The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2–15). This study produced some interesting compounds endowed with good hA3 receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA3 receptor–ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds 16–23). These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor–ligand interaction, have a very low hA3 adenosine receptor affinity, the only exception being compound 23 (1-[3-(4-methoxyphenyl)- 1-phenyl-1H-1,2,4-triazol-5-yl]-3-phenylurea) endowed with a Ki value in the micro-molar range and high hA3 selectivity versus both hA1 and hA2A AR subtypes. Evaluation of the side products obtained in the herein reported synthetic pathways led to the identification of some new triazolo[1,5- a]quinoxalines as hA3AR antagonists (compounds 24–27). These derivatives, though lacking the classical structural requirements for the anchoring at the hA3 receptor site, show high hA3 affinity and in some case selectivity versus hA1 and hA2A subtypes. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA3 receptor.

1,2,4-Triazolo[1,5-a]quinoxaline derivatives and their simplified analogues as adenosine A3 receptor antagonists. Synthesis, structure–affinity relationships and molecular modeling studies

CATARZI, DANIELA;VARANO, FLAVIA;SQUARCIALUPI, LUCIA;BETTI, MARCO;COLOTTA, VITTORIA
2015

Abstract

The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2–15). This study produced some interesting compounds endowed with good hA3 receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA3 receptor–ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds 16–23). These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor–ligand interaction, have a very low hA3 adenosine receptor affinity, the only exception being compound 23 (1-[3-(4-methoxyphenyl)- 1-phenyl-1H-1,2,4-triazol-5-yl]-3-phenylurea) endowed with a Ki value in the micro-molar range and high hA3 selectivity versus both hA1 and hA2A AR subtypes. Evaluation of the side products obtained in the herein reported synthetic pathways led to the identification of some new triazolo[1,5- a]quinoxalines as hA3AR antagonists (compounds 24–27). These derivatives, though lacking the classical structural requirements for the anchoring at the hA3 receptor site, show high hA3 affinity and in some case selectivity versus hA1 and hA2A subtypes. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA3 receptor.
9
21
Daniela Catarzi ; Flavia Varano; Daniela Poli ; Lucia Squarcialupi; Marco Betti ; Letizia Trincavelli; Claudia Martini ; Diego Dal Ben ; Ajiroghene Thomas ; Rosaria Volpini ; Vittoria Colotta
File in questo prodotto:
File Dimensione Formato  
catarziBIOMEDCHEM.pdf

Accesso chiuso

Tipologia: Pdf editoriale (Version of record)
Licenza: DRM non definito
Dimensione 2.11 MB
Formato Adobe PDF
2.11 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Catarzi_BMC_23, 9-21, 2015.pdf

accesso aperto

Tipologia: Versione finale referata (Postprint, Accepted manuscript)
Licenza: Creative commons
Dimensione 1.02 MB
Formato Adobe PDF
1.02 MB Adobe PDF Visualizza/Apri

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2158/998008
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 19
  • ???jsp.display-item.citation.isi??? 17
social impact