Abstract
Giardia duodenalis is an ubiquitous parasitic pathogen that causes significant morbidity and mortality worldwide. Failures in drug therapy are commonly due to poor patient compliance as a result of the need for repeated administration, off target drug effects and increasing parasite drug resistance. In this study the in vitro efficacy and selectivity of the aminoguanidine compound robenidine and 2 structural analogues against Giardia were determined. After 5 h exposure to each compound the IC50 was as low as 0.2 μM with corresponding MLCs as low as 2.8 μM. This is in contrast to metronidazole which required 24 h to exhibit inhibitory activity. A modified adherence assay, developed for this study, demonstrated that three of the compounds inhibited in vitro adherence of the parasite. The lead compound exhibited rapid giardicidal activity (<5hr). In addition, microscopy studies demonstrated damage to the plasma membrane of trophozoites. In conclusion, a class of aminoguanidines, represented by robenidine, has shown antigiardial activity warranting further investigation.
Highlights
In this study we explored the potential of robenidine, a symmetrical chloroaromatic compound linked via a guanidinal core, as a lead compound for the development of novel antigiardial drugs (Fig. 1)
Transmission electron microscopy To determine any effects robenidine has on the ultrastructure of Giardia trophozoites, transmission electron microscopy (TEM) was performed
We demonstrated that robenidine, NCL 062 and NCL 099 have potent rapid in vitro activity against G. duodenalis (Fig. 2)
Summary
The most frequently used nitroimidazoles, metronidazole and tinidazole, have a treatment success rate of 80–90%; while albendazole, a benzimidazole, has a reported efficacy of 62–95% (Wright et al, 2003). Treatment failures with these drugs are frequently reported and many exhibit unwanted side effects including but not limited to, nausea, fatigue and malaise (Wright et al, 2003). Treatment failure due to the development of resistant organisms has been reported for all commonly used antigiardial drugs (Nagel and Aronoff, 2015; Jokipii and Jokipii, 1979). We evaluated the antigiardial activity of robenidine and the activity of two structural analogues, (E)-N'-((E)-1-(4-chlorophenyl)ethylidene)-2-(1-(4-chlorophenyl) ethylidene)hydrazine-1-carboximidhydrazide hydrochloride (NCL 062) and N′,2-bis((E)-4-(tert-butyl)benzylidene)hydrazine-1-carboximidhydrazide hydrochloride (NCL 099) (Fig. 1)
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