No abstract

Forty-three 2-[(benzotriazol-1/2-yl)methyl]benzimidazoles, bearing either linear (dialkylamino)alkyl- or bulkier (quinolizidin-1-yl)alkyl moieties at position 1, were evaluated in cell-based assays for cytotoxicity and antiviral activity against viruses representative of two of the three genera of the Flaviviridae family, i.e. Flaviviruses (Yellow Fever Virus (YFV)) and Pestiviruses (Bovine Viral Diarrhoea Virus (BVDV)), as Hepaciviruses can hardly be used in routine cell-based assays. Compounds were also tested against representatives of other virus families. Among ssRNA+ viruses were a retrovirus (Human Immunodeficiency Virus type 1 (HIV-1)), two picornaviruses (Coxsackie Virus type B2 (CVB2), and Poliovirus type-1, Sabin strain (Sb-1)); among ssRNA- viruses were a Paramyxoviridae (Respiratory Syncytial Virus (RSV)) and a Rhabdoviridae (Vesicular Stomatitis Virus (VSV)) representative. Among double-stranded RNA (dsRNA) viruses was a Reoviridae representative (Reo-1). Two representatives of DNA virus families were also included: Herpes Simplex type 1, (HSV-1; Herpesviridae) and Vaccinia Virus (VV; Poxviridae). Most compounds exhibited potent activity against RSV, with EC(50) values as low as 20 nM. Moreover, some compounds, in particular when bearing a (quinolizidin-1-yl)alkyl residue, were also moderately active against BVDV, YFV, and CVB2.

As a follow up of an anti-Flaviviridae project, a new series of variously substituted 2-styryl-benzimidazoles were synthesized and tested in vitro for biological activity. Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Pestiviruses and Flaviviruses; ii) other RNA virus families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae) as well as for cytotoxicity tests, run in parallel with antiviral assays,against MDBK, BHK and Vero 76 cells. In the series examined, new leads emerged against BVDV, CVB-2 and RSV. Compounds 11, 12, 17, 18, 24, 31 exhibited anti-BVDV activity in the concentration range 1.7-16 microM; among them, compound 17 was the most active, with an EC(50) = 1.7 microM. Compounds 18 and 21 were equally active against CVB-2, with EC(50) values of 7 - 8 microM, while the derivative 30 was active against RSV with EC(50)= 1 microM and represents a new lead compound.

In prosecution of an anti-Flaviviridae project a new series of variously substituted 2-diphenyl-benzimidazoles were synthesized and tested in vitro for antiviral and antiproliferative activities. Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Flaviviruses and Pestiviruses; ii) other RNA virus families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae). The 5-Acetyl-2-(4'-nitrobiphenyl-4-yl)-1H-benzimidazole (24) emerged as potent active lead compound against Yellow Fever Virus (a Flavivirus) (EC(50) = 0.5 microM) and CVB-2 at 1 microM and was not cytotoxic, whereas the other title benzimidazoles showed no antiviral activity at concentrations not cytotoxic for the resting cell monolayers. Among the examined series, the most cytotoxic derivatives (11,12,14,16,18,19,20,21,23,25-30) against mock-infected MT-4 cells (CC50 < 8.0 microM) were evaluated against a panel of human cell lines derived from haematological and solid tumours,using 6-mercaptopurine (6-MP) and etoposide as reference drugs. In particular, compounds 26 and 28 showed a similar potency of 6-MP and etoposide.

Antibacterial and antifungal activity of 10-(diphenylmethylene)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives were examined by the disc-diffusion method (growth inhibition zone diameter in agar medium). The MIC’s for the most active agents were determined. Title compounds were also evaluated in vitro against representatives of different virus classes. Most of the tested compounds exhibit activity against CVB-2 virus.