Antimalarial Bicyclic Peroxides Belonging to the G-Factor Family: Mechanistic Aspects of their Formation and Iron (II) Induced Reduction

Abstract

Artemisinin and its derivatives are peroxide-containing compounds targeting P. falciparum. We review here structural analogues of bicyclic peroxides belonging to the G factors family presenting antimalarial properties. They were synthesised under Mannich type conditions, followed by an autoxidation step resulting exclusively in the peroxide. As the electron transfer from haem or free iron to the peroxide is the first step in the mode of action of artemisinin-like compounds, the redox properties of some endoperoxides were studied by electrochemistry allowing the evaluation of the reduction standard potentials. The Fe(II) induced reduction was also investigated and the reactivity of the C-centered radical intermediate formed was linked to the antimalarial activity. These bicyclic peroxides both with various hybrid molecules containing the endoperoxide framework were evaluated in vitro against Plasmodium falciparum. They exhibited moderate to good activities.

Synthesis and Antiplasmodial Activity of Novel Fosmidomycin Derivatives and Conjugates with Artemisinin and Aminochloroquinoline

“…In this respect, five compounds were synthesized, two of them bearing the ACQ and three the ART moiety (compounds 19 – 20 ( Scheme 2 ) and 21 – 23 , respectively, Scheme 3 and Scheme 4 ). For the FSM-ACQ conjugates, two different ACQ amine derivatives ( 44 and 45 ), bearing a piperazine or an ethylenediamine linker attached in position 4 of the 4,7-dichloroquinoline [ 38 ], were prepared. While coupling of O -benzyl compound 42 with the piperazino chloroquinoline 44 worked well, the following cleavage of the benzyl group proved to be harsh, affording a mixture of compounds, where hydrogenolysis of the quinoline group was also observed.…”

Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity

“…25 An alternative synthesis of this key-intermediate has been described. 15 Finally for the needs of the present work, the N 1 -(7-chloroquinolin-4-yl)ethane-1,2-diamine (15) and the 7-chloro-4-(piperazin-1-yl)quinoline ( 16) were readily obtained in 56% and 76% yield, respectively, from the commercially available 4,7-dichloroquinoline through the nucleophilic aromatic substitution of the latter with 1,2-diaminoethane and piperazine, respectively 17 ditritylhomospermidine (19). These compounds are readily available, in 48% overall yield, from butane-1,4-diamine (putrescine, Put) through a three-steps sequence depicted in Scheme S1 (Supporting Information).…”

“…For many years now, we have been interested in the naturally occurring phytormones known as G- factors ( G1 , G2 , G3 ) synthesized from syncarpic acid and incorporating an endocyclic endoperoxide frame . The natural compounds and many synthetic analogs have been synthesized. , Among them, the methylated compound G3Me (Figure ) and its derivatives have been shown to be potent antimalarial agents. In particular, the G3Me-derived amino-endoperoxide spiro compound (endoperoxide GMeP, 3 ), suitable for the synthesis of G factor hybrids through a succinic acid type linker (compound 4 ), has been developed and two compounds also incorporating CQ proved to be very active …”

“…The natural compounds and many synthetic analogs have been synthesized. , Among them, the methylated compound G3Me (Figure ) and its derivatives have been shown to be potent antimalarial agents. In particular, the G3Me-derived amino-endoperoxide spiro compound (endoperoxide GMeP, 3 ), suitable for the synthesis of G factor hybrids through a succinic acid type linker (compound 4 ), has been developed and two compounds also incorporating CQ proved to be very active …”

“…Hybrid molecules have probably less chance to develop drug resistance . Examples of ART–CQ ( S1 - S2 ) , or a G-factor–CQ ( S3 ) hybrids, and of conjugates ( S4–S6 ) of ART with the naturally occurring polyamines (PAs), e.g. spermidine (Spd) or spermine (Spm), − of relevance to the present work are provided in Figure S1.…”