Piperazine-based pyrido[1,2-a]benzimidazoles: synthesis and pharmacological evaluation as potential antimalarial and antischistosomal agents

Master Thesis


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The emergence and spread of parasites resistant to first-line antimalarial drugs comprising artemisinin combination therapies (ACTs) threaten malaria control. There is therefore a need to develop novel and chemically diverse alternatives that are safe, efficacious, and able to circumvent drug resistance. Schistosomiasis is the second most prevalent tropical disease in the world after malaria, and treatment relies on a single drug: praziquantel. Although praziquantel shows multiple benefits over drugs previously used to treat schistosomiasis, dependence on it will result in therapeutic limitations and drug resistance threats. Therefore, there is a dire need to develop novel antischistosomal drugs that are effective and affordable. One attractive approach to accelerate the drug discovery and development process is the exploration of current drugs and drug leads as probable therapies for other diseases. This strategy is known as drug repurposing or drug repositioning, of which the latter is applied in this research project. The cytological similarities in the degradation of haemoglobin performed by Plasmodium parasites and Schistosoma blood flukes in malaria and schistosomiasis, respectively, suggest an opportunity for the repositioning of antimalarial scaffolds as antischistosomal agents. Pyrido[1,2-a]benzimidazoles (PBIs) demonstrate various biological and pharmacological properties such as anti-inflammatory, analgesic, antimicrobial, antiviral, and antineoplastic activities. More recently, PBI derivatives showed favourable in vitro activities against both Plasmodium falciparum and adult Schistosoma mansoni, but modest in vivo potencies. Pharmacokinetic analysis suggests that the sub-optimal in vivo efficacy of PBIs is related to solubility-limited absorption and poor metabolic stability. With the aim of circumventing these challenges, structural modifications have been employed to explore structure-activity and structure-property relationships to produce target compounds with improved druglikeness (Figure A). This study aimed to expand the SAR by performing chemical modifications on the PBI scaffold with the purpose of maintaining or improving biological activity, and to address solubility-limited absorption challenges with this series of compounds (Figure A). The synthesized derivatives were tested against the chloroquine-sensitive (NF54) strain of P. falciparum and against adult S. mansoni concurrently. The most active compound in this PBI series, a di-fluoro-substituted derivative composed of a cyclohexyl piperazine side-chain (33), showed improved in vitro activity against the NF54 strain of P. falciparum (IC50 = 0.012 µM) and enhanced solubility (Figure A). Compounds with methylene or ethylene linkers at the R1 position (Figure A) showed comparable potency, although the directly linked phenyl piperazine analogue showed poor antiplasmodium activity. Compounds containing hydrophobic electron-withdrawing fluoro, chloro, and trifluoromethyl Craig plot substituents at the para position of the phenyl group showed enhanced antiplasmodium activity compared to those containing hydrophobic electron-releasing methyl groups and hydrophilic electron-withdrawing cyano groups. In the LHS-unsubstituted series of compounds, regio-isomerism at substituent R2 (Figure A) resulted in comparable antiplasmodium activity, and this observation was maintained with LHS-substituted PBI derivatives. Notably, unsubstituted derivatives and di-substituted groups displayed moderate to high antiplasmodium potency. Mechanistic evaluations of the compounds revealed non-existent to weak correlations between antiplasmodium activities and their potential to inhibit hemozoin (Hz) formation. This suggests that Hz inhibition is not the sole target of this class of compounds, although it may be a contributory mode of action. Compounds were also screened at 10 µM against newly transformed schistosomula and adult S. mansoni. Two compounds showed high antischistosomal activity against both larval and adult parasites, resulting in > 70% inhibition of worm viability. A turbidimetric assay was carried out to assess the solubility of target PBI compounds. In most cases, the synthesized compounds displayed high in vitro activities and slight improvements in solubility. This therefore encourages further optimization of piperazinyl PBI compounds to improve efficacy and solubility.