In vitro antiplasmodium and antitrypanosomal activities, β-haematin formation inhibition, molecular docking and DFT computational studies of quinoline-urea-benzothiazole hybrids

Quinoline-urea-benzothiazole hybrids exhibited low to sub-micromolar <i>in vitro</i> activities against the <i>Plasmodium falciparum</i> (<i>P. falciparum</i>) 3D7 chloroquine (CQ)-sensitive strain, with compounds <b>5a</b>, <b>5b</b> and <b>5f</b> showing activities ranging from 0.33 to 0.97 μM. Against the formation of β-haematin, the majority of the tested compounds were comparable to the reference drug, chloroquine (CQ), with compounds <b>5c</b> (IC₅₀ = 9.55 ± 0.62 μM) and <b>5h</b> (IC₅₀ = 9.73 ± 1.38 μM), exhibiting slightly better <i>in vitro</i> efficacy than CQ. The hybrids also exhibited low micromolar to submicromolar activities against <i>Trypanosoma brucei brucei</i>, with <b>5j</b>-<b>5k</b> being comparable to the reference drug, pentamidine. Compound <b>5b</b> displayed higher <i>in silico</i> binding energy than CQ when docked against <i>P. falciparum</i> dihydroorotate dehydrogenase enzyme. Compounds <b>5j</b> and <b>5k</b> showed higher binding energies than pentamidine within the trypanothione reductase enzyme binding pocket. The root means square deviations of the hit compounds <b>5b, 5j</b> and <b>5k</b> were stable throughout the 100 ns simulation period. Post-molecular dynamics MMGBSA binding free energies showed that the selected hybrids bind spontaneously to the respective enzymes. The DFT investigation revealed that the compounds have regions that can bind to the electropositive and electronegative sites of the proteins.