## 4 Computer-Aided Molecular Design (CAMD) of Coumarins for Potential Plant Protection Application
### Environmental and Health Hazards Properties of Coumarins  
Pesticides and their residues have detrimental effects on the environment, non-target soil organisms and microorganisms, and human health. Plant protection products must first be approved at the EU level before being authorized at the national level. By adopting the 2009 \"pesticide package,\" the EU proposed a common approach to limiting pesticide harmful effects, promoting integrated pest management, and the progressive replacement of the most dangerous pesticides with low-risk alternatives [154]. The EU proposed a common approach to limiting pesticide harmful effects. The new pesticides should be: effective at an extremely low dosage; readily degradable and less residual in the environment; selective against toxic agrochemicals. Also, active components of plant protection products, including their residues in food, must be safe for people's and animal health, as well as for the environment [155]. Entomopathogenic nematodes (EPNs) are beneficial organisms used in insect pest management programs and are often combined with plant stimulants, inorganic and organic plant fertilizers, or evaluated on chemical pesticide compatibility [156]. EPN family Heterorhabditidae has evolved mutual associations with insect pathogenic Photorhabdus symbiotic bacteria, while Steinernematididae with Xenorhabdus bacteria, to deliver that symbiotic bacterium into the insect hemocoel causing rapid insect mortality [157]. Testing of entomogenic nematodes' compatibility with pesticides under laboratory conditions may contribute to cost-effective and sustainable pest management. Thus, the mortality, infectivity, and reproductive capacity of EPNs \(H\). _heteriorophora_ and _Steinerhema feltiae_ were tested on six registered pesticides in Turkey. Pesticides affect nematodes differently due to diverse insect physiology and specific feeding patterns [158]. Although coumarins and their derivates as botanical nematicides have attracted considerable interest due to their favorable biorational profile, the methods are still not standardized [159]. However, the study of [PERSON] et al. [35] has shown that coumarin derivatives with the highest antifungal effects were not harmful against infective juveniles (IJs) of two beneficial nematode species, _H. bacteriophora and S. feltiae_, as well as, against beneficial soil bacteria _Bacillus mycoides_ and _Bradynhizobium japonicum_. Most of the coumarinyl Schiff bases did not exhibit nematicidal activity against the same infective juveniles, except Schiff base with 4-methoxybenzylidenen which was also most effective against fungi _S. sclerotium_[36]. Although coumarins have an important role in plant growth regulation and defense against phytopathogens, they also have adverse effects on plant germination. Inhibitory effect of coumarin on the germination of durum wheat (_Tritcium turgidium_ ssp. durum, cv. [PERSON]) [160], and rice seeds [161] was observed. Coumarins is also a potentially toxic for livestock. Dicoumarol toxicosis was confirmed in blood from Friesian cattle fed with wrapped, bailed silage containing approximately 90% sweet vernal grass (_Anthoxanthum odoratum_) [162]. The fodder plant, sweet clover (_Melidus_ spp. ), or weeds such as bracken fern (_Pteridium aquilinum_), and giant fennel (_Ferula communis_), contain coumarins that cause hemorrhagic disease in animals) [163]. Active components of plant protection products, including food residues, must be proven safe for people's health, and their effects on animal health and the environment. Plant protection products are registered following extensive laboratory testing on animals to assess their short-term and long-term effects on health. Chronic coumarin administration resulted in liver lesions, liver tumors, and cholangiocarcinoma in rats and mice, as well as lung tumors in mice [164]. A recently demonstrated hepatotoxic effect of psoralen in oral doses of 80 mg/kg bw in rats and 320 mg/kg in mice [165].