Conversion of artemisinin into novel unprotected N-alkylamine-11-azaartemisinins with enhanced antimalarial activity.

Two novel azaartemisinin scaffolds N-ethanamine-11-azaartemisinin (EAZA) 10 and N-propanamine-11-azaartemisinin (PAZA) 11 were synthesized from artemisinin 1 on multigram scale in excellent yields without the need for further column chromatography purification and evaluated for their in vitro antimalarial potential. Relative to artemisinin (IC₅₀ = 6.978 nM), EAZA (IC₅₀ = 1.43 nM) and PAZA (IC₅₀ = 144.4 pM) exhibited approximately 3.5-fold and 30-fold greater antimalarial potency, respectively, while maintaining low cytotoxicity toward HepG2 cells, as indicated by their high cytotoxic concentration values. Thermogravimetric Analysis (TGA), isothermal titration calorimetry (ITC), and density functional theory (DFT) provided insights into their structure-property relationships. This study highlights the profound impact of minimal structural variations on the biological and thermal properties of azaartemisinins.