Design and synthesis of pyridine‐containing pyrimidinedione sulfonamides with improved grass‐weed activity and potent Nt PPO inhibition

BACKGROUND Protoporphyrinogen IX oxidase (PPO) is an established herbicide target. Building on a previously reported pyrimidinedione sulfonamide lead with limited grass‐weed activity, we designed and synthesized 21 pyrimidinedione sulfonamide derivatives using molecular hybridization and bioisosteric modification. RESULTS In post‐emergence greenhouse assays, compounds I‐5 and II‐2 showed the most favorable activity profiles within the tested series. At 150 g a.i. ha −1 , I‐5 provided 98.0 ± 2.0% and 95.0 ± 4.4% control of Setaria glauca and Echinochloa crus‐galli , respectively, whereas II‐2 provided 100.0 ± 0.0% and 80.0 ± 8.7% control. At 37.5 g a.i. ha −1 , II‐2 retained 90.0 ± 5.2% and 70.0 ± 8.5% control of S. glauca and E. crus‐galli , respectively, compared with 20.0 ± 8.7% and 10.0 ± 5.2% for the previous lead 13a under the same conditions. At the lowest application rate tested (9.375 g a.i. ha −1 ), II‐2 provided 100.0 ± 0.0% and 90.0 ± 1.7% control of Zinnia elegans and Abutilon theophrasti , respectively. In the Nicotiana tabacum PPO ( Nt PPO) catalytic assay, II‐2 gave a half‐maximal inhibitory concentration (IC 50 ) of 11.99 n m [95% confidence interval (CI) 9.03–15.09 n m ], similar in numerical magnitude to saflufenacil (13.28 n m ; 95% CI 9.30–17.66 n m ). Computational analyses were used only for qualitative interpretation of possible binding poses and electronic features. CONCLUSION II‐2 is an active PPO‐inhibiting lead that combines improved grass‐weed control relative to 13a with low‐nanomolar Nt PPO inhibition. Crop selectivity, lower‐rate whole‐plant potency, and the relationship between Nt PPO inhibition and grass‐weed efficacy remain to be established before practical development can be assessed.