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

Abstract

Quinoline-urea-benzothiazole hybrids exhibited low to sub-micromolar in vitro activities against the Plasmodium falciparum (P. falciparum) 3D7 chloroquine (CQ)-sensitive strain, with compounds 5a, 5b and 5f 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 5c (IC₅₀ = 9.55 ± 0.62 μM) and 5h (IC₅₀ = 9.73 ± 1.38 μM), exhibiting slightly better in vitro efficacy than CQ. The hybrids also exhibited low micromolar to submicromolar activities against Trypanosoma brucei brucei, with 5j-5k being comparable to the reference drug, pentamidine. Compound 5b displayed higher in silico binding energy than CQ when docked against P. falciparum dihydroorotate dehydrogenase enzyme. Compounds 5j and 5k showed higher binding energies than pentamidine within the trypanothione reductase enzyme binding pocket. The root means square deviations of the hit compounds 5b, 5j and 5k 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.

Keywords: Ligand-receptor complex and density functional theory (DFT) studies; Molecular docking; Quinoline-urea-benzothizole hybrids; β-haematin formation inhibition.

Fig. 1

Some of the 4-aminoquinolines and benzothiazole with activity against malaria and trypanosomiasis.

Fig. 2

Components making up the desired quinoline-urea-benzothiazole hybrid compounds.

Fig. 3

Previously synthesised quinoline-urea-benzothiazole hybrids 5a-k, and intermediate 6.

Fig. 4

Single concentration viability screening of the target compounds against P. falciparum and T. b. brucei at 20 μM concentration.

Fig. 5

Comparison of the RMSD of the C-α of the complexes of (left) compounds 6, 5a, 5b, 5f and CQ with unbound 6I4B (APO); and (right) compounds 5j, 5k, 5l and pentamidine with unbound 2JK6 (APO). APO indicates free/unbound protein (i.e., protein without a ligand bound).

Fig. 6

The RMSF plots of 6I4B-6, 6I4B-5a, 6I4B-5b, 6I4B-5f and 6I4B-CQ complexes with unbound protein, 614B (APO) (top); and 2JK6-5j, 2JK6-5k, 2JK6-5l, and 2JK6-pentamidine with unbound protein, 2JK6 (APO) residues (bottom).