BACKGROUND: Weeds are a serious problem in worldwide agricultural production. Natural products are a notable source for discovering new lead compounds. Phloretin is a dihydrochalcone compound which was discovered in 1835 and named after its concentrated content in roots, stems or bark of fruits. Within apple orchards, there are typically fewer weeds on the areas covered with fallen leaves compared to areas without fallen leaves. This interesting phenomenon suggested that phloretin may have potential herbicidal activity. Through the principle of bioisosterism and combination of active structural moieties, structures of amide, chalcone and flavanone were integrated with phloretin, with the objective to obtain novel phloretin derivatives to test as herbicides. RESULTS: Fifty-seven novel phloretin derivatives were designed and assayed for their herbicidal activity. Some compounds showed safety to rape and excellent inhibitory activity against purslane. Modeling of ligand docking suggested that phytoene desaturase and protoporphyrinogen oxidase may be potential herbicidal targets of phloretin derivatives. CONCLUSION: Most compounds that combined phloretin and amide together showed significant inhibition of purslane growth while retaining safety on rape. Some of these compounds warrant further structural modification with potential for becoming lead compounds. Virtual screening also explored two possible targets of phloretin derivatives and they deserve further biological verification. © 2025 Society of Chemical Industry.