Synthesis, in vitro anti-plasmodial potency, in-silico-cum-SPR binding with inhibition of PfPyridoxal synthase and rapid parasiticidal action by 3,5-bis{(E) arylidene}-N-methyl-4-piperidones

Abstract

Twenty-five (Ia–Iu, IIa–IIb, IIIa, and IVa) diarylidene-N-methyl-4-piperidones (DANMPs) were synthesized and characterized via UV, FT-IR, NMR, and MS while Id was characterized also by single crystal XRD. Twenty-one compounds shortlisted after initial in vitro anti-plasmodial activity successive screenings at 100 μM and 10 μM were evaluated for their IC₅₀s against chloroquine-sensitive Pf3D7, chloroquine-resistant PfINDO, and artemisinin-resistant PfMRA-1240 strains. The four most promising compounds were Ie (IC₅₀s μM 0.35^MRA, 1.39^INDO, 1.92^3D7), If (IC₅₀s μM 1.07^MRA, 1.36^INDO, 3.39^3D7), Ir (IC₅₀s μM 0.74^MRA, 2.45^INDO, 1.44^3D7), and In (IC₅₀s μM 1.27^MRA, 1.8^INDO, 1.7^3D7). Resistance indices as low as 0.2 to 0.5 for these potent compounds and <1 for most other compounds suggest their greater potency against drug resistant strains than the drug sensitive strain. The parasiticidal action of Ir was seen within 4 h against the trophozoite stage of the parasite, which is known to express the highest levels of PLP synthase. In silico docking scores of −7.0 to −8.0 kcal mol⁻¹ between potent DANMPs and PfPLP synthase, the direct binding of Ir studied by SPR to recombinantly expressed and purified PfPdx-1 and inhibition of Pdx1 enzymatic activity by Ir suggest this vital enzyme to be a probable target for the DANMPs. The non-hemolytic nature of Ir and conformity of most DANMPs to Lipinski's parameters indicate their potential as new anti-plasmodial leads with PfPLP synthase as one of their targets.