Mixed tetraoxanes containing the acetone subunit as antimalarials.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Drug resistance in malaria necessitates novel therapeutic agents.
• Tetraoxanes represent a promising class of antimalarial compounds.
• Cholic acid derivatives offer a potential scaffold for drug development.

Purpose of the Study:

• To synthesize novel tetraoxane compounds incorporating a cholic acid-derived moiety.
• To evaluate the in vitro and in vivo antimalarial efficacy of these new compounds.
• To assess the antiproliferative and toxicological profiles of the synthesized tetraoxanes.

Main Methods:

• Synthesis of eleven new tetraoxanes featuring a cholic acid-derived carrier and isopropylidene group.
• In vitro screening against chloroquine-susceptible (D6) and resistant (W2) Plasmodium falciparum strains.
• In vitro evaluation against multi-drug resistant (TM91C235) strain, comparing with artemisinin and mefloquine.
• In vivo efficacy studies in mice using specific tetraoxane derivatives (amine 8, anilide 9).
• Antiproliferative assays (GI50, TGI, LC50) for compound 13.
• Toxicological assessment of all tested compounds.

Main Results:

• Nine of the eleven synthesized tetraoxanes exhibited enhanced potency against chloroquine-resistant W2 strain compared to CQ-susceptible D6 strain.
• Two compounds demonstrated equal or superior activity to artemisinin and mefloquine against the multi-drug resistant TM91C235 strain.
• Amine 8 successfully cured all mice at a dosage of 160mg/kg/day.
• Anilide 9 showed a maximum cure dose (MCD) of ≤20mg/kg/day.
• Diol 13 displayed potent antiproliferative activity with GI50, TGI, and LC50 values of 0.98 µM, 3.80 µM, and 11.22 µM, respectively.
• No toxic effects were observed for any of the tested compounds.

Conclusions:

• The novel tetraoxanes synthesized from cholic acid are effective against drug-resistant malaria strains.
• Specific derivatives show promising in vivo antimalarial activity and potent antiproliferative effects.
• The absence of toxicity suggests a favorable safety profile for further development.