Inhibitors of HIV-1 attachment. Part 4: A study of the effect of piperazine substitution patterns on antiviral potency in the context of indole-based derivatives

• Published in: Bioorganic & medicinal chemistry letters 2009-09, Vol.19 (17), p.5140-5145
• Main Authors: Wang, Tao, Kadow, John F., Zhang, Zhongxing, Yin, Zhiwei, Gao, Qi, Wu, Dedong, Parker, Dawn DiGiugno, Yang, Zheng, Zadjura, Lisa, Robinson, Brett A., Gong, Yi-Fei, Blair, Wade S., Shi, Pei-Yong, Yamanaka, Gregory, Lin, Pin-Fang, Meanwell, Nicholas A.
• Format: Article
• Language: English
• Subjects: A 1,3 strain; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cell Line; gp120; HIV; HIV attachment; HIV Envelope Protein gp120 - antagonists & inhibitors; HIV Envelope Protein gp120 - metabolism; HIV-1 - drug effects; Human immunodeficiency virus 1; Humans; Indoles - chemistry; Medical sciences; Pharmacology. Drug treatments; Piperazine; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Structure-Activity Relationship; Virus Attachment - drug effects
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.07.076

4-Fluoro- and 4-methoxy-1-(4-benzoylpiperazin-1-yl)-2-(1 H-indol-3-yl)ethane-1,2-dione ( 2 and 3, respectively) have been characterized as potent inhibitors of HIV-1 attachment that interfere with the interaction of viral gp120 with the host cell receptor CD4. As part of an effort to understand fundamental aspects of this pharmacophore, discovered originally using a high throughput cell-based screen, modification and substitution of the piperazine ring was examined was examined in the context of compounds 6a–ah. The piperazine ring was shown to be a critical element of the HIV-1 attachment inhibiting pharmacophore, acting as a scaffold to deploy the indole glyoxamide and benzamide in a topographical relationship that complements the binding site on gp120. 4-Fluoro- and 4-methoxy-1-(4-benzoylpiperazin-1-yl)-2-(1 H-indol-3-yl)ethane-1,2-dione ( 2 and 3, respectively) have been characterized as potent inhibitors of HIV-1 attachment that interfere with the interaction of viral gp120 with the host cell receptor CD4. As part of an effort to understand fundamental aspects of this pharmacophore, discovered originally using a high throughput cell-based screen, modification and substitution of the piperazine ring was examined in the context of compounds 6a–ah. The piperazine ring was shown to be a critical element of the HIV-1 attachment inhibiting pharmacophore, acting as a scaffold to deploy the indole glyoxamide and benzamide in a topographical relationship that complements the binding site on gp120.