Analysis of the Physicochemical Properties of Acaricides Based on Lipinski's Rule of Five

Abstract

This study aimed to explore the similarity between the physical and chemical properties of different acaricides, determine whether Lipinski's Rule of Five (RO5) used in the design of drug molecules is suitable for screening acaricides, and provide methods for selection of new acaricides. We evaluated and predicted the molecular properties of >180 acaricides using Molinspiration. We calculated physicochemical property parameters, such as log p, molecular weight (MW), and number of hydrogen bond donors (HBDs), hydrogen bond acceptors (HBAs), and rotatable bonds (Rot B). We then conducted qualitative and quantitative analyses of the physicochemical properties of acaricides. The MW of all acaricides ranged from 141 to 663, with an average value of 337.8. The number of HBDs ranged from 0 to 5, with an average value of 0.46. The number of HBAs ranged from 0 to 9, with an average value of 4.07. The log p ranged from −0.79 to 8.74, with an average value of 4.61. The number of Rot B ranged from 0 to 14, with an average value of 5.62. Except for the microbial and plant-derived acaricides, the molecular properties of the remaining acaricides are in accordance with the Lipinski's RO5. Therefore, the Lipinski's RO5 can provide a basis for screening new acaricide drugs.

1. Introduction

Acaricides are among the cornerstones of an efficient control program for phytophagous mites (Van Leeuwen et al., 2015) and have the widest range of pharmaceutical applications. Advances in research on mites and control of acarids and the continuous development of control technologies have led to increasingly close links between mites and humans (Kungu et al., 2019; Wu et al., 2019).

Given the diversity of morphological habits and habitats and the wide distribution, adaptability, and variety of acaricides, the demand for this type of pesticide increases and its research and application have developed rapidly (Pavela, 2017; Zhang et al., 2017; Agut et al., 2018). The variety and number of species are also increasing (Chen et al., 2018). Acaricides are currently classified according to their chemical structure.

Classification based on the mechanism of action has been increasingly implemented with the emergence of many new types of acaricides. Acaricides can be classified into the following major categories based on their chemical structure: (1) mineral source acaricides; (2) organochlorines; (3) organotins; (4) organophosphorus; (5) pyrethroids; (6) organic sulfur; (7) carbamates; (8) nitrobenzenes; (9) aniline; (10) heterocyclic acaricides; (11) amidine; and (12) microbial- and plant-derived acaricides.

According to the mechanism of action, acaricides can be divided into four categories: physical acaricides, respiratory chain complex inhibitor acaricides, growth regulating inhibitor acaricides, and neurotoxic agent acaricides (Cullen and Reynoldson, 1987; Wood et al., 1996; Motoba et al., 2000; Devine and Khambay, 2001; Stumpf and Nauen, 2001; Dekeyser, 2005; Nakano et al., 2015; Snoeck et al., 2019).

According to the object of action, acaricides can be divided into the following categories: acaricides for killing eggs, larva, and prosopon and acaricides that are effective for each state (Roush and Mckenzie, 1987; Liu et al., 2009; Beugnet and Franc, 2012; Hayashi et al., 2013).

An ideal drug molecule would comply with the physicochemical property guidelines of Lipinski's Rule of Five (RO5). It predicts the drug likeness of a chemical compound with a certain biological activity designed for oral route of administration (Lipinski et al., 2001). According to the RO5, a drug-like compound should have a molecular weight (MW) of <500 g/mol, a log p value of <5 representing its hydrophobicity, no >5 hydrogen bond donors (HBDs), and no >10 hydrogen bond acceptor (HBA) sites (Doak et al., 2014). Further research has added two more conditions: a polar surface area (PSA) of ≤140 Å and <10 rotatable bonds (Rot B) (Veber et al., 2002; Ali et al., 2018; Chagas et al., 2018; Huang et al., 2019), which are correlated with drug permeability and flexibility, respectively (Fig. 1).

FIG. 1.

Visual scheme of the Rule of Five criteria: molecular weight (MW), polar surface area (PSA), rotatable bonds (Rot B), hydrogen bond acceptors (HBAs), hydrogen bond donors (HBDs), log p. (Revised from Chagas et al., 2018).

If a compound meets the five principles, then it will have enhanced pharmacokinetic properties and increased bioavailability in the metabolic process of the organism.

In the field of drug research and development, the Lipinski's RO5 is widely used in the following aspects. (1) For compounds that need to be registered, this rule can be used to check predictions and determine whether registration is necessary. (2) This rule can be used for initial screening of small-molecule drugs, preliminary screening of drug molecules that do not meet the rules, narrowing the scope of drug screening, and saving costs for drug research and development. (3) This rule can also be used as a standard for synthesis of compounds when establishing drug databases. (4) This rule can provide guidance for a clinical backup drug.

After the publication of the Lipinski's rule, it has been widely used in medical research. Clarke and Delaney (2003) studied and analyzed the synthesis of pesticide compounds from the screening of target molecules to design of commercial drugs. They concluded that most herbicides and fungicides follow the Lipinski's rule. Therefore, this rule should also be applied to pesticide chemistry.

Molinspiration is a database provided by Molinspiration Cheminformatics and can be used to calculate and predict molecular properties. Molinspiration provides a wide range of chemical and molecular information processing tools, including SMILES and SDfile conversion, molecular standardization, tautomerization, molecular fragmentation, molecular characterization calculations required for Quantitative structure-activity relationship (QSAR), molecular modeling and drug design, high-quality molecular description, and support substructures and similarity searches. The software program also supports fragment-based virtual screening, bioactivity prediction, and data visualization. Molinspiration is written in Java and can be used on any computer platform (Mabkhot et al., 2016; Bhat, 2018).

Molinspiration can be used to calculate log p, PSA, MW, number of HBAs and ligands, number of Rot B, MW, and other parameters of the drug molecule based on its molecular structure. This tool can also be used to predict the bioactivity scores of important drug targets [G-protein-coupled receptor (GPCR) ligands, kinase inhibitors, ion channel regulators, and nuclear receptors]. Mites have many kinds and have ∼300,000–500,000 species worldwide, which can harm >150 kinds of crops and cause great losses to agriculture and forestry production. Agricultural mites are small, widely distributed, and adaptable and have the characteristics of rapid propagation, short life cycle, arrhenotokous parthenogenesis, haplodiploid sex determination system, and extraordinary ability to adapt to different hosts and environmental conditions, and easily developed resistance to acaricides. Mites have a complex population structure and can exist in all growth stages, including eggs, nymph, larva, and prosopon (Jarrahpour et al., 2012).

Prevention and treatment of mites are extremely difficult because of their nature. Therefore, continuous development of high-efficiency, low-toxicity, and highly selective acaricides is an important way to improve the chemical control effect and protect the ecological balance.

Through quantitative and qualitative analyses of the molecular structure of existing acaricides, this study explored the similarity properties of acaricide molecules in terms of log p, MW, and number of HBAs and ligands to provide theoretical basis for research and screening of new acaricides.

2. Methods

2.1. Experimental materials

One hundred eighty-one kinds of acaricides, including seven kinds of mineral source acaricides, 13 kinds of organochlorines, 4 kinds of organotins, 38 kinds of organophosphorus, 15 kinds of pyrethroids, 15 kinds of organic sulfurs, 16 kinds of carbamates, 12 kinds of nitrobenzenes, 4 kinds of anilines, 29 kinds with a heterocyclic structure, 5 kinds of amidine, 12 kinds of microorganisms, 5 kinds of plant source acaricides, and 6 kinds of other types.

2.2. Experimental methods

According to existing literature, the physicochemical properties, such as melting point, boiling point, density, vapor pressure, solubility, stability, and toxicity, of acaricides were summarized and analyzed. The log p, PSA, MW, number of HBAs and ligands, number of Rot B, and molecular volume of acaricides can be calculated using Molinspiration.

2.3. Data acquisition and data processing

Data were obtained by Molinspiration calculation, and all parameters were summarized and stored in an Excel spreadsheet. The data were classified and statistically analyzed. Relevant data are detailed in the attachment.

3. Results

3.1. Qualitative description of the physicochemical properties of acaricides

The molecular composition of acaricides varies, which determines their different physicochemical properties. Different types of acaricides have different action modes and mechanisms. Similar types of acaricides have similar molecular structures, and their physicochemical properties have some commonalities.

3.1.1. Mineral source acaricides

These types consist of inorganic compounds, including sulfides, arsenides, and copper-containing compounds (Mitchell, 1996). These acaricides are some inorganic compounds with high melting point and boiling point, and poor water solubility and fat solubility. These acaricides have a single mode of action, mainly fumigation and physical and mechanical effects, but the contact effect is poor.

3.1.2. Organochlorine acaricides

These types include Dichloro diphenyl trichloroethane (DDT), its analogs, namely, cyclodienes and hexachlorocyclohexane, and its derivatives, namely, urea and sulfamines (Uspensky and Ioffeuspensky, 1992). Organochlorine acaricides have high melting point, low vapor pressure and volatility, and poor water solubility. They are almost insoluble in water, have strong fat solubility, are soluble in most organic solvents, have stable chlorobenzene structure, and do not easily degrade enzymes in the body. They disappear slowly in the living body, and their residual time is long. These acaricides have an extremely high acaricidal activity, kill by contact, and exert low toxicity to higher animals. However, this type of acaricide is no longer produced due to resistance, residue, and pollution problems.

3.1.3. Organotin acaricides

These types are not the main acaricide variety and have four common types, such as triazolyl tin, phenbutyltin, triphosphorus tin, and tricyclotin (Bigg and Purvis, 1976; Zhang et al., 2019). Organotin acaricides are organic compounds containing metal tin and are characterized by low vapor pressure, poor water solubility, insolubility in water, good fat solubility, solubility in most organic solvents, and strong contact and killing effects. This type of pesticide causes stomach poisoning, exerts antifeeding effect but not egg-killing effect, and exhibits high acaricidal activity and special effects on acarids with developed resistance. Organotin acaricides are a temperature-sensitive agent that works efficiently at 20°C–22°C or above.

3.1.4. Organic phosphorus acaricides

Except for a few types, acaricides have very high melting and boiling points, density of >1, high refractive index, high MW (∼200–400), low vapor pressure, and high volatility in air. The solubility of this type of acaricide in different solvents varies. These acaricides cannot tolerate high temperatures and decompose at 200°C; most of them have contact and stomach toxicity and moderate toxicity (Gauer and Seiber, 1971; Ako et al., 2006; Kumar et al., 2015).

3.1.5. Pyrethroid acaricides

Pyrethroid acaricides are synthesized according to the chemical structure of natural pyrethrin. This type of acaricide has a high melting point, high boiling point, density of above 1, low vapor pressure, and poor water solubility, but is soluble in most organic solvents. Stereoisomerism is widely present in the molecular structure of pyrethroid acaricides, which have strong contact killing effect and stomach toxicity but do not have systemic and fumigation activity. These acaricides have high acaricidal activity, strong knockdown effect, low toxicity to higher animals, and easy biodegradability in the environment (Wang et al., 2014; Liu et al., 2016; Sun et al., 2016; Bandara and Karunaratne, 2017; Cossío-Bayúgar et al., 2018).

3.1.6. Organic sulfur acaricides

Organic sulfur acaricides include sulfites, thiourea, ethers, thioethers, hydrazines, and sulfonates. Organic sulfur acaricides have high melting and boiling points, low vapor pressure, and density >1. Most of the species are insoluble in water but soluble in organic solvents. Most of them mainly utilize contact killing and have low toxicity to higher animals.

3.1.7. Carbamate acaricides

Carbamate acaricides have high melting point and low boiling point, vapor pressure, and solubility in water. They are soluble in organic solvents, and most of them are mainly based on contact. Most varieties have low toxicity to higher animals and are easily degraded by organisms and environment. This type of acaricide has no chronic toxicity and low toxicity to fish (McDougall and Machin, 1988).

3.1.8. Acaricides with heterocyclic structure

These types include azobenzene, hydrazine derivatives, and nitrophenol derivatives. Acaricides with heterocyclic structure generally exhibit contact toxicity and have evident systemic effect and low toxicity. These acaricides can be divided into several classes, such as those with growth-regulating activity, neurotoxicity, and respiratory metabolism control activity. Growth-regulating acaricides have strong fat solubility and strong egg-killing effect.

3.1.9. Amidine acaricides

Amidine acaricides are easily soluble in water and organic solvents and have strong contact effects on mite and eggs, fumigating effect, long-lasting effect, low toxicity, and low accumulation in animals. This type of acaricide exerts no chronic poisoning phenomenon and the “3R” effect and is safe for humans, animals, and plants. Amidine acaricides are natural enemies of pests.

3.1.10. Microbial acaricides

Microbial acaricides use mite pathogenic microorganisms and their metabolites as acaricidal agents. They do not pollute the environment and are conducive to improving the environment and protecting water resources. They are selective and can effectively utilize the protection of natural enemies. They have high specificity, are safe for humans and animals, do not allow pests to easily produce drug resistance, and can protect natural enemies of pests (Yao et al., 2015).

3.1.11. Plant source acaricides

Plant source acaricides are low-molecular-weight secondary metabolites produced by plants and have the effect of repelling, antifeeding, regulating growth and development, and poisoning at low concentrations. They exert low pressure on the environment and are safe for nontarget organisms. Most plant-derived acaricides have low toxicity to mammals and are safe for humans and animals during use. However, most of the effects are slow, and the application period should be improved. Botanical acaricides are generally multicomponent systems and are less susceptible to drug resistance (Pavela, 2017; Rosado-Aguilar et al., 2017; Zhang et al., 2017; Li et al., 2018; Singh et al., 2018).

3.2. Quantitative analysis of physicochemical properties of acaricides

3.2.1. Statistical analysis of MW of acaricides

According to the Lipinski's RO5, the MW of the drug molecule should be <500 to obtain increased bioavailability. The MW of acaricides is calculated using Molinspiration software (Table 1).

Table 1.

Molecular-Weight Range Parameters of Acaricides

Classification	Amounts of acaricides	Range of MW	Amounts of MW <500	Percentage of compliance with Lipinski rule (%)
Organochlorines	13	267.15–663.08	12	92.31
Organotins	4	436.23–1052.76	2	50
Organophosphates	38	141.13–456.55	38	100
Pyrethroid	15	349.43–541.46	11	73.33
Organic sulfur	15	218.28–384.59	15	100
Carbamate	16	165.19–380.55	16	100
Nitrobenzene	12	182.23–370.43	12	100
Anilines	4	349.16–465.09	4	100
Heterocycles	29	166.19–555.29	26	89.65
Amiones	5	196.68–293.41	3	60
Microorganism	12	495.5–914.14	1	8.33
Botanical origin	5	162.24–690.7	3	60
Others	6	212.25–488.77	6	100

MW, molecular weight.

The results showed that the calculated drug molecules are bai chongqing, phenbutyltin, flumethrin, fluvalinate, biomethrin, acrinathrin, vaniliprole, fluazuron, chlorfluazuron, microbial, and botanical acaricides, and the MWs of the other species are <500. In the above categories, only phenbutyltin and microbial and plant-derived acaricides have an MW of >600, and the percentage of MWs that followed the Lipinski's rule in all acaricides is 82.32%.

3.2.2. Statistical analysis of the number of HBDs of acaricide

The number of HBDs of the acaricide molecule was calculated and statistically analyzed (Table 2).

Table 2.

Hydrogen Bond Number Range Parameters of Acaricides

Classification	Amounts of acaricides	Range of hydrogen bond number	Amounts of hydrogen bond number <5	Percentage of compliance with Lipinski rule (%)
Organochlorines	13	0–2	13	100
Organotins	4	0–1	4	100
Organophosphates	38	0–2	38	100
Pyrethroid	15	0–1	15	100
Organic sulfur	15	0–2	15	100
Carbamate	16	0–2	16	100
Nitrobenzene	12	0–1	12	100
Anilines	4	1–3	4	100
Heterocycles	29	0–5	29	100
Amiones	5	0–1	5	100
Microorganism	12	0–11	10	83.33
Botanical origin	5	0–2	5	100
Others	6	0–2	6	100

The results showed that except for nikkomycin and thuringiensin in microbial acaricides, the number of HBDs of the other kinds of acaricide is <5, and the percentage of acaricides that followed the Lipinski's rule is 98.89%. For all acaricide species, the number of HBDs is small, and the number of HBDs in >100 acaricides is 0.

3.2.3. Statistical analysis of the number of HBAs

The results of the statistical analysis of the number of HBAs of acaricide molecules are shown in Table 3.

Table 3.

Number and Range Parameters of Hydrogen Bond Receptors of Acaricides

Classification	Amounts of acaricides	Range of hydrogen bond acceptors	Amounts of hydrogen bond acceptor number <5	Percentage of compliance with Lipinski rule (%)
Organochlorines	13	0–6	13	100
Organotins	4	1–3	4	100
Organophosphates	38	2–6	38	100
Pyrethroid	15	1–6	15	100
Organic sulfur	15	0–5	15	100
Carbamate	16	3–7	16	100
Nitrobenzene	12	2–9	12	100
Anilines	4	6–8	4	100
Heterocycles	29	0–7	29	100
Amiones	5	2–5	5	100
Microorganism	12	7–21	3	25
Botanical origin	5	2–3	4	80
Others	6	3–15	6	100

The results showed that in all acaricides, the number of HBAs is <5, except for some species of azadirachtin and microbial acaricides. The percentage of the molecular HBA of acaricides that follow the Lipinski's rule is 94.48%.

3.2.4. Statistical analysis of the lipid–water partition coefficient

Acaricide molecules are organic molecules, and most of them are easily soluble in organic solvents. The partition coefficient of lipid–water is large. Based on the statistical analysis of the lipid–water partition coefficient of acaricides, >50% of the acaricide molecular lipid–water partition coefficient is >5 (Table 4).

Table 4.

Range Parameters of Lipid–Water Partition Coefficient of Acaricides

Classification	Amounts of acaricides	Range of lipid–water partition coefficient	Amounts of lipid–water partition coefficient <5	Percentage of compliance with Lipinski rule (%)
Organochlorines	13	3.73–8.17	6	46.15
Organotins	4	1.97–6.59	3	75
Organophosphates	38	−0.79 to 5.92	33	86.84
Pyrethroid	15	5.27–8.31	0	0
Organic sulfur	15	2.65–6.76	8	53.33
Carbamate	16	−0.72 to 5.55	15	93.75
Nitrobenzene	12	1.94–7.32	8	66.67
Anilines	4	2.52–6.1	1	25
Heterocycles	29	−0.13 to 8.74	11	37.93
Amiones	5	1.65–5.09	4	80
Microorganism	12	−4.74 to 8.74	10	83.33
Botanical origin	5	1.09–2.82	5	100
Others	6	3.58–6.98	3	50

3.2.5. Statistical analysis of the number of Rot B

Based on the statistical analysis of the number of Rot B of the acaricide molecule (Table 5), the number of Rot B is <10, except for the species of Decis, malathion, methacrifos, acrinathrin, 2,4-dinitroo-cresol, dinocton, octyl nitrite, thuringiensin, nikkomycin, and acequinocyl. The percentage of the number of Rot B in the acaricide molecule that conforms to the Lipinski's rule is 94.47%.

Table 5.

Number and Range Parameters of Rotatable Bonds of Acaricide Molecules

Classification	Amounts of acaricides	Range of Rot B number	Amounts of Rot B number <10	Percentage of compliance with Lipinski rule (%)
Organochlorines	13	0–7	13	100
Organotins	4	3–9	4	100
Organophosphates	38	2–12	35	92.11
Pyrethroid	15	6–14	14	93.33
Organic sulfur	15	2–9	15	100
Carbamate	16	2–9	16	100
Nitrobenzene	12	2–12	9	75
Anilines	4	5–6	4	100
Heterocycles	29	0–10	29	100
Amiones	5	2–5	5	100
Microorganism	12	0–17	10	83.33
Botanical origin	5	0–3	5	100
Others	6	4–13	5	83.33

Rot B, rotatable bonds.

4. Discussion

Mites are among the most difficult pests to prevent and control. Only few types of mite control agents are currently available, and the prevention and treatment of mites require further study of acaricides. A complex process is required for a target compound to become a commercial drug. The drug then undergoes a complex screening and pharmacodynamic testing process. An effective method for screening acaricide molecules should be established to explore common laws existing in acaricide molecules. Clarke and Delaney (2003) found that the Lipinski's rules apply to the screening of fungicides and herbicides. In this regard, the present work conducted statistical analysis of the relevant parameters of the chemical structure of existing acaricides. Our results showed that in 181 kinds of acaricide, the MW of 82.32% species is <500, the number of molecular hydrogen bonds in 98.89% of the species is <5, the number of molecular HBAs in 94.48% of the species is <10, and the number of Rot B in 94.47% of the species is <10. The lipid–water distribution coefficient of acaricide molecules is large because they are organic molecules. As such, their molecular lipid–water distribution coefficient is slightly >5 (Supplementary Table S1). Except for the low lipid–water distribution coefficient, the range of other parameters is almost the same as that of the Lipinski's rule. Therefore, the Lipinski's rule is also applicable for screening acaricide drugs.

5. Conclusions

Through qualitative and quantitative analyses of the related physicochemical properties of acaricide molecules, this study found that all acaricides have MW of 141–663, with an average value of 337.8. About 82.32% of the acaricides conform to the Lipinski's rule. The number of HBDs ranged from 0 to 5, with an average value of 0.46, and 98.89% of the acaricides conform to the Lipinski's rule. The number of HBAs ranged from 0 to 9, with an average value of 4.07, and about 94.48% of the acaricides conform to the Lipinski's rule. The log p ranged from −0.79 to 8.74, with an average value of 4.61. The number of Rot B ranged from 0 to 14, with an average value of 5.62. About 94.47% of the acaricides conform to the Lipinski's rule. The MW of the acaricide molecule, the number of HBDs, the number of acceptors, and the number of Rot B are highly consistent with the range of parameters specified in the Lipinski's rule. Therefore, the Lipinski's rule can be applied for screening new acaricides and can provide theoretical guidance for further research on acaricides.

Footnotes

Author Disclosure Statement

The authors declare they have no competing financial interests.

Funding Information

We acknowledge financial support from Chongqing Basic Research and Frontier Exploration Project (cstc2018jcyjAX0501), Fundamental Research Funds for the Central University (XDJK2019B035), the Science and Technology Innovation Project of Social Career and People's Livelihood Guarantee in Chongqing (cstc2017shms-xdny80001; cstc2017shms-xdny80023), and the National Citrus Engineering Research Center opening project (NCERC2019006).

Supplementary Material

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