*2.8. Structure-Activity Relationship*

The activity of the 2,4-dichloro derivative (compound **5c** or **4c** ) was better than those of the 4- chloro analogues (compound **5d** or **4d** respectively), emphasizing the geometrical role of aryl moieties in the activities of the compounds. This result was consistent with that of our previous studies, which indicated the effect of such substitution patterns and showed that the 2,4-dichloro substitution was favorable to the activities of the compounds [19,20].

Hetero aryl (compound **5k**, **5j**), bulky (compound **5i**), or EDG (**5h**) reduced the activity indicated the site which was adopted by aryl groups in the side chain. The substitution site on both phenyl rings was important in the activity and physicochemical parameters of the compounds. This was clearly observed in compounds **5c**, **5e**, and **5l** compared to compounds **5f** and **5m**. Strong EWG (**5g**) exhibited the best activity.

### **3. Materials and Methods**

General information of the equipment used in the synthesis and the characterization of the compounds can be found in the supplementary materials. Additionally, the anticancer activity along with shape alignment and ROCS can be found in the supplementary materials.
