Antiviral activity of benzimidazole derivatives. III. Novel anti-CVB-5, anti-RSV and anti-Sb-1 agents.

A library of eighty-six assorted benzimidazole derivatives was screened for antiviral activity against a panel of ten RNA and DNA viruses. Fifty-two of them displayed different levels of activity against one or more viruses, among which CVB-5, RSV, BVDV and Sb-1 were the most frequently affected. In particular, fourteen compounds exhibited an EC50 in the range 9-17µM (SI from 6 to >11) versus CVB-5, and seven compounds showed an EC50 in the range 5-15µM (SI from 6.7 to ⩾20) against RSV, thus resulting comparable to or more potent than the respective reference drugs (NM108 and ribavirin). Most of these compounds derive from 2-benzylbenzimidazole, but also other molecular scaffolds [as 1-phenylbenzimidazole (2), 2-trifluoromethylbenzimidazole (69), dihydropyrido[3',2':4,5]imidazo[1,2-a][1,4]benzodiazepin-5-one (3), dibenzo[c,e]benzimidazo[1,2-a]azepine (22), and 2-(tetrahydropyran-2-yl)benzimidazole (81, 82 and 86)] are related to interesting levels of activity against these or other viruses (BVDV, Sb-1). Thus, these scaffolds (some of which, so far unexplored), represent valid starting points to develop more efficient agents against pathologies caused by CVB-5, RSV, BVDV and Sb-1 viruses.

Cytotoxic phloroglucinols from the leaves of Myrtus communis.

Bioactivity-guided fractionation of a dichloromethane extract of the leaves of Myrtus communis led to the isolation of phloroglucinol derivatives. The structures of the new myrtucommulones J, K, and L (1-3) and the previously known myrtucommulone A (4) were elucidated on the basis of extensive 1D and 2D NMR experiments as well as high-resolutionmass spectrometry. Myrtucommulone J was obtained as a tautomeric pair (1/1a). The compounds were tested in vitro for their cytotoxic and antibacterial activities.

Synthesis, cytotoxicity and antiviral evaluation of new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives.

Linear aromatic N-tricyclic compounds with promising antiviral activity and minimal cytotoxicity were prepared and analyzed in the last years. Specifically, the pyrido[2,3-g]quinoxalinone nucleus was found endowed with high potency against several pathogenic RNA viruses as etiological agents of important veterinary and human pathologies. Following our research program on new antiviral agents we have designed, synthesized and assayed new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives. Lead compounds 1-4 were further modified to enhance their antiviral activity and reduce their cytotoxicity. Thus, different substituents were introduced on N atom at position 1 or the O atom at position 2 of the leads; contextually, several groups were inserted on the nitrogen atom at position 7 of diaminoquinoline intermediates. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against RNA virus families containing single-stranded (either positive-sense (ssRNA+) or negative-sense (ssRNA-)), and double-stranded genomes (dsRNA), and against two representatives of DNA virus families. Some derivatives emerged as potential leads for further development as antiviral agents against some viruses of public health significance, such as RSV, Reo, BVDV and HCV. Particularly, compounds 4, 11b, 11c, 13c, 15a, 18 and 21 resulted active against BVDV at concentrations ranging from 1.3 to 5 µM. Compound 21 was also evaluated for its activity on the BVDV RdRp. Compound 4 was also tested as potential anti-HCV compound in a subgenomic replication assay. Molecular simulation results provided a molecular rationale for the anti-BVDV activity of these compounds.

Synthesis and antiviral activity of new phenylimidazopyridines and N-benzylidenequinolinamines derived by molecular simplification of phenylimidazo[4,5-g]quinolines.

Continuing our program of research concerning the antiviral activity of a wide series of new angular and linear azolo bicyclic and tricyclic derivatives, now we have simplified and modified the 4-chloro-2-(4-nitrophenyl)-3H-imidazo[4,5-g]quinoline 1, which previously resulted the most active derivative, through either the elimination of the central ring or the opening of the imidazole ring, obtaining various imidazopyridines and N-benzylidenequinolinamines respectively. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against representatives of two DNA virus families as wells as against representatives of RNA virus families containing single-stranded, either positive-sense (ssRNA(+)) or negative-sense (ssRNA(-)), and double-stranded genomes (dsRNA). Some imidazo[4,5-b]pyridines emerged as new derivatives endowed with antiviral activity against Vaccinia Virus (VV) at concentrations ranging from 2 to 16 µM. In particular, compound 2b demonstrate to be about 10 times more potent than Cidofovir, used as reference drug. Similarly, the imidazo[4,5-c]pyridines and N-benzylidenequinolinamines derivatives resulted active against Bovine Viral Diarrhoea virus (BVDV), at concentrations ranging from 1.2 to 28 µM. Above all compounds 1, 3a and 3f showed an EC50 of the same order of magnitude of the reference drug, the 2'-C-methyl-guanosine. Moreover, several N-benzylidenequinolinamines showed an interesting activity against Respiratory Syncytial Virus (RSV) at concentrations between 12 and 26 µM.

5-acetyl-2-arylbenzimidazoles as antiviral agents. Part 4.

Within a project aimed at discovering new Flaviviridae inhibitors, new variously substituted 2-phenylbenzimidazoles were synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against viruses representatives of the three genera of the Flaviviridae family, i.e.: Pestivirus (BVDV), Flavivirus (YFV) and Hepacivirus (HCV). Title compounds were also tested against RNA viruses representative of other single-stranded, positive-sense (ssRNA(+)) negative-sense (RNA(-)), or double-stranded (dsRNA) genomes, as well as against representatives of two DNA virus families. Nine compounds showed activity against BVDV (EC(50) = 0.8-8.0 µM), compound 31 being the most potent (EC(50) = 0.80 µM) and selective (SI = CC(50)/EC(50) = >100). When tested in an HCV replicon assay, compound 31 resulted again the most potent, displaying an EC(50) value of 1.11 µM and an SI of 100. Besides inhibiting BVDV, two compounds (35 and 38) showed a moderate activity also against YFV (EC(50) = 13 µM). Interestingly, 35 was moderately active also against RSV (EC(50) = 25 µM).

Acridine derivatives as anti-BVDV agents.

Twenty-six 9-aminoacridine derivatives were evaluated in cell-based assays for cytotoxicity and antiviral activity against a panel of 10 RNA and DNA viruses. While seven compounds (9, 10, 14, 19, 21, 22, 24) did not affect any virus and two (6, 11) were moderately active against CVB-5 or Reo-1, 17 compounds exhibited a marked specific activity against BVDV, prototype of pestiviruses which are responsible for severe diseases of livestock. Most anti-BVDV agents showed EC(50) values in the range 0.1-8 µM, thus comparing favorably with the reference drugs ribavirine and NM 108. Some compounds, particularly those bearing a quinolizidinylalkyl side chain, displayed pronounced cytotoxicity. Further studies are warranted in order to achieve still better anti-BVDV agents, and to explore the potential antiproliferative activity of this kind of compounds.