellal

− 4.16

I19, D20, N23, R24, Q25, V26

11

β-Citronellol

− 5.29

I19, D20, N23, R24, Q25, V26, L48

12

m-Cresol

− 6.26

I19, R24*, Q25*, F105

13

o-Cresol

− 6.11

I19, R24, Q25, F105

14

Cuminaldehyde

− 5.72

N23, R24, Q25, V26, L48

15

p-Cymene

− 5.28

D20, N23, R24, Q25, V26

16

t-Dihydrocarvone

− 5.97

R15*, I19, D20, R24, N23, Q25, V26, F105

17

3,4-Dimethylcumene

− 5.22

D20, N23, R24, Q25, V26

18

Eucalyptol

− 5.03

R15, L16, L102

19

Geranial

− 5.96

I19, D20, N23, R24, Q25, V26

20

Geraniol

− 5.96

I19, D20, N23, R24, Q25, V26, L48, L102, F105

21

Germacrene-D

− 7.65

R15, L16, I19, V26, L48, L102, F105

22

α-Humulene

− 7.87

R15, L16, I19, V26, L48, L102

23

Hydrocarvone

− 5.72

I19, D20, R24, N23, Q25, V26

24

Hydrodihydrocarvone

− 5.81

R15, I19, D20, R24, N23, Q25, V26

25

3-Isopropylphenol

− 5.22

D20, N23, R24, Q25, V26

26

Isoborneol

− 5.21

R15, L16, L102

27

Isopulegol

− 6.26

I19, D20, R24, N23, Q25, V26, L48, L102

28

t-Isopulegone

− 6.44

R15*, I19, D20, R24, N23, Q25, V26, L48

29

Lavandullol

− 4.72

D20, N23, R24, Q25

30

Limonene

− 5.81

I19, N23, R24, Q25, V26, L48, L102

31

Linalool

− 5.76

I19, D20, N23, R24, Q25, V26

32

Menthol

− 5.69

I19, R24, Q25, V26, Q25

33

Menthone

− 5.51

R15, I19, R24, N23, Q25, V26

34

Myrcene

− 6.05

I19, N23, R24, Q25, L102, F105

35

Neoisopulegol

− 6.34

I19, N23, R24, Q25, V26

36

(− )-Perillaldehyde

− 5.95

R15, L16, I19, N23, R24, Q25, V26

37

Phellandrene

− 5.1

D20, N23, R24, Q25, V26

38

α-Pinene

− 5.85

R15, I19, N23, R24, Q25, V26, L48

39

β-Pinene

− 5.96

R15, I19, N23, R24, Q25, V26, L48

40

(+)-Pulegone

− 6.51

R15, I19, N23, R24, Q25, V26

41

Rotundifolone

− 6.33

I19, R24, Q25, V26, L48

42

Sabinene

− 5.5

I19, N23, R24,Q25, V26

43

α-Terpinene

− 6.76

I19, N23, R24, V26, L48

44

γ-Terpinene

− 6.85

I19, N23, R24, Q25, V26, L48

45

4-Terpineol

− 5.77

R15, I19, R24, V26, L102

46

α-Terpineol

− 5.46

I19, R24, V26, L102

47

β-Terpineol

− 5.13

I19, D20, R24, N23, Q25, V26

48

γ-Terpineol

− 5.14

I19, D20, R24, N23, Q25, V26

49

Terpinolene

− 6.01

I19, R24, V26, L48, L102, F105

50

Thymol

− 6.66

I19, D20, N23, R24, Q25, V26, L48

* Hydrogen bonds interaction

Results showed that monoterpenes and monoterpenoids with the highest larvicidal activity were also the compounds with better binding energy values, being carvacrol the most active followed by α-terpinene and terpinolene. Another important observation is that monoterpenes and monoterpenoides with the highest larvicidal activity are capable of interact with the Phe105 residue.

All cyclic terpenes and cyclic terpenoids interact with Arg24 and Val26 by hydrophobic interactions; only terpinene, terpinolene and carvacrol have interaction with the Phe105 residue. In these compounds, the greater number of π conjugated bonds, provides better interaction with SCP-2 (Fig. 7a). Carvone interacts to a lesser extent than limonene with the SCP-2 protein, since the keto group present in carvone makes the molecule more hydrophilic and therefore does not interact with and Leu48 residues Leu102, as does limonene (Fig. 7b). Results agree with QSAR descriptors related to their poor biological activity.
Fig. 7
Fig. 7

Interaction of cyclic terpenes and terpenoids with SCP-2. a Interaction of carvacrol (green), α-Terpinene (orange) and terpinolene (yellow). b Interaction of limonene (brown) and carvona (green). c Interaction of p-cimene (yellow), menthol (pink) and thymol (purple)

The relevance of the phenol group is observed when the binding energies of cymene, menthol, thymol and carvacrol are compared. Cymene binding energy is − 5.28 kcal, while menthol is − 5.69 kcal, this energy difference can be attributed to the hydroxyl group; on the other hand, thymol has a binding energy of − 6.66 kcal, which shows that the phenolic group is also important. This characteristics are also observed when comparing the bonding energy of carvomenthol and carvacrol. These results are consistent with the QSAR models also included in this work. The structural difference between the aromatic ring present in thymol and menthol without π bonds, generates a change in the arrangement of the later in the SCP-2 protein active site. It can be observed that the larger aliphatic chain in para position of cymene and thymol is in the direction of Phe105 residue, but does not interact with it, while the menthol is in the opposite position; however the hydroxyl group is kept in the same coordinates as for thymol (Fig. 7c). This is because the hydroxyl group of thymol and menthol are capable of forming hydrogen bonds with the amino group of Arg24 residue.

The position of the hydroxyl group in the phenolic group is also relevant. The hydroxyl group in the meta position of carvacrol leaves more exposed to larger aliphatic chain, which interacts with the Phe105 residue; the results is an increased biological activity as well as a more favorable binding energy as compared to thymol. The hydroxyl group of carvacrol can form hydrogen bonds with the amino group in Arg24 and with the amino group of the peptide bond between Gln25 and Val26 residues. The isopropyl group, on the other hand, also plays a fundamental role in the recognition of monoterpenes; for example, m-cresol and o-cresol, does not have the isopropyl residue and have no affinity on the SCP-2. This observation also agrees with the QSAR models, which propose that nCt are important in biological activity.

The results on acyclic terpenes denote the importance of π bonds despite not being aromatic moieties. Citronellol, the molecule with lower number of π bonds, is an acyclic terpene less able to interact with SCP-2 and is also the molecule with lower larvicidal activity. On the other hand, myrcene has the highest number of π bonds, presented the highest larvicidal activity and is also the best to interact with SCP-2. Geraniol and myrcene are the acyclic terpenes with the higher larvicidal activity and both interact with the Phe105 residue (Additional file 1: Figure S2). All acyclic terpenes, except those with ketone groups, are capable of interact with residues Ile19, Asn23, Arg24 and Gln25. Geraniol has the ability to form a hydrogen bond with the amino group of the backbone between the Ile19 and Asn20.

Anisaldehyde presented a binding energy of − 5.72 kcal/mol and was able to interact with the Phe105 residue and form a hydrogen bond with the amino group of Arg24 (Additional file 1: Figure S3a). The cuminaldehyde does not interact with the Phe105 residue and was not able to form hydrogen bonds. Sesquiterpenes presented the highest affinity on the SCP-2 active site, presented interactions with the Phe105 residue and with the hydrophobic pocket (Additional file 1: Figure S3b).

Conclusions

The larvicidal activity of terpenes and terpenoids was analyzed by LC50 determination for different stairs of Culex quinquefasciatus Say. The description of the molecular properties and the structural characteristics responsible for larvicidal activity of the tested compounds, were used for the development of mathematical models of structure–property–activity relationship. The docking studies were able to show that molecular and structural descriptors provide evidence of SCP-2 as a possible biological target, an important protein in cholesterol and fatty acid catabolism, which cleaves the 3-oxoacyl-CoAs of methyl-branched fatty acid and bile acid intermediates. However experimental studies should be conducted to elucidate this effect.

Declarations

Authors’ contributions

BNT and LEST coordinated the larvicidal bioassay. SAO developed the larvicidal bioassays. LMRV coordinated the first electronic structure calculations and advised SAO on the analysis of the results and development of the QSAR model. SAO and JCB developed the docking studies. JCB and LEST revised the first draft. GVNM and SAO wrote the manuscript. GVNM conceived the study and participated in its design and coordination. All authors read and approved the final manuscript.

Acknowledgements

SAO wishes to acknowledge the support of Eric Contreras-Suarez, Manuel Villanueva-García and Alejandro D. Camacho during the experimental development of this work.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Data is available from the authors by request.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Funding

SAO which to thank the Consejo Nacional de Ciencia y Tecnología for his graduate studies scholarship (Fellowship No. 278488).

Publisher’s Note

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Authors’ Affiliations

(1)
Facultad de Ciencias Químicas, Universidad Autónoma de Chihuahua, Circuito Universitario S/N, Campus Universitario II., Chihuahua, Chihuahua, Mexico
(2)
Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N. Col. Santo Tomas, 11340 México, DF, Mexico
(3)
Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Col. Casco de Santo Tomas, Delegación Miguel Hidalgo, C.P. 11340 México, DF, Mexico

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