In vitro antiplasmodium and antitrypanosomal activities, β-haematin formation inhibition, molecular docking and DFT computational studies of quinoline-urea-benzothiazole hybrids
Oluwatoba E. Oyeneyin,
Rashmika Moodley,
Chakes Mashaba,
Larnelle F. Garnie,
Damilola A. Omoboyowa,
Goitsemodimo H. Rakodi,
Mabuatsela V. Maphoru,
Mohamed O. Balogun,
Heinrich C. Hoppe,
Timothy J. Egan,
Matshawandile Tukulula
Affiliations
Oluwatoba E. Oyeneyin
School of Chemistry and Physics, University of KwaZulu Natal, Westville Campus, Durban, 4000, South Africa; Department of Chemical Sciences, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria; Corresponding author. School of Chemistry and Physics, University of KwaZulu Natal, Westville Campus, Durban, 4000, South Africa.
Rashmika Moodley
School of Chemistry and Physics, University of KwaZulu Natal, Westville Campus, Durban, 4000, South Africa
Chakes Mashaba
School of Chemistry and Physics, University of KwaZulu Natal, Westville Campus, Durban, 4000, South Africa
Larnelle F. Garnie
Department of Chemistry, Faculty of Science, University of Cape Town, Rondebosch, Cape Town, 7700, South Africa
Damilola A. Omoboyowa
Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria
Goitsemodimo H. Rakodi
Department of Chemistry, Faculty of Science, Tshwane University of Technology, Pretoria, 001, South Africa
Mabuatsela V. Maphoru
Department of Chemistry, Faculty of Science, Tshwane University of Technology, Pretoria, 001, South Africa
Mohamed O. Balogun
Bio-Polymer Modification and Therapeutics Laboratory, Council for Scientific and Industrial Research (CSIR), Pretoria, 0001, South Africa
Heinrich C. Hoppe
Centre for Chemico- and Biomedical Research, Rhodes University, Makhanda, 6140, South Africa; Department of Biochemistry and Microbiology, Faculty of Science, Rhodes University, Makhanda, 6140, South Africa
Timothy J. Egan
Department of Chemistry, Faculty of Science, University of Cape Town, Rondebosch, Cape Town, 7700, South Africa; Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Rondebosch, 7701, South Africa
Matshawandile Tukulula
School of Chemistry and Physics, University of KwaZulu Natal, Westville Campus, Durban, 4000, South Africa; Corresponding author.
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.
