Glioblastomas are highly aggressive brain tumors for which therapeutic options are very limited. In a quest for new anti-glioblastoma drugs, we focused on specific structural modifications of benzoyl-phenoxy-acetamide (BPA) present in a common lipid-lowering drug, fenofibrate, and in our first prototype glioblastoma drug, PP1. Here, we propose extensive computational analyses to improve selection of the most effective glioblastoma drug candidates. Initially over 100 structural BPA variations were analyzed and their physicochemical properties such as water solubility (-logS), calculated partition coefficient (ClogP), probability for BBB crossing (BBB_SCORE), probability for CNS penetration (CNS-MPO) and calculated cardiotoxicity (hERG), were evaluated. This integrated approach allowed us to select pyridine variants of BPA that show improved BBB penetration, water solubility, and low cardiotoxicity. Herein the top 24 compounds were synthesized and analyzed in cell culture. Six of them demonstrated glioblastoma toxicity with IC50 ranging from 0.59 to 3.24mM. Importantly, one of the compounds, HR68, accumulated in the brain tumor tissue at 3.7+/-0.5mM, which exceeds its glioblastoma IC50 (1.17mM) by over 3-fold.