Methoxylated 2'-hydroxychalcones as antiparasitic hit compounds.

Area of Science:

• Medicinal Chemistry
• Parasitology
• Pharmacology

Background:

• Chalcones are known for diverse pharmacological effects.
• Neglected tropical diseases like African sleeping sickness require new treatments.

Purpose of the Study:

• To synthesize and evaluate 2'-hydroxy methoxylated chalcones against Trypanosoma brucei, Trypanosoma cruzi, and Leishmania infantum.
• To identify potent and selective drug candidates for trypanosomiasis.

Main Methods:

• Synthesis of a library of 2'-hydroxy methoxylated chalcones.
• In vitro screening against Trypanosoma brucei, T. cruzi, and L. infantum.
• Pharmacokinetic studies in BALB/c mice.

Main Results:

• Compounds 1, 3, 4, 7, and 8 exhibited potent and selective anti-T. brucei activity (EC50 = 1.3–4.2 μM, SI >10).
• Compound 4 displayed the most favorable early-toxicity and antiparasitic profile.
• Formulation of compound 4 with hydroxypropyl-β-cyclodextrins increased oral bioavailability 7.5-fold in mice.

Conclusions:

• 2'-hydroxy methoxylated chalcones are promising leads for anti-trypanosomal drug discovery.
• Compound 4 warrants further investigation as a potential therapeutic agent for African sleeping sickness.
• Enhanced oral bioavailability of compound 4 is achievable through formulation strategies.