Respiratory syncytial virus fusion inhibitors. Part 6: An examination of the effect of structural variation of the benzimidazol-2-one heterocycle moiety

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 17; pp. 4784 - 4790
• Main Authors: Combrink, Keith D., Gulgeze, H. Belgin, Thuring, Jan W., Yu, Kuo-Long, Civiello, Rita L., Zhang, Yi, Pearce, Bradley C., Yin, Zhiwei, Langley, David R., Kadow, Kathleen F., Cianci, Christopher W., Li, Zhufang, Clarke, Junius, Genovesi, Eugene V., Medina, Ivette, Lamb, Lucinda, Yang, Zheng, Zadjura, Lisa, Krystal, Mark, Meanwell, Nicholas A.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-09-2007; Elsevier
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - pharmacology; Benzimidazole derivatives; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biological and medical sciences; Chemistry, Pharmaceutical - methods; Drug Design; Electrons; Humans; Inhibitory Concentration 50; Medical sciences; Models, Chemical; Models, Molecular; Molecular Conformation; Pharmacology. Drug treatments; Respiratory syncytial virus; Respiratory Syncytial Virus Infections - drug therapy; Respiratory syncytial virus inhibitors; Respiratory Syncytial Viruses - metabolism; RSV; RSV fusion inhibitors; Viral Fusion Proteins - antagonists & inhibitors; Antiviral agents; RSV; Benzimidazole derivatives; Respiratory syncytial virus inhibitors; RSV fusion inhibitors; Human respiratory syncytial virus; Sulfur nitrogen heterocycle; Benzoxazole derivatives; Pneumovirinae; Nitrogen heterocycle; Lactam; In vitro; Paramyxoviridae; Virus; Mononegavirales; Side chain; Structure activity relation; Bicyclic compound; Antiviral; Aromatic compound; Pneumovirus; Indole derivatives; Benzothiazine derivatives; Oxygen nitrogen heterocycle
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.06.065

The effect of structural variation of the benzimidazol-2-one ring of RSV fusion inhibitors related to BMS-433771 (
1) was examined in conjunction with side chain modifications and the introduction of an aminomethyl substituent at the 5-position of the core benzimidazole moiety. Replacement of the benzimidazol-2-one moiety with benzoxazole, oxindole, quinoline-2-one, quinazolin-2,4-dione and benzothiazine derivatives provided a series of potent RSV fusion inhibitors
4. However, the intrinsic potency of 6,6-fused ring systems was generally less than that of comparably substituted 5,6-fused heterocycles of the type found in BMS-433771 (
1). The introduction of an aminomethyl substituent to the benzimidazole ring enhanced antiviral activity in the 6,6-fused ring systems.
The effect of structural variation of the benzimidazol-2-one ring of RSV fusion inhibitors related to BMS-433771 (
1) was examined in conjunction with side chain modifications and the introduction of an aminomethyl substituent at the 5-position of the core benzimidazole moiety. Replacement of the benzimidazol-2-one moiety with benzoxazole, oxindole, quinoline-2-one, quinazolin-2,4-dione and benzothiazine derivatives provided a series of potent RSV fusion inhibitors
4. However, the intrinsic potency of 6,6-fused ring systems was generally less than that of comparably substituted 5,6-fused heterocycles of the type found in BMS-433771 (
1). The introduction of an aminomethyl substituent to the benzimidazole ring enhanced antiviral activity in the 6,6-fused ring systems.