Synthesis and evaluation of antichlamydial, antileishmanial and antimalarial activity of benzimidazole and benzoxadiazole derivatives

by Leena Keurulainen

Institution: University of Helsinki
Department: Division of pharmaceutical chemistry and technology
Year: 2015
Keywords: farmaseuttinen kemia
Record ID: 1130698
Full text PDF: http://hdl.handle.net/10138/155028


The aim of this thesis was to synthesize 1H-benz[d]imidazole- and benzo[c][1,2,5]oxadiazole-derived compounds active against intracellular bacterium Chlamydia pneumoniae and protozoan parasites Leishmania donovani, and Plasmodium falciparum, and to find new potent compounds as hit molecules for further development. A number of issues dictate the importance of the pursuit of this work. First, C. pneumoniae contributes to human health by being a widespread bacterium and causing respiratory infections such as pneumonia. In addition, atherosclerosis has been shown to be connected to the bacterium s persistent form. Second, a neglected tropical disease, visceral leishmaniasis in turn is caused by a protozoan parasite L. donovani and can be fatal if left untreated. Its current treatments suffer from toxicity, poor compliance and prevalent parasite resistance. Third, another tropical disease, malaria is caused by protozoan parasites belonging to the genus Plasmodium. P. falciparum resistance to recent antimalarial drugs is an ever growing and alarming issue, and there is an unmet medical need for new antimalarial chemotypes targeting the different parasite forms present in various stages of the Plasmodium life cycle. Heterocyclic chemical structures are widely used in the early drug discovery process and in compound screening. At the outset of this study, a series of 2-arylbenzimidazole derivatives was designed to target C. pneumoniae and L. donovani. Further development of these 2-arylbenzimidazoles resulted in a set of 2-aminobenzimidazoles against P. falciparum. Benzoxadiazole derivatives were designed against L. donovani. Facile and general synthesis routes for the preparation of both benzimidazole and benzoxadiazole derivatives were developed. In order to study structure-activity relationships of the antichlamydial and antileishmanial 2-arylbenzimidazoles, the left, right and central parts of the core molecular structure were modified and different substitution patterns were employed. Antichlamydial, antileishmanial and antimalarial inhibition activities were related to the different structural modifications carried out. Antichlamydial and antileishmanial 2-arylbenzimidazoles or benzoxadiazole derivatives inhibited target pathogens at the micromolar level. Furthermore, 2-aminobenzimidazoles were studied as antimalarial compounds. The best derivative from this study inhibits growth of P. falciparum (IC50 94 nM) and has a good pharmacokinetic profile. The compound turned out to be efficacious in vivo against P. falciparum upon once a day oral administration. In this study, selectivity of the 2-arylbenzimidazoles against selected intracellular parasites over free living (planktonic) pathogens e.g.Escherichia coli was observed. This is a great advantage from the antimicrobial drug discovery point of view. In spite of the mechanisms of action of the studied derivatives remaining elusive, it was possible to show in this study that antimicrobial compound design can be successful even in the case of unknown…