Novel structural hybrids of 8-Aminoquinoline and Thiazole based heterocycles: design, synthesis, in-vitro and in-silico approaches.

Significant advancements have occurred in the creation of antimalarial agents during the past few decades, resulting in the development of various novel agents from both natural and synthetic sources. Thiazole, a unique 5-membered heterocyclic structure containing sulphur and nitrogen atoms, serves as a crucial core scaffold in numerous pharmacologically significant molecules. The thiazole nucleus is a crucial part of some clinically effective antibacterial and antimalarial drugs. Thiazole-containing compounds have been successfully developed as potential inhibitors of a variety of biological targets, such as blood-stage agonists (7SQM), TbDHFR inhibitor (3QG2), the liver stage of Plasmodium (4IGE), chloroquine resistance (6UKJ), oxidoreductase inhibitor (1LDG), and liver- and blood-stage agonists (4TMR) of the malaria parasite Plasmodium falciparum. The reference drug CQ (chloroquine) exhibited a docking score of -7.9 kcal/mol, whereas the newly designed 8-aminoquinoline-based novel thiazole derivatives showed improved docking scores between -11.0 and -9.9 kcal/mol. The compounds generally exhibited enhanced or comparable activities to those of the reference clinical medication chloroquine against both chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-9) strains, with a higher selectivity for the sensitive phenotype, with EC50 values primarily in the micromolar range (EC50: 0.39 and 0.46 μM). In addition, compounds were further evaluated for cytotoxicity against the HEK293 cell line to assess their safety and selectivity profile. Molecular dynamics simulations were carried out for all compounds to examine the stability and behaviour of the protein-ligand complex obtained from molecular docking under in silico physiological conditions. Compounds 1 h, 1c, 1 l, and 1j exhibited significant antimalarial efficacy against both strains (3D7 and RKL-9), characterized by a minimum inhibitory concentration. Even though all other compounds demonstrated better antimalarial potency, Compound 1 h was the most effective and consistently exhibited good potency against all strains. Additionally, it exhibited a positive molecular interaction through in silico studies. Free energy landscape mapping, PCA, and MM/GBSA calculations further substantiated the favourable binding and stability of the complexes.