ABSTRACT
The synthesis and preliminary structure-activity relationship of a series of pyrrolidinones are described. These pyrrolidinones have been characterized as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) which are highly potent against wild-type and drug-resistant human immunodeficiency viruses (HIV-1).
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , HIV-1/drug effects , Pyrrolidinones/chemical synthesis , Pyrrolidinones/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Anti-HIV Agents/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , Humans , Microbial Sensitivity Tests , Molecular Structure , Pyrrolidinones/chemistry , Reverse Transcriptase Inhibitors/chemistry , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
A novel oxindole was discovered as an HIV non-nucleoside reverse transcriptase inhibitor via HTS using a cell-based assay. Systematic structural modifications were carried out to establish its SAR. These modifications led to the identification of oxindoles with low nanomolar potency for inhibiting HIV replication. These novel and potent oxindoles could serve as advanced leads for further optimizations.
Subject(s)
HIV-1/drug effects , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Drug Resistance, Viral , Indoles/chemical synthesis , Indoles/pharmacology , Stereoisomerism , Structure-Activity Relationship , Virus ReplicationABSTRACT
A series of heterocycle-containing oxindoles was synthesized and their HIV antiviral activities were assessed. Some of these analogs exhibited potent inhibitory activities against both wild-type virus and a number of drug-resistant mutant viruses. In addition, oxindole 9z also showed promising pharmacokinetics.
Subject(s)
HIV-1/drug effects , Indoles/chemical synthesis , Indoles/pharmacokinetics , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacokinetics , Virus Replication/drug effects , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Drug Design , Drug Resistance, Viral , Stereoisomerism , Structure-Activity RelationshipABSTRACT
HIV-1 integrase (HIV-IN) is a well-validated antiviral drug target catalyzing a multistep reaction to incorporate the HIV-1 provirus into the genome of the host cell. Small molecule inhibitors of HIV-1 integrase that specifically target the strand transfer step have demonstrated efficacy in the suppression of virus propagation. However, only few specific strand transfer inhibitors have been identified to date, and the need to screen for novel compound scaffolds persists. Here, the authors describe 2 homogeneous time-resolved fluorescent resonance energy transfer-based assays for the measurement of HIV-1 integrase 3'-processing and strand transfer activities. Both assays were optimized for high-throughput screening formats, and a diverse library containing more than 1 million compounds was screened in 1536-well plates for HIV-IN strand transfer inhibitors. As a result, compounds were found that selectively affect the enzymatic strand transfer reaction over 3beta processing. Moreover, several bioactive molecules were identified that inhibited HIV-1 reporter virus infection in cellular model systems. In conclusion, the assays presented herein have proven their utility for the identification of mechanistically interesting and biologically active inhibitors of HIV-1 integrase that hold potential for further development into potent antiviral drugs.
