Compound 5l(Poznan University of Medical Sciences)

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 (IC₅₀ = 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, IC₅₀ = 46 nM; 5l, IC₅₀ = 48 nM), and in vitro micromolar cytotoxicity against the A2780 ovarian cancer (5i, IC₅₀ = 3.82 μM; 5l, IC₅₀ = 1.98 μM) and HeLa cells (5i, LD₅₀ = 10.85 μM; 5l, LD₅₀ = 5.8 μM). 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.