Ultrasound-assisted synthesis and structure elucidation of novel quinoline-pyrazolo[1,5-a]pyrimidine hybrids for anti-malarial potential against drug-sensitive and drug-resistant malaria parasites and molecular docking

Abstract

Novel (E)-3-(dimethylamino)-1-(quinolin-3-yl)prop-2-en-1-one and (E)-3-(dimethylamino)-1-(quinolin-3-yl)but-2-en-1-one (2) were synthesized in excellent yields by reacting 3-acetylquinoline with DMF-DMA and DMA-DMA respectively. Subsequently, 2 were used as the precursors for the synthesis of 3-(pyrazolo[1,5-a]pyrimidin-7-yl)quinolines and 3-(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)quinolines (4). All the synthesized compounds were subjected to structure elucidation and evaluated for their antiparasitic potential with special reference to their anti-malarial properties. The in-vitro studies of the synthesized compounds revealed moderate anti-malarial efficacy for compounds 4b, 4c, 4d, 4k, 4l and 4m. Compounds 4g and 4i showed highest activity displaying IC₅₀ values of 2.10 and 2.77 \(\mu\)M, respectively, for the chloroquine-sensitive strain of P. falciparum, and 4.26 and 2.87 \(\mu\)M, respectively, for the chloroquine-resistant strain. The in-vitro cytotoxicity of the compounds showed CC₅₀ as >500 µM and thus, found to be safe. Molecular docking of the novel series of ligand 4a–4n against the target protein P. falciparum PfLDH enzyme target (PDB ID 1LDG) revealed good binding energies ranging from –8.06 to –11.02 kcal/mol with low inhibition constants summed up as 1.04, 473.55, 352.51, 290.9, 437.86, 1.23, 41.18, 26.81, 162.76, 300.38, 70.2, 29.84, 4.14, 8.4 µM, respectively. The lower the inhibition constant (µM), the greater is the binding affinity and lower the medication required to inhibit the activity of the target receptor.

Graphical abstract

(E)-3-(dimethylamino)-1-(quinolin-3-yl)but-2-en-1-one with 3-aminopyrazole under ultrasonic irradiation in aqueous medium yielded novel 3-(pyrazolo[1,5-a]pyrimidin-7-yl)quinolines and 3-(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)quinolines. Antimalarial studies against Pf3D7 strain resulted in moderate activity with compound 4g showing highest activity. Molecular docking analysis of the compounds reveals the potentiality of the series to serve as antimalarial agents against CQ-sensitive (Pf3D7) and multi-drug-resistant (PfK1).