Novel antimalarial 2-substituted quinoline thiosemicarbazone derivatives: Rational designing, molecular docking studies, ADME-tox properties, synthesis & in vitro activity

Malaria remains a dangerous threat to nearly half of the world’s population, with the potential to be life-threatening. The most effective treatment currently available for uncomplicated and severe malaria caused by Plasmodium falciparum is Artemisinin Based Combination Therapy. Drug-resistant malaria parasites are believed to emerge through mutations in the active sites of drug targets. The continued search for new molecular targets for drug design should broaden the therapeutic arsenal and strategies to fight drug resistance in human malaria. A series of 60 thiosemicarbazone derivatives was computationally designed using in silico and docking protocol. Molecular docking study were carried out on P. falciparum lactate dehydrogenase enzyme (PDB ID: 1CET ) & falcipain-2 (PDB ID: 3BPF ) using Autodock tool 4.2.6. The docked confirmation of the ligands was analyzed for their binding interactions using 2D & 3D visualizations by Biovia discovery studio. Molecules reported with good score by ADME-Tox studies and docking analysis were selected for synthesis. Twenty four thiosemicarbazone derivatives were synthesized by utilizing Vilsmeier-haack reagent and their structures were examined by spectral techniques. Further, the compounds were screened in vitro to inhibit β-hematin formation and against chloroquine resistant and sensitive strains of P. falciparum. Compounds QTSC-11 , QTSC-12 , QTSC-23 and QTSC-24 showed higher β-hemozoin inhibition and exhibited higher potency against resistant strain of P. falciparum . The findings of the ADME-Tox properties, docking analysis & in vitro activity demonstrated that the synthesized compounds have potential of anti-malarial activity and can be further optimized to serve as lead compounds.