Two-Step Synthesis of Achiral Dispiro-1,2,4,5-tetraoxanes with Outstanding Antimalarial Activity, Low Toxicity, and High-Stability Profiles

Abstract

A rapid, two-step synthesis of a range of dispiro-1,2,4,5-tetraoxanes with potent antimalarial activity both in vitro and in vivo has been achieved. These 1,2,4,5-tetraoxanes have been proven to be superior to 1,2,4-trioxolanes in terms of stability and to be superior to trioxane analogues in terms of both stability and activity. Selected analogues have in vitro nanomolar antimalarial activity and good oral activity and are nontoxic in screens for both cytotoxicity and genotoxicity. The synthesis of a fluorescent 7-nitrobenza-2-oxa-1,3-diazole (NBD) tagged tetraoxane probe and use of laser scanning confocal microscopy techniques have shown that tagged molecules accumulate selectively only in parasite infected erythrocytes and that intraparasitic formation of adducts could be inhibited by co-incubation with the iron chelator desferrioxamine (DFO).

Antimalarial Mannoxanes: Hybrid Antimalarial Drugs with Outstanding Oral Activity Profiles and A Potential Dual Mechanism of Action

“…A variety of amines were investigated in our structure-activity relationship (SAR) analyses, and cyclohexyl, adamantyl and menthyl fused ring systems were explored (Table 1 and table S1, Supporting Information). As noted previously in our tetraoxane SAR, [3,11] whilst the cyclohexyl and menthyl ring fusion provides analogues with low nanomolar activity (< 30 nm in most cases), the best activity levels were seen for the adamantylidene fused mannoxanes with activity consistently in the single digit nanomolar range. Given the promising activity seen, we expanded this set to cover fourteen mono-Mannich analogues.…”

“…No drug 6.0 (6,6,6) 0 11 9.0 (9,9,9,9,9) 55.2 17 15.2 (14,15,15,15,16,16) 99.8 Amodiaquine (8) 11.2 (9,11,11,12,13) 100.0 Amodiaquine + 11 [a] 8.2 (7,7,8,8,11) 87.7 Artesunate (2) 8.2 (7,8,8,9,9) 99.1…”

Reactions of Antimalarial Peroxides with Each of Leucomethylene Blue and Dihydroflavins: Flavin Reductase and the Cofactor Model Exemplified

“…Thus, the much-publicized chemical reactions of artemisinins with heme represents an attrition pathway for artemisinins in the intraparasitic environment. [11,12] 1,2,4,5-Tetraoxanes such as 4 and 5 [13,14] and 1,2,4-trioxolanes such as 6, [15,16] have potent antimalarial activities ( Figure 1). Although the reactivity of 6 with Fe II was not assessed, other trioxolanes are readily decomposed.…”

“…Although the reactivity of 6 with Fe II was not assessed, other trioxolanes are readily decomposed. [14,16,17] The arylsulfonamide tetraoxane 5 is remarkably resistant to Fe II under anhydrous conditions (1.0 equiv FeBr 2 in THF to 48 h). [14] Nevertheless, 'ferrous iron-reductive bio-activation' for the tetraoxanes is maintained by those that made this striking observation; [18] this requires Fe II , relatively transient under normoxic aqueous conditions and likely bearing oxygen ligands within the intraparasitic labile iron pool, [19] to be appreciably more active in vivo in generating carbon radicals than a pumped-up anhydrous Fe II halide, present at much higher concentrations in an organic solvent in an inert atmosphere in a laboratory flask.…”

Alternative conditions for the synthesis of novel spiro[1,3-N,N-heterocyclic-adamantanes]

“…2 The 1-adamantyl group is crucial for the antiparasitic activity of 1,2,4-trioxane derivatives, 3 and replacement of the 2-(adamantan-1-yl)acetyl group with other hydrophobic moieties abolished the anti-EboV activity of a new class of antiviral dipeptides. 4 The incorporation of a spiroadamantane unit into 1,2,4-trioxanes 5 and 1,2,4,5-tetraoxanes 6 enhanced the antimalarial activity, together with low toxicity and high stability profiles both in vitro and in vivo. In the search for new analogues of adamantine and rimantadine, a number of six-membered spiroadamantane rings bearing one or two nitrogens, has been prepared.…”