Fig. 1: Initial hit finding and synthetic optimization strategy. | Nature Chemistry

Fig. 1: Initial hit finding and synthetic optimization strategy.

From: Discovery of isoquinoline sulfonamides as allosteric gyrase inhibitors with activity against fluoroquinolone-resistant bacteria

Fig. 1

a, The initial library screen of 352 compounds at a single 100 µM dose. The 12 hits found were further investigated in MIC assays, resulting in the most potent hit 1. b, SAR overview of 1. The 5-isoquinoline (coral), linker (blue), inner ring (gold) and outer ring (purple) were systematically modified using structure 1 as reference. The essential groups are noted in corresponding colours. c, Conformational restriction using a pyrrolidine linker retains all the core molecular features, while reducing loss of entropy upon binding. The trans-2R,5S isomer is the only diastereomer that is more potent than the parent compound. The trans-2R,5R isomer still inhibits growth but at higher concentrations, while the cis-2S,5R and the trans-2S,5S isomers both do not show activity. d, Synthetic route to make conformationally restricted isoquinoline sulfonamide LEI-800. The synthesis consists of 12 individual steps, of which steps 2–4 introduce a second stereocentre. The synthetic procedures are found in full in Supporting Information. DMAP, dimethylaminopyridine; THF, tetrahydrofuran; ACN, acetonitrile; DCM, dichloromethane.

Back to article page