## 4 Computer-Aided Molecular Design (CAMD) of Coumarins for Potential Plant Protection Application
### Environmental and Health Hazards Properties of Coumarins
Results of an acute toxicity study suggested that osthole is a moderately toxic substance when administered intraperitoneally to mice (lethal dose that causes the death of 50% of a group of test animals (LD50) = 710 mg/kg), but results of the subchronic study revealed histopathological changes in organs, especially in the kidney [166]. Studies of toxicity and carcinogenicity from the European Food Safety Authority in 2004 rejected the possibility of natural coumarins being genotoxic. In addition, exposure to coumarin from food and/or cosmetic products poses no health risk to humans [167]. However, clinical studies performed on patients treated with coumarin as a medicinal drug demonstrated its hepatotoxic effect. The hepatotoxic effect appeared among breast cancer patients taking coumarin for chronic lymphedema [168]. Several natural coumarins like psoralen, bergapten, and xanthotoxin, present in large concentrations in celery or lime, may cause a limited number of photoallergic reactions in humans [169]. No data has been published on natural coumarin's reproductive and developmental toxicity [170]. The REACH guidelines [56] suggest \"in-silico\" prediction methods. In order to reduce these expensive and time-consuming experiments, the quantitative structure-toxicity relationship (QSTR) method is valuable. Only robust QSTR models with an adequate external predictive ability could be used for the prediction of experimentally undermined toxicity of known pesticides, as well as new pesticides. [PERSON] et al. [47] derived a QSAR model for estimating the acute toxicity of pesticides on honey bee by means of a three-layer feedforward neural network trained by the back-propagation algorithm based on the experimentally determined toxicity of 100 pesticides. Thus [PERSON] et al. [171] developed a predictive (\(R^{2}_{\text{external}}=0.75\)) QSAR model using Feedforward Neural Networks (FNNs) and implemented it in the publicly available BeeToxAI web application ([[http://beetoxai.labmol.com.br/](http://beetoxai.labmol.com.br/)]([http://beetoxai.labmol.com.br/](http://beetoxai.labmol.com.br/)) (accessed on 27 April 2023)) for prediction of acute toxicity of chemicals in honey bees. Also, [PERSON] et al. [172] generated a k-Nearest Neighbor (k-NN) QSTR model for pesticide toxicity prediction in bees. Coumarin derivatives [35] were estimated by the Toxicity Estimation Software Tool (T.E.S.T.) program (v.4.1) [173]. Among 38 derivatives only five compounds are characterized as \"toxic\" for rats, and three of them have a benzoyl radical at position C-3. Also, the same compounds exhibit the highest aquatic toxicity against _Tetrahymena pyriformis_. Nine coumarinyl Schiff bases were also estimated by the program T.E.S.T. Eight of the nine compounds are characterized as \"harmful if swallowed\" by rats. Only the most lipophilic compounds have been estimated as not mutagenic but lethal for water organisms. Tested compounds have no significant high bioaccumulation factor, which means organisms have difficulty absorbing them from the environment [36].