Synthesis, antimalarial activity, and cytotoxicity of ethyl 4-oxocyclohexane-1-carboxylate-based 1,2,4,5-tetraoxanes: an in vitro and in silico-based analysis

Abstract

In this study of antiplasmodium activity of ethyl 4-oxocyclohexane-1-carboxylate-based 1,2,4,5-tetraoxane analogs containing aromatic and alicyclic moieties, tetraoxanes were synthesized using a non-metallic approach in two steps from ethyl 4-oxocyclohexane-1-carboxylate, aromatic aldehydes, and ketones; the yields of 1,2,4,5-tetraoxane analogs varied from 29% to 54%. The newly synthesized tetraoxanes were evaluated for their in vitro antiplasmodium activity against chloroquine-sensitive (3D7) strains of Plasmodium falciparum. The compounds exhibited antiplasmodial activity ranging from 43.41 nM to 7.89 nM. Two tetraoxanes (3 and 4) had comparable antiplasmodial activity with artemisinin (5.97 nM), which was taken as a standard drug. The cytotoxicity (CC50) of the tested compounds was not detectable. The ligand binding mechanism was further corroborated using the molecular docking analysis on the most active compound, i.e., 2k, from the series of tetraoxanes having an aromatic moiety, and compounds 3 and 4 from the series of tetraoxanes having an alicyclic moiety with the active site of Plasmodium cysteine protease falcipain-2 enzyme. Among them, compound 2k showed a docking score of −4.36 kcal mol−1, and artemisinin portrayed a score of −4.46 kcal mol−1. Evidence suggests that synthesized compounds derived from tetraoxanes exhibit antiplasmodial activity, and further biological validation may be required to advance their potential for malaria treatment.