Chalcone and Quinoline Derived Thiosemicarbazones : Synthesis, in Vitro Anti-plasmodial Activity, Crytotoxicity and in Silico Molecular Docking Study

Ho, Sheng Zhou (2023) Chalcone and Quinoline Derived Thiosemicarbazones : Synthesis, in Vitro Anti-plasmodial Activity, Crytotoxicity and in Silico Molecular Docking Study. Masters thesis, Tunku Abdul Rahman University of Management and Technology.

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Abstract

Malaria is an endemic disease that occurred in many countries and caused more than 400,000 deaths per year. Malaria infection is caused by protozoan parasites namely the Plasmodium genus, that are transmitted into the bloodstream of human hosts through the female Anopheles mosquito bite. Meanwhile, the emergence of drug resistance against the mainstream treatment, artemisinin combination therapy (ACT) was discovered since a few years ago. Hence, the development of new antimalarial drugs is urgently required to overcome the drug resistant strains. In this study, chalcone and quinoline derivatives were reacted with N-substituted thiosemicarbazides with different substituents through condensation reaction, to form a total of ten thiosemicarbazone derivatives. All compounds were characterized with Differential Scanning Calorimetry (DSC), Fourier Transform Infrared-Attenuated Total Reflection spectrometer (FTIR-ATR), CHNS elemental analysis and 1H and 13C Nuclear Magnetic Resonance (NMR) spectrometer. The synthesized compounds were evaluated in vitro against the chloroquine sensitive of P. falciparum strain (3D7) through schizont maturation assay. The antimalarial activities of compounds exhibited IC50 value ranging from 5.98 to 205.1 μM, where the compound (E)-2-((E)-3-(4-chlorophenyl)-1-phenylallylidene)-N-phenylhydrazine-1-carbothioamide (PT4Cl) exhibited the highest antimalarial activities among the synthesized compounds. The in vitro cytotoxicity of the synthesized compounds was carried out against the fibroblast-like human diploid (MRC-5) cell line and PT4Cl showed non-toxic at the maximum concentration (200 μM) tested. The in silico molecular modelling of synthesized compounds was docked against the cysteine protease (falcipain-2) of P. falciparum with Protein Data Bank ID of 3BPF. The docking result of compound PT4Cl reviewed that PT4Cl showed good interaction within the active site with binding energy of -5.309 kcal/mol, through covalent bonding, π-π interaction, hydrogen bonding and hydrophobic interaction.