Objective: To evaluate new compounds synthesized by integrating quinoline, quinazoline, and acridine rings with the active moiety of (5-nitroheteroaryl) methylene hydrazine.Methods: A new series of compounds (1a, 1b, 2a, 2b, 3a, and 3b) were synthesized and evaluated for cytotoxicity against COS-7 cells using the MTT assay. In vitro anti-plasmodial activity of the compounds was measured against CQ-sensitive (3D7) and CQ-resistant (K1) Plasmodium (P.) falciparum strains. β-hematin assay was performed to assess the inhibitory effects of β-hematin formation for new compounds. Results: The synthetic compounds had anti-plasmodial activity against blood-stage of 3D7 [IC50=(0.328-5.483) μM] and K1 [IC50=(0.622-7.746) μM] strains of P. falciparum, with no cytotoxicity against COS-7 cells in effective doses. Compounds 1a, 1b, and 2b were the most effective derivatives against P. falciparum 3D7 and K1 strains. Based on the β-hematin assay, the inhibition of β-hematin formation is the main mechanism of the inhibitory effect of these compounds. Conclusions: The synthetic compounds could inhibit the erythrocytic stages of CQ-sensitive and resistant P. falciparum strains without toxicity towards mammalian cells. Compounds 1b, 2a, and 2b had comparable anti-plasmodial activity against both CQ-sensitive (3D7) and resistant (K1) P. falciparum strains. These compounds may be promising lead structures for the development of new anti-malarial drugs.