Discovery and design of benzimidazolone based inhibitors of p38 MAP kinase

A new class of benzimidazolone p38 MAP kinase inhibitors was discovered through high-throughput screening. X-ray crystallographic data of the lead molecule with p38 were used to design analogues with improved binding affinity and potency in a cell assay of LPS-induced TNF production. Herein, we report the SAR of this new class of p38 inhibitors.     

Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists

A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (c log P <3.5, chrom log D_7.4 <5.3 and CLND solubility >116 μg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA₂ <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom log D_7.4 (2.4), high LE (0.43), and solubility (152 μg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation.     

Synthesis and SAR studies of benzimidazolone derivatives as histamine H3-receptor antagonists

A novel series of benzimidazolone-containing histamine H₃-receptor antagonists were prepared and their structure–activity relationship was explored. These benzimidazolone analogs demonstrate potent H₃-receptor binding affinities, no P450 enzyme inhibition, and strong H₃ functional activity. Compound 1o exhibits the best overall profile with H₃K_i = 0.95 nM and rat AUC = 12.9 μM h.     

Synthesis and cytotoxicity studies of 1-propenyl-1,3-dihydro-benzimidazol-2-one

A heterocyclic compound 1-propenyl-1,3-dihydro-benzimidazol-2-one was synthesized by a palladium-catalyzed rearrangement reaction. Anticancer activities were confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against Neura 2a (neuroblastoma cell), HEK 293 (kidney cancer) and MCF-7 (breast cancer) cell lines at low micromolar range. Furthermore, clear images from phase-contrast and fluorescence microscopes and confocal images unambiguously confirm the cancer cell death. The single X-ray crystal structure of the compound unambiguously proves the structure of the benzimidazolone compound.