Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site

Abstract

Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogues, we identified low micromolar inhibitors of Escherichia coli DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli topoisomerase IV and of Staphylococcus aureus homologues. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and ΔtolC E. coli strains suggests that they are efflux pump substrates and/or do not possess the physicochemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.

Inhibition of Hepatitis C Replication by Targeting the Molecular Chaperone Hsp90: Synthesis and Biological Evaluation of 4,5,6,7‐Tetrahydrobenzo[1,2‐d]thiazole Derivatives

“…[24] The amino group at position 2ofthe 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole central scaffold of 1 was acylated using different carboxylic acids in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) in N,N-dimethylformamide (DMF) to obtain amides 2-4, 7,a nd 9-12.A mines 5, 6, 8,a nd 13 were obtained from carbamates 3, 4, 7,a nd 12, respectively,b yr emoval of the Boc protecting group using acidolysis. Compound 1 was synthesized as reported previously.…”

Dual Escherichia coli DNA Gyrase A and B Inhibitors with Antibacterial Activity

“…[2f-h] We recently reported several structural types of low-nanomolar pyrrole-2-carboxamide GyrB inhibitors [4][5][6] and established the binding mode of 2-((2-(4,5dibromo-1H-pyrrole-2-carboxamido)benzo[d]thiazol-6-yl) amino)-2-oxoacetic acid (1 a; IC 50 E. coli = 58 nM), [6] a 4,5dibromo-pyrrole analog of 1 b (IC 50 E.coli = 43 nM), [7] to GyrB from E. coli with X-ray crystallography. We report firstin-class DNA gyrase B (GyrB) inhibitor/ciprofloxacin hybrids that display antibacterial activity against Escherichia coli.…”

“…[2f-h] We recently reported several structural types of low-nanomolar pyrrole-2-carboxamide GyrB inhibitors [4][5][6] and established the binding mode of 2-((2-(4,5dibromo-1H-pyrrole-2-carboxamido)benzo[d]thiazol-6-yl) amino)-2-oxoacetic acid (1 a; IC 50 E. coli = 58 nM), [6] a 4,5dibromo-pyrrole analog of 1 b (IC 50 E.coli = 43 nM), [7] to GyrB from E. coli with X-ray crystallography. The final compounds 2 a-b and 3 a-b were purified on Sephadex LH-20 to remove traces of ciprofloxacin.A DNA gyrase supercoiling assay [4][5][6] demonstrated weaker inhibition of E. coli DNA gyrase by the hybrids 2 a-b and 3 a-b (IC 50 values from 0.17 to 6.2 μM) than by the GyrB inhibitors 1 a-e (IC 50 values from 9 to 66 nM) and slightly weaker inhibition than by the GyrA inhibitor ciprofloxacin (Table 1). [6,7] Dual targeting of GyrB and structurally similar topoisomerase IV ParE subunits has been suggested to prolong the onset of resistance in bacteria because mutations at both essential sites are less probable than single mutations at GyrB or ParE ATP-binding sites.…”

“…[2f-h] We recently reported several structural types of low-nanomolar pyrrole-2-carboxamide GyrB inhibitors [4][5][6] and established the binding mode of 2-((2-(4,5dibromo-1H-pyrrole-2-carboxamido)benzo[d]thiazol-6-yl) amino)-2-oxoacetic acid (1 a; IC 50 E. coli = 58 nM), [6] a 4,5dibromo-pyrrole analog of 1 b (IC 50 E.coli = 43 nM), [7] to GyrB from E. coli with X-ray crystallography. [2] Whereas fluoroquinolones targeting the GyrA subunit of a heterodimeric A 2 B 2 enzyme are widely used to treat infections with gram-positive and gram-negative bacteria, [2b,d,3] GyrB inhibitors interfering with ATP binding to subunit B have not advanced into the clinic despite intensive research over the last 50 years after the discovery of novobiocin as the first ATP-competitive GyrB inhibitor in the 1960s.…”

“…A DNA gyrase supercoiling assay [4][5][6] demonstrated weaker inhibition of E. coli DNA gyrase by the hybrids 2 a-b and 3 a-b (IC 50 values from 0.17 to 6.2 μM) than by the GyrB inhibitors 1 a-e (IC 50 values from 9 to 66 nM) and slightly weaker inhibition than by the GyrA inhibitor ciprofloxacin (Table 1). The hybrids 2 a and 2 b with ciprofloxacin bound to position 6 of a benzothiazole core were better (sub-micromolar) inhibitors than 3 a and 3 b that possessed low micromolar E. coli gyrase IC 50 values.…”