Trifluoromethyl-substituted quinoline and tetrazole derivatives :design, synthesis, antimalarial activity and cytotoxicity / Joseph L. Kgokong

• Main Author: Kgokong, Joseph Lebese
• Published: North-West University 2010
• Online Access: http://hdl.handle.net/10394/3732

Malaria is a complex parasitic disease caused by the Plasmodium falciparum. It has been found to be responsible for the death of many people particularly in under-developed and developing countries. For many years chloroquine and quinine have been the mainstay of therapy for this disease. The research on new therapies against malaria have been hampered by factors such as the development of resistance against these and some of the new drugs or combinations thereof, the lack of adequate knowledge on the exact causes and mechanisms of resistance to the drugs and their mode of action, together with the fact that the disease occurs predominantly in poor countries where there is no adequate funding and monitoring facilities. Residual insecticides where they have been tried are not appropriate because of technical constraints and the vaccine development is still in infancy stage. Of the more than 200 000 compounds developed by Antimalarial Drug Development program of the Walter Reed Army Institute of Research (WRAIR) since its inception in the early 1960s, only 3% have been found to be active in the primary screening tests. Very few of these have reached the Phase III clinical trials. The successes gained in the use of mefloquine and halofantrine in the treatment of resistant malaria has aroused considerable interest in the contribution made by the trifluoromethyl group as a substituent on antimalarial activity of many molecules. The objective of the current studies was to design, synthesise and evaluate the antimalarial activity of a group of compounds containing the quinoline, triazine and tetrazole as basic structures but with either one or two trifluoromethyl groups as substituents in addition to other groups. These new compounds were evaluated for activity against the chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. The assessments made it possible to construct possible structure-activity relationship profiles. The new compounds included a series of 2- and 8-trifluoromethyl- and 2,8-jb/s(trifluoromethyl)quinolines and those of trifluoromethyl substituted triazine and tetrazine derivatives with other substituents to form compounds containing the 4-(pyrimidine-5-yl)methanone and 2-(1-ethyl-5-nitro-1H-imidazol-4-yl)ethan-1-one moieties, the N,N-/}/s(trifluoromethyl)quinolin-4-yl)diamino alkyl derivatives and 1,2,4-triazine-[5,6b]indole and the 5H-1,2,4-triazolo[1',5',2,3]-1,2,4-triazino[5,6b]indole derivatives. All the compounds were characterised by elemental analysis, 1H and 13C NMR, mass and infrared spectrometric determinations. Comparative activities of the compounds were assessed using the chloroquine-sensitive and chloroquine-resistant strains of P. falciparum and cytotoxicity was evaluated using the human promyelocytic leukaemia (HL-60) and Chinese Hamster Ovarian (CHO) cell lines against normal human cells. In each series of the new compounds, a trifluoromethyl group has been found to enhance antimalarial activity. Except for the tetrazoles, the presence of the two trifluoromethyl groups appears to be essential for activity against the chloroquine-resistant strains of P. falciparum. The 2,8-/}/s(trifluoromethyl)- quinolin-4-yl]-2-(1-ethyl-5-nitro-1/-/-imidazol-4-yl)ethan-1-one also exhibit inhibition of the leukemia cell growth. The N,N-b/s(trifluoromethylqumolin-4-yl)diaminoalkane series have a high selectivity index. The ferriprotoporphyrin IX-drug complexation and DNA-drug intercalation and binding studies do not provide a convincing support for the actual mode of action of these new compounds. === Thesis (Ph.D. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2009.