Design, Synthesis, Structure‐Activity Relationship and Docking Studies of Novel Functionalized Arylvinyl‐1,2,4‐Trioxanes as Potent Antiplasmodial as well as Anticancer Agents

Abstract A novel series of synthetic functionalized arylvinyl‐1,2,4‐trioxanes ( 8 a – p ) has been prepared and assessed for their in vitro antiplasmodial activity against the chloroquine‐resistant Pf INDO strain of Plasmodium falciparum by using a SYBR green‐I fluorescence assay. Compounds 8 g (IC 50 =0.051 μM; SI=589.41) and 8 m (IC 50 =0.059 μM; SI=55.93) showed 11‐fold and >9‐fold more potent antiplasmodial activity, respectively, as compared to chloroquine (IC 50 =0.546 μM; SI=36.63). Different in silico docking studies performed on many target proteins revealed that the most active arylvinyl‐1,2,4‐trioxanes ( 8 g and 8 m ) showed dihydrofolate reductase (DHFR) binding affinities on a par with those of chloroquine and artesunate. The in vitro cytotoxic potentials of 8 a – p were also evaluated against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS‐2B) and liver (LO2) cell lines. Following screening, five derivatives viz. 8 a , 8 h , 8 l , 8 m and 8 o (IC 50 =1.65–31.7 μM; SI=1.08–10.96) were found to show potent cytotoxic activity against (A549) lung cancer cell lines, with selectivity superior to that of the reference compounds artemisinin (IC 50 =100 μM), chloroquine (IC 50 =100 μM) and artesunic acid (IC 50 =9.85 μM; SI=0.76). In fact, the most active 4‐naphthyl‐substituted analogue 8 l (IC 50 =1.65 μM; SI >10) exhibited >60 times more cytotoxicity than the standard reference, artemisinin, against A549 lung cancer cell lines. In silico docking studies of the most active anticancer compounds, 8 l and 8 m , against EGFR were found to validate the wet lab results. In summary, a new series of functionalized aryl‐vinyl‐1,2,4‐trioxanes ( 8 a – p ) has been shown to display dual potency as promising antiplasmodial and anticancer agents.