40828-56-6Relevant articles and documents
In silico optimization of a fragment-based hit yields biologically active, high-efficiency inhibitors for glutamate racemase
Whalen, Katie L.,Chau, Anthony C.,Spies, M. Ashley
, p. 1681 - 1689 (2013)
A novel lead compound for inhibition of the antibacterial drug target, glutamate racemase (GR), was optimized for both ligand efficiency and lipophilic efficiency. A previously developed hybrid molecular dynamics-docking and scoring scheme, FERM-SMD, was used to predict relative potencies of potential derivatives prior to chemical synthesis. This scheme was successful in distinguishing between high- and low-affinity binders with minimal experimental structural information, saving time and resources in the process. In vitro potency was increased approximately fourfold against GR from the model organism, B.subtilis. Lead derivatives show two- to fourfold increased antimicrobial potency over the parent scaffold. In addition, specificity toward B.subtilis over E.coli and S.aureus depends on the substituent added to the parent scaffold. Finally, insight was gained into the capacity for these compounds to reach the target enzyme in vivo using a bacterial cell wall lysis assay. The outcome of this study is a novel small-molecule inhibitor of GR with the following characteristics: Ki=2.5μM, LE=0.45kcalmol-1atom-1, LiPE=6.0, MIC50=260μgmL-1 against B.subtilis, EC50,lysis=520μgmL-1 against B.subtilis.
Benzimidazoles as NMDA glycine-site antagonists: Study on the structural requirements in 2-position of the ligand
Dannhardt, Gerd,Kohl, Beate K.
, p. 123 - 129 (2007/10/03)
A series of different substituted benzimidazole derivatives has been synthesized and evaluated for the ability to displace [3H]MDL-105,519 to rat cortical membranes. Two benzimidazole-2-carboxylic acids 9 b and 9 c, in this substitution pattern not yet described as glycine antagonists, showed IC50 values of 0.89 μM (9 b) and 38.0 μM (9 c). Replacement of the carboxylate function in 2-position by a sulfonic acid moiety appreciably increased solubility, but decreased the affinity giving evidence for the strong need of the carboxylate group within the ligand. Further structure-activity studies using benzimidazol-2-one derivatives with an acetic acid moiety adjacent to a ring nitrogen revealed new insights into the importance of amide functionalities within the heterocycle for the affinity of antagonist glycine-site ligands.
SYNTHESIS OF 2-HYDRAZINOBENZIMIDAZOLES AND THEIR ANTINFLUENZA ACTIVITY
Mokrushina, G. A.,Kotovskaya, S. K.,Tyurenkova, G. N.,Il'enko, V. I.,Platonov, V. G.,Kiseleva, I. V.
, p. 146 - 150 (2007/10/02)
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