Bovine viral diarrhea virus (BVDV) is a pestivirus whose infection in cattle is globally distributed being endemic in many countries. The use of antivirals could complement vaccination as a tool of control and reduce economic losses.
We have identified potential molecules that dock into the allosteric binding pocket of BVDV RdRp via structure-based virtual screening approach. Five of these compounds resulted active against BVDV in vitro and displayed EC50 values in the sub and low-micromolar range. One of them, N-(2-morpholinoethyl)-2-phenylquinazolin-4-amine (EC50= 9.68 ± 0.49 µM), was selected to perform different chemical modifications in order to improve its antiviral profile. Thirty-nine derivatives were obtained, seven of which showed improved antiviral activity. Between them, 2-(4-(2-phenylquinazolin-4-yl)piperazin-1-yl)ethanol afforded the best values of antiviral activity and selectivity index (SI) and their physicochemical properties was examined in vitro, in terms of solubility and stability.
The solubility (S) of the last compound was evaluated at pH 1.2, 6.8, and 7.4, employing the shake flask method by UV spectroscopy, while the stability was tested in mouse plasma by HPLC. The compound presented good solubility values at pH 1.2, 6.8 and 7.4, which were in concordance within the range normally observed for oral drugs, i.e., 4-4000 µg/mL (corresponding to S values ranging from 10-2 to 10-5 M for molecules with a molecular weight of 400). Stability studies in mouse plasma showed that the compound is stable at least for 120 min.
