Synthesis and in silico ADME/Tox profiling studies of heterocyclic hybrids based on chloroquine scaffolds with...

A series of heterocyclic chloroquine hybrids containing either a β-phenethylamine fragment or a 2-aminoindane moiety were synthesized and screened in vitro as inhibitors of β-hematin formation and in vivo for their antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA. Although these new compounds were not found to be more active than chloroquine in vivo, all new compounds significantly reduced heme crystallization with IC₅₀ values < 1 μM. Compounds 12 and 13 were able to inhibit heme crystallization with IC₅₀ values of 0.39 ± 0.09 and 0.48 ± 0.02 μM, respectively, and these values were comparable to that of chloroquine with an IC₅₀ value of 0.18 ± 0.03. It was also determined that the physicochemical and pharmacokinetic properties were moderately favorable after in silico evaluation, derivatives 8 and 10 did not present hepatotoxicity, and the in vitro hemolytic activity against red blood cells was found to be low. Spectral (infrared, nuclear magnetic resonance, and elemental analysis) data for all final compounds were consistent with the proposed structures.