Synthesis, Antiproliferative Activity, and Pre-Admet Studies of P-Aminophenyl Substituted Benzoxazole Derivatives Designed Based on Phortress

Abstract

In this study, a series of p-aminophenyl substituted benzoxazole derivatives were designed based on the pro-drug phortress structure, a clinical candidate in anticancer drug research. The benzothiazole structure in the phortress was replaced with benzoxazole using the bioisosterism approach, and the p-amino group in its active metabolites was substituted with the N,N-dimethyl amino or piperidino group. The antiproliferative effect of the synthesized compounds on A549, HepG2, Caco-2, and PANC-1 cancer cells was compared to that on CCD-34Lu healthy cells. The results revealed higher antiproliferative effects of the compounds against HepG2 and Caco-2 cells. Among the compounds, compounds 5 (SI > 2.81) and 10 (SI > 2.45) exhibited good antiproliferative effects for HepG2 cells, while compounds 1 (SI = 2.70), 2 (SI = 2.59), 4 (SI > 2.77), and 5 (SI > 2.32) demonstrated notable antiproliferative effects for Caco-2 cells. It is important to note that, although their selectivity indexes were lower than the reference drug doxorubicin (SI > 3.63 for HepG2 and SI > 20 for Caco-2), these compounds still showed promising results. Additionally, predicted absorption, distribution, metabolism, excretion, and toxicity studies suggest that the lead compounds (1, 2, 4, 5, and 10) may have suitable pharmacokinetic properties as potential drug candidates. These results may contribute to future anticancer drug research.