LAUSR

Screening identified 2‐hydroxy‐3‐oxo‐3,4‐dihydro‐2H‐benzo[b][1,4]oxazine‐6‐carboxylic acid (1) as a 55 µM dynaminGTPase inhibitor. Synthesis of three 1‐based libraries shows no potency enhancement. However, S‐isostere‐based 3‐oxo‐3,4‐dihydro‐2H‐benzo[b][1,4]thiazine‐6‐carboxylic acid (16) gives rise to Libraries 4–6. Library 4 retains the C6‐ester of 1; only H‐bond capable analogs (–OH, –CO2H) improves dynamin inhibition (IC50 < 20 µM), with C3′‐CO2H 17j returning an IC50 = 1.3 ± 0.5 µM. N‐methylation gives Library 5 and essentially removes activity. Most (>80%) of Library 6 analogs are dynamin active. Highest potency is noted with H‐bond‐accepting aromatic moieties: C3′‐OAc 19p, C2′,C3′,C4′‐tri‐OAc 19r, and C3′,C4′‐di‐OMe 19y (IC50 values of 5.1, 5.2 and 7.2 µM, respectively). A N,N‐dimethylaminopropyl chain enhances activity with C4′‐OH 19u to 21, but has no effect with C4′‐OH 17u to 20. This may be due to compound remodeling within the active site to best align two of the three H‐bond‐donating groups (of 19u vs. 17u). There appears to be a minimum requirement of two H‐bond donors. Combined this work has identified seven new analogs: C3′–CO2H 17j, C2′–OH 17s, C3′,C4′‐di‐OMe 18y, C3′‐OAc 19p, C2′,C3′,C4′‐tri‐OAC 19r, C3′,C4′‐di‐OMe 19y, and C4′‐O(CH2)3NMe2 21 with dynamin IC50 values of 1.3–10.0 µM. 118 compounds aresynthesized and screened.