Artemisinin-inspired novel functionalized aryloxy-arylvinyl-1,2,4-trioxanes as potent anticancer agents: Design, synthesis, bioevaluation, SAR and in silico studies

Abstract

Herein, a range of substituted aryloxy-arylvinyl-1,2,4-trioxanes (8a-8i), inspired from naturally occurring artemisinin, has been synthesized and then evaluated for their in vitro anticancer activity against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines. Out of the 34 synthesized aryloxy-arylvinyl-1,2,4-trioxanes, six compounds (8b2, 8d1, 8f2, 8f3, 8g1, 8h1) (IC50=11-37.73 µM; SI=1.7-9.6) displays promising in vitro anticancer activity. While these six compounds were proven to be more efficient and selective than those of reference standards such as artemisinin (IC50 = 100 µM) and chloroquine (IC50 = 100 µM), at the same time these were showing comparable in vitro anticancer activity with respect to one of standard reference compound artesunic acid (IC50 = 9.85 µM; SI = 0.76) against (A549) lung cancer cell line. Compound 8d1 from the series of synthesized aryloxy-arylvinyl-1,2,4-trioxanes was found out to be equipotent (IC50 = 11 µM; SI > 9) with respect to standard reference compound artesunic acid and likewise compound 8g1 (IC50 = 17.7 µM; SI > 2.4) also showed promising anticancer activity. In silico molecular docking studies of potent aryloxy-arylvinyl-1,2,4-trioxanes (8d1 & 8g1) along with standard drug molecules against the epidermal growth factor receptor (EGFR; PDB ID: 1M17) revealed a strong virtual interaction.