Skip to main content
Download PDF

Benzimidazole and aminoalcohol derivatives show in vitro anthelmintic activity against Trichuris muris and Heligmosomoides polygyrus

Parasites & Vectors volume 15, Article number: 243 (2022) Cite this article

Abstract

Background

Infections by gastrointestinal nematodes cause significant economic losses and disease in both humans and animals worldwide. The discovery of novel anthelmintic drugs is crucial for maintaining control of these parasitic infections.

Methods

For this purpose, the aim of the present study was to evaluate the potential anthelmintic activity of three series of compounds against the gastrointestinal nematodes Trichuris muris and Heligmosomoides polygyrus in vitro. The compounds tested were derivatives of benzimidazole, lipidic aminoalcohols and diamines. A primary screening was performed to select those compounds with an ability to inhibit T. muris L1 motility by > 90% at a single concentration of 100 µM; then, their respective IC50 values were calculated. Those compounds with IC50 < 10 µM were also tested against the adult stage of T. muris and H. polygyrus at a single concentration of 10 µM.

Results

Of the 41 initial compounds screened, only compounds AO14, BZ6 and BZ12 had IC50 values < 10 µM on T. muris L1 assay, showing IC50 values of 3.30, 8.89 and 4.17 µM, respectively. However, only two of them displayed activity against the adult stage of the parasites: BZ12 killed 81% of adults of T. muris (IC50 of 8.1 µM) and 53% of H. polygyrus while BZ6 killed 100% of H. polygyrus adults (IC50 of 5.3 µM) but only 17% of T. muris.

Conclusions

BZ6 and BZ12 could be considered as a starting point for the synthesis of further structurally related compounds.

Graphical Abstract

Background

Soil transmitted helminths (STHs) are a group of human parasitic nematodes that affect around 1.5 billion of the world’s population causing substantial disease and disability [1]. These infections are more common in people living in low- and middle-income countries, in areas with poor access to adequate drinking water, sanitation and hygiene [2]. Of particular importance are infections caused by roundworms (Ascaris lumbricoides), whipworms (Trichuris trichiura) and hookworms (Necator americanus or Ancylostoma duodenale) [3]. According to the latest studies, the global incidence of T. trichiura infections is estimated to range between 450 million to 1 billion active cases [4].

In animals, the presence of helminth infections has an important economic impact arising directly from reductions in productive yields associated with weight gain, milk production and wool quality [5]. In Europe, the annual economic losses caused by helminth infections in livestock have been estimated at 1.8 billion euros, while those caused only by anthelmintic resistance in the group of gastrointestinal nematodes reach approximately 38 million euros annually [6].

The main control of these infections in humans is based on preventive chemotherapy, employing large-scale administration of anthelmintic drugs to populations at risk. Currently, there are four drugs on the World Health Organization (WHO) model list of essential medicines that are recommended for the treatment of soil-transmitted helminths: albendazole (ABZ), mebendazole (MBZ), levamisole (LEV) and pyrantel pamoate (PYR) [7]. However, the administration of these drugs is not always highly effective, reflecting low cure rates, especially against trichuriasis, when a single oral dose is administered [8, 9]. Moreover, the efficacy of these compounds has decreased significantly over time, showing egg reduction rates dropping from 72.6% in 1995 to 43.3% in 2005 [10].

Additionally, in gastrointestinal nematodes infecting livestock, multiple cases of rapid resistance development have been reported in all continents as a consequence of the abusive use of anthelmintics, mainly benzimidazoles, such as ABZ, and macrocyclic lactones, such as ivermectin (IVM) [11,12,13].

Considering the spread of anthelmintic resistance in animals and the low efficacy of some benzimidazoles against certain STHs in humans, it is clear that there is an urgent need to search for new drugs to control helminth infections. Therefore, the present study is focused on the determination of the potential in vitro anthelmintic activity of a series of synthetic compounds from different chemical families including benzimidazoles (BZ), lipidic diamines (AA) and aminoalcohols (AO) using two rodent models of gastrointestinal nematodes: Trichuris muris and Heligmosomoides polygyrus [14, 15]. For this purpose, a total of 41 compounds (15 BZ, 11 AA and 15 AO) were evaluated against two different stages of the parasites, the first stage larvae 1 (L1) and adult forms.

Methods

Chemical compounds

Compounds belonging to three different chemical families, namely 2-aminoalkan-1-ol (AO), alkane-1,2-diamine (AA) and 2-phenylbenzimidazoles (BZ), were synthesised by previously reported procedures [16,17,18] (structures summarized in Tables 1, 2 and 3). Stock solutions (10 mM) of these compounds were prepared in 100% dimethyl sulphoxide (DMSO; Sigma-Aldrich®) while final dilutions were made with distilled water to maintain a maximum concentration of 1% (v/v) DMSO in the well. All compounds were stored at 4 ºC pending use. To perform all the in vitro assays, levamisole (LEV) at 50 µM was used as positive control (Sigma-Aldrich®) and 1% DMSO as negative control.

Animals and parasites

The complete life cycles of T. muris and H. polygyrus are maintained at the Swiss Tropical and Public Health Institute (TPH). Experiments were approved by the Swiss national and cantonal authorities (permission no. 2070). Three-week-old female mice (NMRI for H. polygyrus and C57BL/6 N for T. muris) were allowed to acclimatise to the new environment for 1 week before use. During the acclimatisation period, from day 2 after arrival the animals received 0.25 mg/l dexamethasone (Sigma-Aldrich®) in the drinking water to immunosuppress them and facilitate parasite establishment. During the experiment, mice were kept at 22 °C, 50% humidity, with a 12-h light/dark cycle, and water and rodent food (KLIBA NAFAG, Switzerland) were available ad libitum according to Swiss Animal Welfare guidelines. Mice were orally infected with 200 embryonated T. muris eggs or 90 H. polygyrus L3 stage.

Drug discovery strategy

To investigate the activity against T. muris, 41 compounds were first subjected to a primary screening to assess their ability to inhibit T. muris motility at the L1 stage at a single concentration of 100 µM. Only compounds with the ability to inhibit the motility of > 90% of larvae (activity higher than 90%) progressed to subsequent dose-response evaluation to estimate their half maximal inhibitory concentration (IC50) value. Then, those with IC50 values < 10 µM were tested on the adult stage of T. muris and H. polygyrus following a similar protocol as mentioned above: initial screening at 10 µM and estimation of IC50 values of those compounds with activities > 80%.

Evaluation of anthelmintic activity on T. muris L1s

The assay was performed according to Wimmersberger et al. [19]. Briefly, unembryonated eggs were collected from faeces of infected mice. After storing the eggs for 3 months at room temperature in a dark box, hatching occurred by incubation with 107–108 cells/ml of Escherichia coli BL-21 stock. Approximately 40 L1 per well was placed into a 96-well plate and incubated for 24 h at 37 ºC and 5% v/v CO2 atmosphere, in the presence of 100 μl RPMI-1640 medium supplemented with antibiotic mixture (12.5 μg/ml amphotericin B, 500 U/ml penicillin and 500 μg/ml streptomycin) and 100 μM of the compound to be tested. As a positive control, LEV (Sigma-Aldrich) at a final concentration of 50 μM was used, while wells with medium and 1% DMSO served as negative control. Each compound was tested in duplicate and the assay was repeated on a different day. After 24 h incubation, larval viability was determined by using a binary scale that discriminates alive from dead larvae: “0” = no sign of motion = dead and “1” = motion observed = alive. The percentage of dead larvae was established for each well. To stimulate the movement of all live larvae, 100 µl of hot water (≈ 80 °C) was added to each well following previous protocols [19]. Each larva was observed for 3–5 s. Compounds that showed a killing effect > 90% at 100 μM were selected to determine their IC50. For this, L1s were incubated with at least six different concentrations of the compound ranging from 100 to 0.41 μM (1:3 serial dilutions).

Evaluation of anthelmintic activity on H. polygyrus and T. muris adult worms

The assay was performed according to Karpstein et al. [20]. Briefly, H. polygyrus and T. muris adults were collected from the caecum (T. muris) and colon (H. polygyrus) of the mice 2 (H. polygyrus) and 7 weeks (T. muris) after infection, respectively. All animals were humanely slaughtered by 100% CO2 inhalation. Three to four adult worms were placed in each well of a 24-well plate and exposed to the test compounds at a final concentration of 10 μM in RPMI 1640 medium supplemented with 100 U/ml penicillin and 100 μg/ml streptomycin in a final volume of 2.5 ml. Heligmosomoides polygyrus medium was supplemented with 12.5 μg/ml amphotericin B and T. muris medium with 5% foetal calf serum (iFCS, 100 U/ml). Wells containing 1% (v/v) DMSO in water were included as negative control. Worms were incubated at 37 °C and 5% CO2 up to 72 h, after which the drug effect was evaluated using a phenotypic readout. The assay was conducted in duplicate and repeated twice at different days. The condition of the worms was microscopically evaluated according to their phenotype, using a viability scale ranging from 3 to 0 (3: good motility; 2: low motility; 1: very low motility; 0: dead). If adult worms did not move enough for a clear scoring, they were stimulated with 500 μl hot water (≈ 80 °C). Therefore, the effect of the compounds was expressed by the percentage of dead larvae, considering dead those with a score of 0 and alive those with a score ranging from 1 to 3. Compounds with efficacies > 80% at 10 µM were then selected for IC50 determination (1:4 serial dilutions ranging from 10 to 0.039 μM).

Data analysis

IC50 values of both assays were calculated based on median effect principle, using the CompuSyn software (CompuSyn, version 3.0.1). These values were defined as the concentration of a drug required to decrease the mean worm’s motility by 50%. The “r” value is the linear correlation coefficient of the median-effect plot; it illustrates the goodness of fit and thus the accuracy of the IC50 value.

Cytotoxicity assays and selectivity indexes

Cytotoxicity assays for most compounds were carried out in a previous study on two different cell lines, the human colorectal adenocarcinoma Caco-2 (ATCC® HTB-37™) and the human hepatocarcinoma HepG2 (ATCC® HB-8065™), using the Alamar Blue staining method, to estimate their toxicity [18, 21]. In the present study, the cytotoxicity of only two compounds, AO14 and AO15, was performed following the protocols mentioned above.

Selectivity indexes (SIs) were calculated by dividing the CC50 values obtained in the cytotoxicity assays by the IC50 values of the in vitro assays. The greater the SI value, the more selective the compound is in inhibiting T. muris activity and the less in inhibiting mammalian cell growth (general cytotoxicity).

Results

Tables 1, 2 and 3 display the basic scaffold of the different classes of compounds tested and the results of the in vitro assays performed against T. muris L1 together with cytotoxicity data and SIs. AO and AA compounds are arranged according to the type and size of substituents present on R1, R2 and R3 and to the length (n) of the alkylside-chain. BZ compounds are distributed first (R1) by the type of substituents at the C-5 (C-6) position of the benzimidazole system and second (R2) by the substituents on the 2-phenyl ring.

Four AO derivatives (AO5, AO11, AO14 and AO15) displayed activities > 90% in the initial screening at 100 µM against L1 T. muris, but only AO14 showed an IC50 < 10 µM. IC50 values of the other three compounds were 25.6, 17.5 and 46.0 µM, respectively (Table 1). For AA derivatives, only compound AA18 reached an activity > 90% (93.55%) in the initial screening showing an IC50 value of 21.9 µM (Table 2), while five BZs (BZ1, BZ2, BZ6, BZ12 and BZ13) reached activities > 90% at 100 µM. IC50 values in the tested BZs were > 15 µM except for BZ12 and BZ6 with values of 8.89 and 4.17 µM, respectively, against L1 T. muris (Table 3).

Table 1 Base structure and results of L1 assays for aminoalcohol (AO) derivatives against T. muris
Full size table
Table 2 Base structure and results of L1 assays for diamine (AA) derivatives against T. muris
Full size table
Table 3 Base structure and results of L1 assays for benzimidazole (BZ) derivatives against T. muris
Full size table

Regarding SIs obtained on L1 assays, only five compounds belonging to the three families tested (AO14, AA18, BZ2, BZ6 and BZ12) obtained values > 1 on both Caco2 and HepG2 cell lines, with BZ6 reaching the highest SI values, 5.41 in Caco2 cells and 4.21 in HepG2 cells.

The assay performed with AO14, BZ12 and BZ6 against T. muris and H. polygyrus adults (Table 4) at a fixed concentration of 10 µM showed that BZ12 had an effect of 81% and 53% on T. muris and H. polygyrus adults after 72 h of exposure, respectively. BZ6 killed 100% of H. polygyrus adults at this concentration while it had an activity of 17% against T. muris. On the other hand, AO14 did not reach an efficacy > 23% against any parasite. IC50 values were calculated on those compounds with activities > 80% at a concentration of 10 µM; therefore, BZ12 showed an IC50 value of 8.1 µM on T. muris adults while BZ6 showed a lower IC50 of 5.3 µM on H. polygyrus adults. In the case of the SIs estimated on the adult stage, BZ6 displayed the highest SIs on both cell lines (4.3 in Caco2 and 3.1 in HepG2 cells), while BZ12 showed values closer to one (1.5 in Caco2 and 1.8 in HepG2 cells).

Table 4 Results of anthelmintic activity for selected compounds (AO14, BZ12 and BZ6) against T. muris and H. polygyrus adults at 10 µM
Full size table

Discussion

In recent years, the number of new anthelmintics compounds introduced to the market to control the infections produced by gastrointestinal nematodes has been limited, mainly because of economic difficulties in the development and marketing of new drugs [22]. In the last 2 decades, only four drugs have been introduced on the market: emodepside [23], monepantel [24], derquantel [25] and tribendimidine [26]. Therefore, there is a clear need to develop novel anthelmintic drugs for the control of these parasitic worms in humans and farm animals. One of the approaches proposed to alleviate the severe scarcity of anthelmintics is the synthesis of new derivatives of known drugs. Although BZ resistance is present in many gastrointestinal species infecting livestock, the synthesis of novel BZ derivatives may lead to compounds with improved properties such as better solubility and pharmacokinetic profile, resulting in increased effectiveness [27]. Some promising compounds, such as tenvermectin [28], diisopropylphenyl-imidazole [29] and mebendazole hydrochloride [30], have been developed in recent years following this approach.

Based on these assumptions, in the present study, a total of 15 AO and 11 AA derivatives, both structurally related to sphingosine, and 15 benzimidazole derivatives were tested against L1 of T. muris and adult stages of T. muris and H. polygyrus. The anthelmintic activity of most of these compounds was previously tested in vitro against the gastrointestinal nematode infecting sheep Teladorsagia circumcincta [18, 21] and some of them were also tested against Leishmania spp. [31, 32], Trypanosoma spp. [17, 33] and Strongyloides venezuelensis [34].

The L1 assay has proven to be a good tool to screen new potential candidate compounds before carrying out adult motility assays, the in vitro assay of choice, which is more expensive, labour intensive and time-consuming, and it requires the use of live animals [19]. Moreover, the results obtained with the motility assay based on L1 seem to correspond to the findings observed with adult T. muris [35]. However, some studies showed that L1 appears to be more sensitive to drugs than older stages of T. muris [36, 37], which can facilitate the discarding compounds with no activity.

In the present study, 10 out of the 41 compounds tested showed activity > 90% against the L1 stage of T. muris at 100 µM, and only three, namely AO14, BZ12 and BZ6, reached an IC50 < 10 µM. The screening performed at a single final concentration of 10 µM on adults showed that only BZ12 and BZ6 had significant activity against the adult stage of T. muris and H. polygyrus, respectively.

Comparing the results obtained with these derivatives with the previous study carried out against T. circumcincta reveals that of the ten compounds screened at 100 µM that showed > 90% activity against T. muris L1, six (BZ1, BZ2, BZ6, AO11, AO15 and AA18) also showed ovicidal activity against T. circumcincta, but only BZ6 reached an IC50 value < 10 µM (IC50 = 6.54 µM). In the case of T. circumcincta L1, four of them (AO5, AO11, AA18 and BZ6) reached IC50 values < 10 µM (IC50 for AO5 = 2.87 µM, IC50 for AO11 = 1.21 µM, IC50 for AA18 = 6.29 µM and IC50 for BZ6 = 5.01 µM) and only AO5 and AO11 showed IC50 values < 10 µM (IC50 for AO5 = 5.55 µM, IC50 for AO11 = 4.58 µM) against T. circumcincta L3. Some of the compounds that did not show activity in the L1 T. muris assay had shown activity against other parasite models such as Trypanosoma brucei (compounds AO4 and AA19 with IC50 values close to 0.5 µM) and Leishmania spp. (compounds AA25 and AA26). This is also the case for the study carried out on S. venezuelensis L3, in which compounds AO6, AA18, AA19, AA24 and AA25 showed activity against this nematode (IC50 values ranging from 31.9 ± 0.5 μM to 39.1 ± 4.7 μM), but only compound AA18 showed activity against L1 of T. muris in the current study.

Thus, BZ6 seems to be the only compound reaching IC50 values < 10 µM in both eggs and L1 of T. circumcincta (IC50 = 6.54 µM in eggs and IC50 = 5.01 µM in L1) and also in L1 of T. muris (IC50 = 4.17 µM), with values quite close to each other). However, BZ6 did not have any affect against the adult stage of T. muris at a concentration of 10 µM (17.2% of activity), but it was effective against H. polygyrus adults (100% of activity) displaying an IC50 of 5.3 µM. On the other hand, BZ12 did not produce an effect against any of the stages of T. circumcincta, eggs, L1 or L3, but it showed activity against T. muris L1 with an IC50 of 8.89 µM. Moreover, this BZ12 reached an efficacy of 53.3 and 81.7% on the adult stage of H. polygyrus and T. muris at 10 µM, respectively, presenting an IC50 of 8.1 µM in the latter.

In terms of the relationship between the structure and efficacy of the compounds and focusing on the benzimidazole derivatives, the only group of compounds that has shown significant efficacy on the adult stage of the parasites in this study, we can observe that the presence of a mild basic group such as the NH2 group on R1 (BZ15) did not induce any measurable effect on the nematode viability, while the combinations of 5-Me–4’-OMe/Cl (BZ1 and BZ2), 5-Cl–4’-Cl (BZ6) and 5-NO2–4’-Cl/diMe (BZ12 and BZ13) produced a deadly effect > 90% on the initial screening of T. muris L1. Regarding the substituent present on the B-phenyl ring (R2), 4’-Cl− is required for the anthelmintic effect since all compounds with this substituent at this position showed anthelmintic activity on T. muris L1 (BZ2, BZ6 and BZ12), including here the two most potent compounds (BZ6 and BZ12), while double substitutions on this ring, such as 3’-NO24’-OMe (BZ4, BZ9 and BZ14) or 3’-NH2 4’-OMe (BZ10), led to inactivity. However, a di-substitution in position 2' and 6' with electron donating groups such as 2',6'-diMe in addition to a polar group in ring A such as 5-NO2 (BZ13), gave good anthelmintic inhibitory activity in T. muris L1 (99.40 inhibition at 100 µM), although its IC50 was > 10 µM.

Comparing the results of the adult motility assay of the present study with previous experiments using the marketed human drugs (ABZ, MBZ, LEV and PYR) showed that the IC50 values obtained are much lower (8.1 µM for BZ12) since BZ compounds showed a lack of activity on T. muris adults and LEV and PYR displayed IC50 values around 68 and 57 µM, respectively [19].

All compounds tested against L1 had a possible toxic potential, as their SIs were very close to one, except BZ6 and AO14, which reached values > 4 in both cell lines. Regarding the SIs obtained in the adult assays, although they were in any case > 1, BZ6 seems to be a safer candidate than BZ12, as it had SI values of 4.3 for Caco2 cells and 3.1 for HepG2 cells.

Conclusions

Compounds BZ6 and BZ12 could represent a starting point for the synthesis of further structurally related compounds, as they showed activity against the adult stage of H. polygyrus and T. muris, respectively.

Availability of data and materials

The datasets supporting the conclusions of this article are included within the article text and additional files.

Abbreviations

AA:

Diamine

ABZ:

Albendazole

ADMET:

Absorption, distribution, metabolism, excretion and toxicity

AO:

Aminoalcohol

BZ:

Benzimidazole

CC50 :

Cytotoxic concentration 50

IC50 :

Inhibitory concentration 50

IVM:

Ivermectin

LEV:

Levamisole

MBZ:

Mebendazole

PYR:

Pyrantel pamoate

SI:

Selectivity index

References

  1. World Health Organization. Investing to overcome the global impact of neglected tropical diseases. Geneva, Switzerland: WHO; 2015.

    Google Scholar 

  2. Hotez PJ, Brindley PJ, Bethony JM, King CH, Pearce EJ, Jacobson J. Helminth infections: the great neglected tropical diseases. J Clin Invest. 2008;118:1311–21.

    Article  CAS  Google Scholar 

  3. Jourdan PM, Lamberton PHL, Fenwick A, Addiss DG. Soil-transmitted helminth infections. Lancet. 2018;391:252–65.

    Article  Google Scholar 

  4. Viswanath A, Yarrarapu SNS, Williams M. Trichuris Trichiura. In: StatPearls. Treasure Island (FL): StatPearls Publishing. 2022.

  5. Charlier J, van der Voort M, Kenyon F, Skuce P, Vercruysse J. Chasing helminths and their economic impact on farmed ruminants. Trends Parasitol. 2014;30:361–7.

    Article  Google Scholar 

  6. Charlier J, Rinaldi L, Musella V, Ploeger HW, Chartier C, Vineer HR, et al. Initial assessment of the economic burden of major parasitic helminth infections to the ruminant livestock industry in Europe. Prev Vet Med. 2020;182:105103.

    Article  CAS  Google Scholar 

  7. World Health Organization. Model List of Essential Medicines (21th list). Geneve, Switzerland: WHO; 2021.

    Google Scholar 

  8. Keiser J, Utzinger J. Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis. JAMA. 2008;299:1937–48.

    Article  CAS  Google Scholar 

  9. Speich B, Ali SM, Ame SM, Bogoch II, Alles R, Huwyler J, et al. Efficacy and safety of albendazole plus ivermectin, albendazole plus mebendazole, albendazole plus oxantel pamoate, and mebendazole alone against Trichuris trichiura and concomitant soil-transmitted helminth infections: a four-arm, randomised controlled trial. Lancet Infect Dis. 2015;15:277–84.

    Article  CAS  Google Scholar 

  10. Moser W, Schindler C, Keiser J. Efficacy of recommended drugs against soil transmitted helminths: systematic review and network meta-analysis. BMJ. 2017;358:j4307.

    Article  Google Scholar 

  11. Rose Vineer H, Morgan ER, Hertzberg H, Bartley DJ, Bosco A, Charlier J, et al. Increasing importance of anthelmintic resistance in European livestock: creation and meta-analysis of an open database. Parasite. 2020;27:69.

    Article  Google Scholar 

  12. Kaplan RM. Biology, epidemiology, diagnosis, and management of anthelmintic resistance in gastrointestinal nematodes of livestock. Vet Clin North Am Food Anim Pract. 2020;36:17–30.

    Article  CAS  Google Scholar 

  13. Martínez-Valladares M, Valderas-García E, Gandasegui J, Skuce P, Morrison A, de Castilla Gómez Agüero V, et al. Teladorsagia circumcincta beta tubulin: the presence of the E198L polymorphism on its own is associated with benzimidazole resistance. Parasit Vectors. 2020;13:453.

    Article  Google Scholar 

  14. Monroy FG, Enriquez FJ. Heligmosomoides polygyrus: a model for chronic gastrointestinal helminthiasis. Parasitol Today. 1992;8:49–54.

    Article  CAS  Google Scholar 

  15. Klementowicz JE, Travis MA, Grencis RK. Trichuris muris: a model of gastrointestinal parasite infection. Semin Immunopathol. 2012;34:815–28.

    Article  Google Scholar 

  16. Del Olmo E, Molina-Salinas G, Escarcena R, Alves M, López-Pérez JL, Hernandez-Pando R, et al. Simple dihydrosphyngosine analogues with potent activity against MDR-Mycobacterium tuberculosis. Bioorg Medi Chem Lett. 2009;19:5764–8.

    Article  CAS  Google Scholar 

  17. Del Olmo E, Diaz-González R, Escarcena R, Carvalho L, Bustos LA, Navarro M, et al. Diamine and aminoalcohol derivatives active against Trypanosoma brucei. Bioorg Med Chem Lett. 2012;22:440–3.

    Article  Google Scholar 

  18. Escala N, Valderas-García E, ÁlvarezBardón M, de Castilla Gómez Agüero V, Escarcena R, López-Pérez JL, et al. Synthesis, bioevaluation and docking studies of some 2-phenyl-1H-benzimidazole derivatives as anthelminthic agents against the nematode Teladorsagia circumcincta. Eur J Med Chem. 2020;208:112554.

    Article  CAS  Google Scholar 

  19. Wimmersberger D, Tritten L, Keiser J. Development of an in vitro drug sensitivity assay for Trichuris muris first-stage larvae. Parasit Vectors. 2013;6:42.

    Article  CAS  Google Scholar 

  20. Karpstein T, Pasche V, Häberli C, Scandale I, Neodo A, Keiser J. Evaluation of emodepside in laboratory models of human intestinal nematode and schistosome infections. Parasit Vectors. 2019;12:226.

    Article  Google Scholar 

  21. Valderas-García E, de la Vega J, ÁlvarezBardón M, de Castilla Gómez Agüero V, Escarcena R, López-Pérez JL, et al. Anthelmintic activity of aminoalcohol and diamine derivatives against the gastrointestinal nematode Teladorsagia circumcincta. Vet Parasitol. 2021;296:109496.

    Article  Google Scholar 

  22. Geary TG, Sakanari JA, Caffrey CR. Anthelmintic drug discovery: into the future. J Parasitol. 2015;101:125–33.

    Article  Google Scholar 

  23. Altreuther G, Borgsteede FHM, Buch J, Charles SD, Cruthers L, Epe C, et al. Efficacy of a topically administered combination of emodepside and praziquantel against mature and immature Ancylostoma tubaeforme in domestic cats. Parasitol Res. 2005;97:S51–7.

    Article  Google Scholar 

  24. Kaminsky R, Ducray P, Jung M, Clover R, Rufener L, Bouvier J, et al. A new class of anthelmintics effective against drug-resistant nematodes. Nature. 2008;452:176–80.

    Article  CAS  Google Scholar 

  25. Little PR, Hodges A, Watson TG, Seed JA, Maeder SJ. Field efficacy and safety of an oral formulation of the novel combination anthelmintic, derquantel-abamectin, in sheep in New Zealand. N Z Vet J. 2010;58:121–9.

    Article  CAS  Google Scholar 

  26. Xiao SH, Hui-Ming W, Tanner M, Utzinger J, Chong W. Tribendimidine: a promising, safe and broad-spectrum anthelmintic agent from China. Acta Trop. 2005;94:1–14.

    Article  CAS  Google Scholar 

  27. Zajíčková M, Nguyen LT, Skálová L, Raisová Stuchlíková L, Matoušková P. Anthelmintics in the future: current trends in the discovery and development of new drugs against gastrointestinal nematodes. Drug Discov Today. 2020;25:430–7.

    Article  Google Scholar 

  28. Fei C, She R, Li G, Zhang L, Fan W, Xia S, et al. Safety and clinical efficacy of tenvermectin, a novel antiparasitic 16-membered macrocyclic lactone antibiotics. Eur J Pharm Sci. 2018;117:154–60.

    Article  CAS  Google Scholar 

  29. Blanco MG, Vela Gurovic MS, Silbestri GF, Garelli A, Giunti S, Rayes D, et al. Diisopropylphenyl-imidazole (DII): a new compound that exerts anthelmintic activity through novel molecular mechanisms. PLoS Negl Trop Dis. 2018;12:e0007021.

    Article  CAS  Google Scholar 

  30. Brusau EV, Cami GE, Narda GE, Cuffini S, Ayala AP, Ellena J. Synthesis and characterization of a new mebendazole salt: mebendazole hydrochloride. J Pharm Sci. 2008;97:542–52.

    Article  CAS  Google Scholar 

  31. Del Olmo E, Alves M, López JL, Inchaustti A, Yaluff G, de RojasArias A, et al. Leishmanicidal activity of some aliphatic diamines and amino-alcohols. Bioorg Med Chem Lett. 2002;12:659–62.

    Article  Google Scholar 

  32. Abengózar MÁ, Bustos LA, García-Hernández R, de Fernández Palencia P, Escarcena R, Castanys S, et al. Mechanisms of action of substituted β-amino alkanols on Leishmania donovani. Antimicrob Agents Chemother. 2015;59:1211–8.

    Article  Google Scholar 

  33. Júnior CO, Alves RO, Rezende CA, da Costa CF, Silva H, Le Hyaric M, et al. Trypanocidal activity of lipophilic diamines and amino alcohols. Biomed Pharmacother. 2010;64:624–6.

    Article  Google Scholar 

  34. Legarda-Ceballos AL, López-Abán J, Del Olmo E, Escarcena R, Bustos LA, Rojas-Caraballo J, et al. In vitro and in vivo evaluation of 2-aminoalkanol and 1,2-alkanediamine derivatives against Strongyloides venezuelensis. Parasit Vectors. 2016;9:364.

    Article  Google Scholar 

  35. Silbereisen A, Tritten L, Keiser J. Exploration of novel in vitro assays to study drugs against Trichuris spp. J Microbiol Methods. 2011;87:169–75.

    Article  CAS  Google Scholar 

  36. Keiser J, Tritten L, Silbereisen A, Speich B, Adelfio R, Vargas M. Activity of oxantel pamoate monotherapy and combination chemotherapy against Trichuris muris and hookworms: revival of an old drug. PLoS Negl Trop Dis. 2013;7:e2119.

    Article  CAS  Google Scholar 

  37. Tritten L, Silbereisen A, Keiser J. Nitazoxanide: In vitro and in vivo drug effects against Trichuris muris and Ancylostoma ceylanicum, alone or in combination. Int J Parasitol Drugs Drug Resist. 2012;2:98–105.

    Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Financial support came from MINECO: RETOS (AGL2016-79813-C2-1R/2R) and Junta de Castilla y León co-financed by FEDER, UE [LE020P17]. EVG was funded by FPU17/00627; VCGA and MAB are recipients of Junta de Castilla y Leon (JCyL) (LE082-18, LE051-18, respectively) and MMV by the Spanish “Ramon y Cajal” Programme (Ministerio de Economía y competitividad; MMV, RYC-2015-18368).

Author information

Authors and Affiliations

  1. Instituto de Ganadería de Montaña, CSIC-Universidad de León, 24346, Grulleros, León, Spain

    Elora Valderas-García, Verónica Castilla-Gómez de Agüero & María Martínez-Valladares

  2. Departamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, 24071, León, Spain

    Elora Valderas-García, María Álvarez-Bardón & Rafael Balaña-Fouce

  3. Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051, Basel, Switzerland

    Cécile Häberli & Jennifer Keiser

  4. University of Basel, 4003, Basel, Switzerland

    Cécile Häberli & Jennifer Keiser

  5. Departamento de Ciencias Farmacéuticas: Química Farmacéutica, Facultad de Farmacia, Universidad de Salamanca, CIETUS, IBSAL, 37007, Salamanca, Spain

    Nerea Escala, Jennifer de la Vega & Esther del Olmo

  6. Departamento de Sanidad Animal, Facultad de Veterinaria, Universidad de León, 12, 24071, León, Spain

    Verónica Castilla-Gómez de Agüero & María Martínez-Valladares

Authors
  1. Elora Valderas-García
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cécile Häberli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. María Álvarez-Bardón
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nerea Escala
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Verónica Castilla-Gómez de Agüero
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jennifer de la Vega
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Esther del Olmo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rafael Balaña-Fouce
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jennifer Keiser
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. María Martínez-Valladares
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, MMV, RBF and JK; methodology, EVG, CH, MAB, NE, JDV, VCG; drafting the manuscript EVG; funding acquisition MMV, RBF, EDO; experimental design, EVG and MMV. All authors read and approved the final manuscript.

Corresponding author

Correspondence to María Martínez-Valladares.

Ethics declarations

Ethics approval and consent to participate

Experiments were approved by national and cantonal Swiss authorities (permission no. 2070).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Valderas-García, E., Häberli, C., Álvarez-Bardón, M. et al. Benzimidazole and aminoalcohol derivatives show in vitro anthelmintic activity against Trichuris muris and Heligmosomoides polygyrus. Parasites Vectors 15, 243 (2022). https://doi.org/10.1186/s13071-022-05347-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13071-022-05347-y

Keywords

Parasites & Vectors

ISSN: 1756-3305

Contact us