ABSTRACT
Several novel amine substituted N-(1H-benzimidazol-2ylmethyl)-5,6,7,8-tetrahydro-8-quinolinamines were synthesized which had potent activity against HIV-1. The synthetic approaches adopted allowed for variation of the substitution pattern and resulting changes in antiviral activity are highlighted. This led to the identification of compounds with low and sub-nanomolar anti-HIV-1 activity.
Subject(s)
Amines/chemistry , Anti-HIV Agents/chemistry , Benzimidazoles/chemistry , HIV-1/drug effects , Receptors, CXCR4/antagonists & inhibitors , Acquired Immunodeficiency Syndrome/drug therapy , Amines/chemical synthesis , Amines/pharmacology , Aminoquinolines , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Butylamines , Cell Line, Tumor , Heterocyclic Compounds, 1-Ring/chemistry , Humans , Receptors, CXCR4/metabolismABSTRACT
Synthesis of a series of tetrahydrocarbazole amides with potent activity against human papillomaviruses is described. Synthetic approaches allowing for variation of the substitution pattern of the tetrahydrocarbazole and the amide are outlined and resulting changes in antiviral activity and certain developability parameters are highlighted. Several compounds with in vitro antiviral activity (W12 antiviral assay) in the single digit nanomolar range were identified and N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-pyridinecarboxamide was selected for further evaluation.
Subject(s)
Amides/chemical synthesis , Carbazoles/chemical synthesis , Papillomaviridae/metabolism , Administration, Oral , Amides/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Carbazoles/pharmacology , Chlorocebus aethiops , Cytochrome P-450 Enzyme System/chemistry , Dogs , Haplorhini , Humans , Inhibitory Concentration 50 , Models, Chemical , Rats , Vero CellsABSTRACT
The synthesis and SAR of a series of substituted 1-aminotetrahydrocarbazoles with potent activity against human papillomaviruses are described. Synthetic approaches allowing for variation of the substitution pattern of the tetrahydrocarbazole are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity (W12 antiviral assay) in the low nanomolar range were identified and (1R)-6-bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazole-1-amine was selected for further evaluation.
