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Updated: Jan 11, 2026

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Substituted Benzylidene-3-Oxo-3,4-Dihydro-2H-Benzo[b][1,4]thiazine-6-Carboxylic Acid Analogs as Dynamin GTPase
Andrew J S Lin1, Nicholas S O'Brien1, Abigail Florence1
1Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, New South Wales, 2308, Australia.
Abstract:
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.
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