ABSTRACT
We identified a novel class of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine compounds as potent HIV-1 replication inhibitors serendipitously during the process of evaluation of triazolothienopyrimidine (TTPM) compounds. Herein, we report synthesis and biological evaluation of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine compounds using a cell-based full replication assay to identify thienopyrimidines 6 and 30, which could be further utilized as viable lead compounds.
Subject(s)
HIV-1/drug effects , Pyrimidines/chemistry , Drug Discovery , Humans , Structure-Activity RelationshipABSTRACT
We identified a novel class of triazolothienopyrimidine (TTPM) compounds as potent HIV-1 replication inhibitors during a high-throughput screening campaign that evaluated more than 200,000 compounds using a cell-based full replication assay. Herein, we report the optimization of the antiviral activity in a cell-based assay system leading to the discovery of aryl-substituted TTPM derivatives (38, 44, and 45), which exhibited significant inhibition of HIV-1 replication with acceptable safety margins. These novel and potent TTPMs could serve as leads for further development.
Subject(s)
Anti-HIV Agents/chemical synthesis , HIV-1/metabolism , Pyrimidines/chemistry , Triazoles/chemistry , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Cell Line , Drug Evaluation, Preclinical , HIV-1/drug effects , High-Throughput Screening Assays , Humans , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
We describe a novel 7-aminopyrazolo[1,5-a]pyrimidine (7-APP) derivative as a potent hepatitis C virus (HCV) inhibitor. A series of 7-APPs was synthesized and evaluated for inhibitory activity against HCV in different cell culture systems. The synthesis and preliminary structure-activity relationship study of 7-APP are reported.
Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , Hepacivirus/drug effects , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug Stability , Humans , Microbial Sensitivity Tests , Molecular Structure , Pyrazoles/chemistry , Pyrazoles/metabolism , Pyrimidines/chemistry , Pyrimidines/metabolism , Rats , Structure-Activity RelationshipABSTRACT
We identified a novel class of aryl-substituted triazine compounds as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) during a high-throughput screening campaign that evaluated more than 200000 compounds for antihuman immunodeficiency virus (HIV) activity using a cell-based full replication assay. Herein, we disclose the optimization of the antiviral activity in a cell-based assay system leading to the discovery of compound 27, which possessed excellent potency against wild-type HIV-1 (EC50 = 0.2 nM) as well as viruses bearing Y181C and K103N resistance mutations in the reverse transcriptase gene. The X-ray crystal structure of compound 27 complexed with wild-type reverse transcriptase confirmed the mode of action of this novel class of NNRTIs. Introduction of a chloro functional group in the pyrazole moiety dramatically improved hERG and CYP inhibition profiles, yielding highly promising leads for further development.
