In this paper, the design, synthesis, and molecular modeling of a new azole-based HO-1 inhibitors was reported, using compound 1 as a lead compound, in which an imidazole moiety is linked to a hydrophobic group by means of an ethanolic spacer. The tested compounds showed a good inhibitor activity and possessed IC50values in the micromolar range. These results were obtained by targeting the hydrophobic western region. Molecular modeling studies confirmed a consolidated binding mode in which the nitrogen of the imidazolyl moiety coordinated the heme ferrous iron, meanwhile the hydrophobic groups were located in the western region of HO-1 binding pocket. Moreover, the new compounds were screened for in silico ADME-Tox properties to predict drug-like behavior with convincing results. Finally, the in vitro antitumor activity profile of compound 1 was investigated in different cancer cell lines and nanomicellar formulation was synthesized with the aim of improving compound’s 1 water solubility. Finally, compound 1 was tested in melanoma cells in combination with doxorubicin showing interesting synergic activity.

Novel structural insight into inhibitors of heme oxygenase-1 (ho-1) by new imidazole-based compounds: Biochemical and in vitro anticancer activity evaluation

Salerno Loredana
;
Amata Emanuele;Modica Maria Nunziata;Romeo Giuseppe;Marrazzo Agostino;Prezzavento Orazio;Sorrenti Valeria;Rescifina Antonio;Floresta Giuseppe;Intagliata Sebastiano;Pittalà Valeria
2018

Abstract

In this paper, the design, synthesis, and molecular modeling of a new azole-based HO-1 inhibitors was reported, using compound 1 as a lead compound, in which an imidazole moiety is linked to a hydrophobic group by means of an ethanolic spacer. The tested compounds showed a good inhibitor activity and possessed IC50values in the micromolar range. These results were obtained by targeting the hydrophobic western region. Molecular modeling studies confirmed a consolidated binding mode in which the nitrogen of the imidazolyl moiety coordinated the heme ferrous iron, meanwhile the hydrophobic groups were located in the western region of HO-1 binding pocket. Moreover, the new compounds were screened for in silico ADME-Tox properties to predict drug-like behavior with convincing results. Finally, the in vitro antitumor activity profile of compound 1 was investigated in different cancer cell lines and nanomicellar formulation was synthesized with the aim of improving compound’s 1 water solubility. Finally, compound 1 was tested in melanoma cells in combination with doxorubicin showing interesting synergic activity.
ADME-toxicity; Docking studies; HO-1; HO-1 inhibitors; HO-2; Imidazole; In silico profiling; Analytical Chemistry; Chemistry (miscellaneous); Molecular Medicine; 3003; Drug Discovery3003 Pharmaceutical Science; Physical and Theoretical Chemistry; Organic Chemistry
File in questo prodotto:
File Dimensione Formato  
molecules-23-01209.pdf

accesso aperto

Tipologia: Versione Editoriale (PDF)
Dimensione 2.27 MB
Formato Adobe PDF
2.27 MB Adobe PDF Visualizza/Apri

I documenti in IRIS 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: https://hdl.handle.net/20.500.11769/329235
Citazioni
  • ???jsp.display-item.citation.pmc??? 22
  • Scopus 38
  • ???jsp.display-item.citation.isi??? 35
social impact