Design, synthesis and in vitro assessment of di-/tri-methoxy-aryl-substituted mono-spiro-1,2,4,5-tetraoxanes for antiplasmodial and anticancer use

In the present article, a library of novel non-symmetrical di- / tri -methoxy-aryl-substituted mono-spiro-1,2,4,5-tetraoxanes ( 5a - m ) has been prepared from methyltrioxorhenium(VII) complex-catalysed two-step one-pot direct oxidation approach. The in vitro antiplasmodial and cytotoxic potentials of all non-symmetrical di- / tri -methoxy-aryl-substituted mono-spiro-1,2,4,5-tetraoxanes ( 5a-m ) have been assessed against the chloroquine-resistant FcB1 strain of Plasmodium falciparum , HeLa, A549 and A2780 cancer cells. The in vitro biological assessment has afforded eight di- / tri -methoxy-aryl-substituted mono-spiro-1,2,4,5-tetraoxane derivatives ( 5b - e , 5g , 5i , 5k - l ) with nanomolar antiplasmodial activity (IC 50 = 34–91 nM and Selectivity Index = 109–2900). Along with this, two tri -OMe-aryl substituted mon-spiro-1,2,4,5-tetraoxane analogues ( 5i and 5l ) have also shown dual potency with strong antiplasmodial ( 5i , IC 50 = 46 nM; 5l , IC 50 = 48 nM), and in vitro micromolar cytotoxicity against the A2780 ovarian cancer ( 5i , IC 50 = 3.82 μ M; 5l , IC 50 = 1.98 μ M) and HeLa cells ( 5i , LD 50 = 10.85 μ M; 5l , LD 50 = 5.8 μ M). In addition, potential drug-target interactions prediction for representative compounds ( 5d , 5i , and 5l ) has been examined using different computational-based techniques. Through this study, the selective incorporation of functionalized di- / tri -methoxy-aryl moieties on the mon-spiro-1,2,4,5-tetraoxane skeleton has proved efficient in improving the overall biological activities of the resulting molecules.