5-(2-Pyrimidinyl)-imidazo[1,2-a]pyridines are antibacterial agents targeting the ATPase domains of DNA gyrase and topoisomerase IV

Pyridine-3-carboxamide-6-yl-ureas as novel inhibitors of bacterial DNA gyrase: Structure based design, synthesis, SAR and antimicrobial activity

“…To test the modelling hypothesis, compound 7 was prepared according to the procedure described in Scheme 1 from commercially available 6-aminonicotinate 8. c data from Starr et al [10]; d data from East et al [8] As indicated from inspection of the data in Table 1, although compound 7 synthesised as part of the present work was 1 -2 orders of magnitude less potent against GyrB than those previously reported, this was encouraging given the lower molecular weight / complexity of this inhibitor. Furthermore, the antimicrobial activity found for this compound, albeit weak, indicated the potential for optimisation.…”

“…[6] More recently, the development of small molecule ATPase inhibitors of gyrase (GyrB) and topo IV (ParE), aided by the elucidation of proteinligand structures of GyrB, has gained attention as a means to inhibit these classical enzyme targets in the pursuit of novel antibacterial compounds. [7][8][9][10] Encouraged by these reports, our interest in the discovery of novel ATPase inhibitors of GyrB / ParE began with the observation that a number of reports in the literature demonstrated that heterocyclic N-ethylurea derivatives to be conducive with potent dualinhibitory ATPase activity coupled to antimicrobial activity. [7,8,10,11].…”

“…[7][8][9][10] Encouraged by these reports, our interest in the discovery of novel ATPase inhibitors of GyrB / ParE began with the observation that a number of reports in the literature demonstrated that heterocyclic N-ethylurea derivatives to be conducive with potent dualinhibitory ATPase activity coupled to antimicrobial activity. [7,8,10,11]. Notably, benzimidazol-2-yl-ureas (1), benzathiazol-2-yl-ureas (2), imidazopyridin-2-yl-ureas (3), triazolopyridine-5-carboxamides (4), isoquinolin-3-yl-ureas (5) and pyridin-3-yl-ureas (6) reported by groups at Vertex [7], Prolysis 11 , Pfizer [10], Evotec [8], Actelion [12] and AstraZeneca [13] respectively, exemplify the prevalence of this moiety amongst antibacterial GyrB / ParE inhibitors ( Fig.…”

“…[7,8,10,11]. Notably, benzimidazol-2-yl-ureas (1), benzathiazol-2-yl-ureas (2), imidazopyridin-2-yl-ureas (3), triazolopyridine-5-carboxamides (4), isoquinolin-3-yl-ureas (5) and pyridin-3-yl-ureas (6) reported by groups at Vertex [7], Prolysis 11 , Pfizer [10], Evotec [8], Actelion [12] and AstraZeneca [13] respectively, exemplify the prevalence of this moiety amongst antibacterial GyrB / ParE inhibitors ( Fig. 1).…”

Challenges of Antibacterial Discovery

“…A number of other groups have reported on GyrB-ParE inhibitor programs, with less-detailed evidence for dual targeting at the antibacterial level. These include Prolysis/Evotec benzimidazoles (102) and Pfizer pyrimidinyl-imidazo-pyridines (353), which are similar to the Vertex compounds. Trius Pharmaceuticals was awarded a large National Institute of Allergy and Infectious Diseases (NIAID) contract in October 2008, for discovery of dual ParE-GyrB inhibitors targeting Gram-negative biodefense organisms.…”