Novel saturated 6-(4′-aryloxy phenyl) vinyl 1,2,4-trioxanes 12a(1–3)–12d(1–3) and 13a(1–3)–13d(1–3) have been designed and synthesized, in one single step from diimide reduction of 11a(1–3)–11d(1–3). All the newly synthesized trioxanes were evaluated for their antimalarial activity against multi-drug resistant Plasmodium yoelii nigeriensis via oral route. Cyclopentane-based trioxanes 12b1, 12c1 and 12d1, provided 100 % protection to the infected mice at 24 mg/kg × 4 days.