Abstract Background The discovery of new lead compounds with desired properties and biological activity is an excellent challenge in pesticide chemistry. Chloroacetamide are an important class of synthetic herbicides. Results To explore the herbicidal activity of chloroacetamides, several new chloroacetamide derivatives have been designed, and synthesized. The compounds have been described by forming Schiff bases followed by chloroacetylation of imines. The herbicidal activity as a chlorophyll inhibition was evaluated against two broadleaf weeds (Chenopodium album and Anagallis arvensis) and two grass weeds (Lolium temulentum and Echinochloa crus-galli) in comparison with acetochlor as a standard herbicide. 1H-NMR, 13C-NMR and mass spectroscopic analyses confirmed the chemical structures of the synthesized compounds. Several compounds have demonstrated highly potent herbicidal activity compared to the standard herbicide acetochlor. Some of them have been described as the most effective against weeds tested, such as compounds 5b and 18b. Molecular docking to the active sites of Very Long Chain Fatty Acid Synthase (VLCFAS) has indicated that most compounds are low-energy binding agents and show high affinity for the active pocket. Conclusion Novel herbicides may be discovered by combining chloroacetamide derivatives with these existing lead structures. Graphical Abstract