Diisopropylphenyl Imidazole (DII): A New And Promising Anthelmintic Agent

Helminths are worm parasites that are transmitted by soil, water, or food. Helminth infections cause human, animal, and plant diseases that produce a significant economic loss and have a devastating impact on human life quality. It is estimated that more than one billion people are affected, particularly in the poorest countries. This means that the inhabitants of thousands of rural and impoverished villages are often chronically infected. Helminth infestations have serious consequences, particularly among children, impairing growth, nutrition, cognition, and school performance.

In spite of the high prevalence of parasitic worm infections, antiparasitic drug discovery is not an attractive goal for the pharmaceutical industry. One reason could be that helminths cause nonlethal symptoms and this may delay the investment for developing pharmacological treatments among other health priorities. Another reason is that most of the countries affected have little money to invest in drug discovery or therapy.

Only a limited number of anthelmintics (agents used to treat helminth infestations) are currently available, and most of them have been developed for veterinary use before being applied to human health.

Moreover, the frequent, and in some occasions inappropriate, use of anthelmintics has generated the appearance of parasite resistance. The rise of resistance against conventional treatments is a constant concern in the field of infectious diseases and represents a threat to livestock production and animal and human health. Although this scenario reveals the urgency to advance in pharmacological research to develop new antiparasitic drugs, only one anthelmintic, tribendimidine, has been developed and entered into human clinical trials in the last 30 years.

In this work, we screened several imidazole derivatives for anthelmintic activity. Imidazole is a molecule of great interest in drug discovery due to its numerous pharmacological properties. Parasitic worms are difficult to grow in the laboratory. Moreover, in these animals, it is difficult to study drug molecular mechanism (how a drug is working) because genetic engineering and molecular tools either cannot be performed or give very variable results. Therefore, we used C. elegans, a non-parasitic worm genetically easy to manipulate, as a model for parasitic nematodes.

C. elegans is a free-living worm that represents an inexpensive, safe, and powerful model that can be used to facilitate the study of anthelmintics. This worm is sensitive to the majority of anthelmintics and has been used as a screening platform for anthelmintic drug discovery and to elucidate the mechanisms of action and resistance of almost all known nematicidal drugs.

In our study, we reported that diisopropylphenyl imidazole (DII) has a nematicidal effect on adult C. elegans. Since the mechanism involved is different from those of currently used anthelmintics, it could constitute a therapeutic option when traditional anthelmintic agents fail. Even more, DII delays development and also has a lethal effect on juvenile C. elegans which depends on a different mechanism than that underlying lethality in adult worms. These properties are a clear improvement among classic anthelmintic treatments given that young animals do not reach fertility and die before leaving progeny.

The nematicidal effect of DII on both immature and mature nematode stages could offer an improvement to classical antiparasitic drugs, such as levamisole, pyrantel, or morantel which are less effective against immature stages. Nowadays, combinations of different anthelmintic drugs that act through different targets are frequently administered. The double-aim of this association is to maintain nematode control even in the presence of resistant worms and to delay resistance development. The fact that DII kills worms through two (or more) different mechanisms in different growth stages may be critical to delay resistance development. These features could provide a significant advantage even over relatively new anthelmintic drugs, such as tribendimidine and monepantel.

Another advantage of DII revealed in our work is that this compound is not toxic for insects or human cell cultures, suggesting that DII lethality is specific to nematodes. This property is extremely important in drug development because it reduces the chances of unwanted consequences for the host.

The harmful effect on worms, the nematode selectivity, and the alternative mechanism of DII, together with the fact that most molecules that kill C. elegans have been proved to be lethal to parasitic nematodes, shape this imidazole-derivative compound as a strong anthelmintic candidate for developing new anthelmintic agents. It is now time to test its efficacy on parasite helminths.

These findings are described in the article entitled Diisopropylphenyl-imidazole (DII): A new compound that exerts anthelmintic activity through novel molecular mechanisms, recently published in the journal PLOS Neglected Tropical Diseases.

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