2(3H)-Benzoxazolone and Bioisosters as “Privileged Scaffold” in the Design of Pharmacological Probes

Abstract

The 2(3H)-benzoxazolone heterocycle and its bioisosteric surrogates (such as 2(3H)-benzothiazolinone, benzoxazinone, etc.) have received considerable attention from the medicinal chemists owing to their capacity to mimic a phenol or a catechol moiety in a metabolically stable template. These heterocycles and pyrocatechol have indeed similar pKa's, electronic charge distribution, and chemical reactivity. Therapeutic applications of this template are very broad, and range from analgesic anti-inflammatory compounds (including PPAR-gamma antagonists) to antipsychotic and neuroprotective anticonvulsant compounds. High affinity ligands have been obtained also for dopaminergic (D2 and D4), serotoninergic (5-HT1A and 5-HT-2A), sigma-1 and sigma-2 receptors. Owing to the high number of positive hits encountered with this heterocycle and its congeners, 2(3H)-benzoxazolone template certainly deserves the title of "privileged scaffold" in medicinal chemistry.

Selective inhibition of Biotin Protein Ligase from Staphylococcus aureus

“…Thus we chose to target triazoles containing aliphatic and aromatic groups (see R group in Table 1) that might be predicted to substitute for adenine and bind in the hydrophobic ATP pocket. A privileged 2-benzoxazolone scaffold (48,49) was also included in this series (see structures 14 and 16 in Table 1). …”

Inside Cover: Benzoxazolone Carboxamides: Potent and Systemically Active Inhibitors of Intracellular Acid Ceramidase (Angew. Chem. Int. Ed. 2/2015)

“…Encouraged by the potency and drug-likeness of 9 a, which is based on the privileged scaffold of benzoxazolone, [17] we sought to expand this chemical class and identify structural features that are critical for AC inhibition. Focused structureactivity relationship (SAR) studies were first aimed at exploring the role of the urea moiety of 9 a, with a small set of compounds (9 b-e) that were prepared as described in Scheme 1.…”

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

“…Many derivatives of 2H-1,4-benzoxazine have been reported as plant resistance factors against insects and also microbial diseases [242], serotonin-3 (5-HT3) receptor antagonists [243][244][245], potassium channel modulators [246], etc. The 3,4-dihydro-3-oxo-2H-1,4-benzoxazine scaffold is also considered a bioisoster for 2(3H)-benzoxazolone [247] and is used as a privileged scaffold in drug design. Benzo [1,4]oxazin-3-one derivatives also exhibit multiple biological activities, such as anti-inflammatory [248], antiulcer [249], antipyretic [250], antihypertensive [251], and antifungal properties [252].…”