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

Abstract

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.

A combined in silico / in vitro approach unveils common molecular requirements for efficient BVDV RdRp binding of linear aromatic N-polycyclic systems

“…Finally, although some new compounds showed a modest and scattered activity against other than BVDV viruses (Table S1) Ordinarily, the development of a pharmacophore model aims at creating a powerful tool for the design of new and possibly more potent molecules with respect to a specific target. In this work, however, the common feature pharmacophore approach was exploited to identify the molecular requirements shared by all series of compounds (i.e., previously synthesized B-F series [23,24], In the successive step, taking advantage of (i) the ligand-binding pharmacophoric requirements determined above, and (ii) the binding mode of compound D2 onto the BVDV RdRp described in our previous work, [25] we docked and scored the free energy of binding ∆G bind for compounds…”

“…Briefly, for compound D2 we already located a putative binding pocket located between the BVDV RdRp fingers domains 1 and 2 (residues 139-313 and 351-410, respectively). [25] By applying a consolidated molecular dynamic (MD) computational recipe, [27,28] some specific interactions between the pyridoquinoxaline derivative D2 and the critical RdRp binding site residues were identified. In details, the aromatic portions of D2 are encased in two receptor cavities comprising residues A221, I261, I287, Y289 and V216, Y303, V306, K307, P408 and A412, respectively.…”

“…8). For the record, the thiophene ring of D2 was involved -through its sulfur atom -in a further HB with S411; however, since the strength of this additional HB was weaker compared to the other two polar interactions, [25] it was classified as a secondary requirement for binding optimization.…”

“…Compound models energy minimization was performed with the CHARMM forcefield [31] and the classical conformational search was carried out using the Poling algorithm [32] as [35] as previously described. [25,27,28] Accordingly, the best energy configuration of each complex wassubsequently solvated by a cubic box of TIP3P [36] water molecules extending at least 10 Å in each direction from the solute. The system was neutralized and the solution ionic strength was adjusted to the physiological value of 0.15 M by adding the required amounts of Na + and Clions.…”

“…inhibition. [25] To expand the SAR investigation on the above linear N-tricyclic systems, in the present paper we initially designed and synthesized new imidazo [4,5-…”