Enantioselective Synthesis and in Vivo Evaluation of Regioisomeric Analogues of the Antimalarial Arterolane

Abstract

We describe the first systematic study of antimalarial 1,2,4-trioxolanes bearing a substitution pattern regioisomeric to that of arterolane. Conformational analysis suggested that trans-3″-substituted trioxolanes would exhibit Fe(II) reactivity and antiparasitic activity similar to that achieved with canonical cis-4″ substitution. The chiral 3″ analogues were prepared as single stereoisomers and evaluated alongside their 4″ congeners against cultured malaria parasites and in a murine malaria model. As predicted, the trans-3″ analogues exhibited in vitro antiplasmodial activity remarkably similar to that of their cis-4″ comparators. In contrast, efficacy in the Plasmodium berghei mouse model differed dramatically for some of the congeneric pairs. The best of the novel 3″ analogues (e.g., 12i) outperformed arterolane itself, producing cures in mice after a single oral exposure. Overall, this study suggests new avenues for modulating Fe(II) reactivity and the pharmacokinetic and pharmacodynamic properties of 1,2,4-trioxolane antimalarials.

Increasing the Strength and Production of Artemisinin and Its Derivatives

“…It has been observed that making modifications in bond rigidity, adding different groups like amines, etc., can increase the potency against the resistant species [ 114 ]. It was also noted that changing the stereochemistry and position of different groups attached to the nucleus of drugs can enhance the antiplasmodial efficacy [ 115 ]. For example a stereoisomeric analogue ( Figure 7 c) of arterolane is more potent than the arterolane itself [ 115 ].…”

“…It was also noted that changing the stereochemistry and position of different groups attached to the nucleus of drugs can enhance the antiplasmodial efficacy [ 115 ]. For example a stereoisomeric analogue ( Figure 7 c) of arterolane is more potent than the arterolane itself [ 115 ].…”

“… ( a ) Chemical structure of artefenomel and its optimized tertiary amine analogues [ 105 ]; ( b ) arterolane; ( c ) arterolane analogue that has higher antiplasmodial activity than arterolane [ 115 ]. …”

Artemisinin inspired synthetic endoperoxide drug candidates: Design, synthesis, and mechanism of action studies

“…Therefore the peroxide bond is more exposed and consequently more susceptible to premature activation (Figure 12C). 125 Heme has been reported as an alkylation target of the antimalarial 1,2,4-trioxolanes, as observed in artemisinins. The reaction of OZ277 with heme gave the covalent heme adduct 85 120,121,126 (Figure 12D).…”

Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold

“…[6][7][8] Spurred by thesec oncerning indicators, the scientific community is actively seeking alternative treatments. In analogy to artemisinin (1), potent inhibitors containing ap harmacophoric peroxide bond have been investigated, such as artemisone( 2); [9] E209 (3); [10] artefenomel (4); [11] as well as arterolane (5) [12] and its regioisomeric analogues, including aminopiperidine 6 [13] (for structures, see SectionS1, Figure S1 in the Supporting Information). Promising efficacy was also achieved with non-endoperoxide scaffolds,i ncluding NITD609 (7), [14,15] KAF156 (8), [16][17][18][19][20] DSM265 (9), [21,22] and aminoxadiazole-based ligands (Supporting Information, Section S1, Figure S2).…”