Novel Harmicines with Improved Potency against Plasmodium.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Parasitology

Background:

• Harmicines are hybrid compounds combining harmine and cinnamic acid derivatives (CADs).
• Understanding structure-activity relationships is crucial for developing new antimalarial drugs.

Purpose of the Study:

• To synthesize novel amide-type harmicines.
• To evaluate their antimalarial activity against Plasmodium falciparum and Plasmodium berghei.
• To assess their cytotoxicity and selectivity against human liver cancer cells.

Main Methods:

• Synthesis of N-harmicines (5a-f) and O-harmicines (6a-h) using HATU and DIEA coupling conditions.
• In vitro evaluation of antimalarial activity against erythrocytic and hepatic stages.
• Cytotoxicity assays using the HepG2 cell line.
• Molecular dynamics simulations to elucidate binding mechanisms.

Main Results:

• Amide-type harmicines demonstrated significant activity against the erythrocytic stage of P. falciparum in submicromolar concentrations.
• Compounds showed higher activity against erythrocytic stages compared to hepatic stages.
• Favorable selectivity indices were observed against HepG2 cells.
• Molecular dynamics simulations identified binding within the ATP binding site of PfHsp90, with N-harmicines showing higher binding free energy than O-harmicines.

Conclusions:

• Amide-type harmicines are promising antimalarial candidates with potent activity and favorable selectivity.
• The study provides insights into the binding interactions and guides future derivatization for enhanced efficacy.
• N-harmicines represent a particularly effective class for antimalarial drug development.