RESUMO
In search of new anti-tuberculars compatible with anti-retroviral therapy we re-identified amicetin as a lead compound. Amicetin's binding to the 70S ribosomal subunit of Thermus thermophilus (Tth) has been unambiguously determined by crystallography and reveals it to occupy the peptidyl transferase center P-site of the ribosome. The amicetin binding site overlaps significantly with that of the well-known protein synthesis inhibitor balsticidinâ S. Amicetin, however, is the first compound structurally characterized to bind to the P-site with demonstrated selectivity for the inhibition of prokaryotic translation. The natural product-ribosome structure enabled the synthesis of simplified analogues that retained both potency and selectivity for the inhibition of prokaryotic translation.
Assuntos
Antituberculosos/química , Desenho de Fármacos , Peptídeos/química , Piranos/química , Animais , Antituberculosos/farmacologia , Chlorocebus aethiops , Cristalografia por Raios X , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Nucleosídeos de Pirimidina/química , Células THP-1 , Thermus thermophilus/química , Células VeroRESUMO
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.
Assuntos
Aminas/química , Fármacos Anti-HIV/química , Benzimidazóis/química , HIV-1/efeitos dos fármacos , Receptores CXCR4/antagonistas & inibidores , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Aminas/síntese química , Aminas/farmacologia , Aminoquinolinas , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Butilaminas , Linhagem Celular Tumoral , Compostos Heterocíclicos com 1 Anel/química , Humanos , Receptores CXCR4/metabolismoRESUMO
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.
Assuntos
Amidas/síntese química , Carbazóis/síntese química , Papillomaviridae/metabolismo , Administração Oral , Amidas/farmacologia , Animais , Antivirais/síntese química , Antivirais/farmacologia , Carbazóis/farmacologia , Chlorocebus aethiops , Sistema Enzimático do Citocromo P-450/química , Cães , Haplorrinos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Ratos , Células VeroRESUMO
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.