## 3 Results and Discussion
### Cheminformatics Prediction
#### 3.2.4. ADMET Prediction
Tables 7 and 8 and qualitatively by Data Warrior, a free tool from the marker of OSIRIS Property Explorer, Table 8.  
From a quantitative point of view, the four toxicity descriptors; cardiotoxicity, hepatotoxicityoxicity, Ames mutagenicity, and median lethal dose (LD\({}_{50}\)) of acute toxicity were predicted. Cardiotoxicity is one of the side effects resulting from the off-target interactions between drugs and ion channels that play crucial roles in adjusting the cardiac action potential, as well as control the cardiac rhythm [69]. Among these ion channels, the human ether-a-go-go-related gene (hERG) a potassium ion channel, was found to be more related to severe cardiotoxicity [70; 71], so the hERG-blockade is considered as a major retardant in providing the pharmaceutical market with safe drugs. Furthermore, the off-target interaction of hERG is the leading cause of drug withdrawal from the pharmaceutical market [72; 73]. Thus, the identification of potential hERG blocker is important at early phases of drug discovery [69]. The assessment results of the hERG-based toxicity show that **5 _anti_** and its isomer **5 _syn_** have no cardiotoxicity and are the safest among other compounds. The highest cardiotoxicity value of the reference drugs **9** is, partially, at least, due to their containing basic amine on their alkyl side chain (hERG: ++ 0.879 for reference drugs **9** vs. -- 0.261 for **5 _syn_**). Hepatotoxicity and cardiotoxicity are the major factors participating for drugs attrition. Unfortunately, a quarter of the marketed drugs are withdrawn due to their adverse hepatic effects [74; 75]. The **5 _syn_** and **7 _anti_** are safe to the liver, in contrast, **5 _anti_**, **6 _anti_**, **6 _syn_**, **7 _syn_** are not safe. Furthermore, reference drug **9** is predicted to be the most hepatotoxic with probability ++ 0.878. The Ames test, referring to the inventor Ames, is an assay to detect the mutagenicity of the compound; the ability of the compound to stimulate the genetic damage and mutations [76; 77]. Similar to reference drug **9**, the **6 _anti_**, **6 _syn_**, **7 _anti_**, and **7 _syn_** exert no mutagenicity effects, while the **5 _anti_** and its isomer **5 _syn_** tend to induce genetic damage and mutations as predicted by Ames test. These results are not consistent with qualitative results obtained by the Data Warrior program, since **6 _anti_** and **6 _syn_** are highly mutagenic, while other compounds are not mutagenic. This may refer to the difference in the reference models used in both tests. Determination of an acute toxicity is another important task in the destination of drug discovery and development. The acute toxicity is expressed as median lethal dose (LD\({}_{50}\)); the dose amount of a tested compound that kill fifty percent (50 %) of the treated animals within a given time [78]. The **7 _anti_**, and its isomer **7 _syn_** exert the highest acute toxicity, and indicate their lowest LD\({}_{50}\) values, while the reference drug **9** is safer due to the highest value (LD\({}_{50}\) (mg/Kg): 262.66, 249.11, and 912.27, respectively). The **5 _anti_** and its isomer **5 _syn_** exhibit no acute toxicity with high LD\({}_{50}\) 802.40, and 811.69 (mg/Kg), respectively, but the **6 _anti_** and its isomer **6 _syn_** may exert low toxicity.