Triazole-linked 1,4-naphthoquinone derivatives : synthesis and antiplasmodial activity

Abstract

Malaria is a protozoan disease transmitted to humans through female Anopheles mosquitoes. The malaria parasite thrives in tropical areas, thus people there are at higher risk, especially in third-world countries like Africa and Asia. Even with preventative measures, like insecticidetreated nets (ITNs) and indoor residual spraying (IRS), taken to help control transmission, malaria still ravages through countries, killing adults and children alike. World Health Organisation recommends artemisinin-based combination therapies (ACTs) as firstline treatment against uncomplicated malaria. However, recent statistics show an increase in resistance towards artemisinins that warrants the search for more efficient, safe and cheaper drug classes. Molecular hybridisation has recently been in the lime light for medicinal chemists. In this study the hybridisation of two pharmacological active chemical moieties, namely 1,4-napthoquinone and 1,2,3-triazole, were utilised to develop a series of novel compounds. This series was further divided into two sub-series based on the major structural difference that is the linker between the pharmacophores. This structural difference was necessary to gauge the impact that the tether might have on the biological activity of these hybrids. Sub-series 1 hybrids are structurally rigid as a result of direct linkage of the pharmacophores. The synthesis of these hybrids followed a two-step synthetic route involving firstly, an aromatic nucleophilic substitution resulting in an azide intermediate, and secondly, Huisgen copper alkyneazide cycloaddition of the intermediate with various alkynes. Sub-series 2 hybrids are flexible owing to an oxymethylene tether between the naphthoquinone and the triazole moieties. A three-step process was used to synthesise these hybrids. (1) a napthoquinolylalkyne intermediate was synthesised using a slightly modified version of Mitsunobu reaction for nucleophilic substitution SN2; (2) benzylazides were obtained in another nucleophilic substitution SN2 involving sodium azide and commercial benzyl bromides; (3) Huisgen copper alkyne-azide cycloaddition ‘‘click chemistry’’ of the napthoquinolylalkyne intermediate with the benzylazide afforded the target hybrids. The CLogP values of the synthesised compounds were estimated to be in the two - five range, suggesting that the hybrids were drug-likeable, thus were expected to be endowed with enhanced biological activities. The cytotoxicity of the compounds was evaluated using normal human embryonic kidney cells (HEK-293) and were found to be generally non-toxic. The antimalarial activity of the hybrids was evaluated in vitro by determining the percentage growth inhibition of asexual stage P. falciparum NF54 strain parasites, at 5 μM and 1 μM concentrations, using SYBR Green I based assays. Sub-series 1 was completely inactive. Subseries 2 on the other hand, was found to be very active with the percentage growth inhibition of hybrids ranging from 70 - 90 % regardless of the concentration, validating this sub-series for further investigation. Of particular interest is hybrid 22, bearing tert-butyl substituent that showed 90 % parasite growth inhibition at 1 μM and moderate cytotoxicity with an IC50-value of 36 μM. This hybrid compared well with atovaquone that had 96% parasite growth inhibition at 1 μM, and an IC50-value of 56 μM. Compound 22 stands as a good candidate for further evaluation