By the antiviral screening of an in house library of pyrazoline compounds, 4-(3-(4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide (5a) was identified as a promising hit compound for the development of anti- Yellow Fever Virus (YFV) agents. Structural optimization studies were focused on the development of 5a analogues which retain the potency as YFV inhibitors and show a reduced cytotoxicity. The synthesized 1-3,5-triphenyl-pyrazolines (4a-j, 5a-j, 6a-j) were evaluated in cell based assays for cytotoxicity and antiviral activity against representative viruses of two of the three genera of the Flaviviridae family, i.e.: Pestivirus (BVDV) and Flavivirus (YFV). These compounds were also tested against a large panel of different pathogenic RNA and DNA viruses. Most of the new 1-3,5-triphenyl-pyrazolines (4a-j, 5a-j, 6a-j) exhibited a specific activity against YFV, showing EC50 values in the low micromolar range with almost a 10-fold improvement in potency compared to the reference inhibitor 6-azauridine. However, the selectivity indexes of the unsubstituted (4a-j) and the phenoxy (5a-j) analogues were generally modest due to the pronounced cytotoxicity against BHK-21 cells. Otherwise, the benzyloxy derivatives (6a-j) generally coupled high potency and selectivity. On the basis of both anti-YFV activity and selectivity index, pyrazolines 6a and 6b were chosen for time of addition experiments. The selected pyrazolines and the reference inhibitor 6-azauridine displayed maximal inhibition when added in the pretreatment or during the infection.

Inhibitors of Yellow Fever Virus replication based on 1,3,5-triphenyl-4,5-dihydropyrazole scaffold: Design, synthesis and antiviral evaluation / Fioravanti, R.; Desideri, N.; Carta, A.; Atzori, E. M.; Delogu, I.; Collu, G.; Loddo, R.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 141:(2017), pp. 15-25. [10.1016/j.ejmech.2017.09.060]

Inhibitors of Yellow Fever Virus replication based on 1,3,5-triphenyl-4,5-dihydropyrazole scaffold: Design, synthesis and antiviral evaluation

Carta A.;
2017

Abstract

By the antiviral screening of an in house library of pyrazoline compounds, 4-(3-(4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide (5a) was identified as a promising hit compound for the development of anti- Yellow Fever Virus (YFV) agents. Structural optimization studies were focused on the development of 5a analogues which retain the potency as YFV inhibitors and show a reduced cytotoxicity. The synthesized 1-3,5-triphenyl-pyrazolines (4a-j, 5a-j, 6a-j) were evaluated in cell based assays for cytotoxicity and antiviral activity against representative viruses of two of the three genera of the Flaviviridae family, i.e.: Pestivirus (BVDV) and Flavivirus (YFV). These compounds were also tested against a large panel of different pathogenic RNA and DNA viruses. Most of the new 1-3,5-triphenyl-pyrazolines (4a-j, 5a-j, 6a-j) exhibited a specific activity against YFV, showing EC50 values in the low micromolar range with almost a 10-fold improvement in potency compared to the reference inhibitor 6-azauridine. However, the selectivity indexes of the unsubstituted (4a-j) and the phenoxy (5a-j) analogues were generally modest due to the pronounced cytotoxicity against BHK-21 cells. Otherwise, the benzyloxy derivatives (6a-j) generally coupled high potency and selectivity. On the basis of both anti-YFV activity and selectivity index, pyrazolines 6a and 6b were chosen for time of addition experiments. The selected pyrazolines and the reference inhibitor 6-azauridine displayed maximal inhibition when added in the pretreatment or during the infection.
Inhibitors of Yellow Fever Virus replication based on 1,3,5-triphenyl-4,5-dihydropyrazole scaffold: Design, synthesis and antiviral evaluation / Fioravanti, R.; Desideri, N.; Carta, A.; Atzori, E. M.; Delogu, I.; Collu, G.; Loddo, R.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 141:(2017), pp. 15-25. [10.1016/j.ejmech.2017.09.060]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

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/11388/244281
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 11
  • ???jsp.display-item.citation.isi??? 9
social impact