Pyrazolyl amide-chalcones conjugates: Synthesis and antikinetoplastid activity

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Kinetoplastid parasites cause neglected tropical diseases like sleeping sickness and leishmaniasis.
• There is a critical need for new, effective treatments against these protozoan parasites.

Purpose of the Study:

• To synthesize and evaluate novel pyrazolyl amide-chalcone conjugates as potential anti-parasitic agents.
• To assess the in vitro activity of these compounds against medically important kinetoplastid parasites and their cytotoxicity.

Main Methods:

• A five-step synthesis was employed to create a series of pyrazolyl amide-chalcone conjugates.
• Compounds were screened in vitro against Trypanosoma cruzi, Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense, and Leishmania infantum.
• Cytotoxicity was evaluated against human lung fibroblasts and primary mouse macrophages.

Main Results:

• Compound 9b exhibited potent activity against Trypanosoma brucei brucei (IC50 = 0.51 ± 0.06 μM).
• Compound 9n demonstrated the highest potency against Trypanosoma brucei rhodesiense (IC50 = 0.46 ± 0.07 μM).
• Compound 9a was the most active against Leishmania infantum (IC50 = 7.16 ± 1.88 μM).

Conclusions:

• Pyrazolyl amide-chalcone conjugates represent a promising scaffold for developing new anti-kinetoplastid agents.
• Structure-activity relationship (SAR) analysis suggests potential for further optimization to enhance potency and selectivity.
• Future modifications are planned to improve the efficacy of these compounds against neglected tropical diseases.