Study On Synthesis Of Capsid Protein Inhibitor CAP-1 Derivatives

AIDS, a serious disease caused by HIV infection, has threatened human health. Currently available drugs for the treatment of HIV infection target the RT and PR enzymes. These drugs are marginally effective when administered independently due to the rapid emergence of resistant strains that are selected under conditions of incomplete viral suppression. Therefore, identifying the new approaches of anti-AIDS drugs is the high priority of anti-AIDS treatment and prevention. Several recent studies have shown that proper capsid assembly is critical for viral infectivity. Mutations in capsid protein that inhibit assembly are lethal and mutations that alter capsid stability severely attenuate replication making the capsid protein an attractive potential antiviral target.Recently, Tang et al reported that compound N-(3-chloro-4-methyphenyl)-N'-{2-[({5-[(dimethylamino)-methyl]-2-furan}-methyl)-sulfanyl]ethyl}urea (CAP-1), can bind to the N-terminal domain of the HIV-1 capsid protein and inhibit capsid assembly in vitro.We attempted to select CAP-1 as a lead compound for preparing a series of N-substituedphenyl-N'-{2-[(5-substitued-2-furanmethyl)-sulfanyl]acetyl}urea derivatives, in order to find some useful compounds for the discovery of new drug which will be used clinically in the treatment of AIDS.We designed some compounds, which structures comprise of acylurea. This kind of structure was not protected in Tang's patent.After seriously retrosynthetic analysis, we selected furanmethanol as starting material. 5-Dialkylamino-2-furanmethanols were prepared under the Mannich reaction condition. Those Mannich base were transformed to 5-dialkylamino-2-furanmethanethiols in the presence of thiourea. By using chloroacetamide and oxalyl chloride, chloroacetyl isocyanate was synthesized. Subsequently substituted benzenamine and their analogs were added to the isocyanate in 'one pot', then we got the N-chloroacetyl-N'-sustituedphenyl urea. Finally we...