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Soil-transmitted helminthiasis (STH), one of 20 neglected tropical diseases, afflicts about a quarter of the world’s population. A handful of medications, albendazole, mebendazole, pyrantel pamoate, levamisole, and ivermectin, have long constituted the cornerstone of therapy for these infections in both humans and animals. The continuous and long-term reliance on these small range of compounds has led to the emergence of drug resistance in many helminthic strains in animals. The threat of resistance also seems inevitable in humans thereby hampering the World Health Organization’s efforts to control or eradicate these neglected tropical illnesses. Hence, there is an urgent need for the discovery and development of new treatment options with broad spectrum activity against various helmintic infections that act via novel mechanisms of action. Different strategies are employed in this endeavor which include the identification of promising compounds from natural and synthetic origin, drug repurposing and modification of existing drugs, and vaccine development. The prospect of a “pan-anthelmintic vaccine” also seems encouraging, despite the various obstacles facing the development of vaccines. Here we discuss drug discovery and development efforts for STH.
Department of Pharmaceutical Chemistry and Pharmacognosy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
Solomon Tadesse*
Department of Pharmaceutical Chemistry and Pharmacognosy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
*Address all correspondence to: solomon.tadesse@aau.edu.et
1. Introduction
Helminthes are large, multicellular, invertebrates with well-developed organ systems with characteristic elongated, flat, or round bodies. This broad range of organisms are mostly active feeders and visible to the naked eye in their adult stages. “Helminth” is a general term for worms. Platyhelminthes (flatworms) and Nemathods (round worms) are recognized as the two parasitologically important phyla (Figure 1) of heminths [1, 2, 3]. Nematodes, the focus of this book, are unsegmented, long cylindrical worms that are tapered at both ends. The alimentary canal is complete with a mouth and anus, where a mouth with three lips is present in some intestinal nematodes, and the mouth contains cutting plates in some. Typically, nematodes are bisexual and males are generally smaller. For fertilization, coupling of the sexes is required except for Strongyloides [1, 4, 5].
Figure 1.
Helmintic infections of humans; * Neglected tropical diseases.
Typically, worms reside in the gastrointestinal tract but may also burrow into other organs like the liver (Fasciola hepatica), lung (Paragonimus westermani), muscle (cysticercosis), skin (Strongyloides), lymph (Wuchereria bancrofti), eye (Onchocerca volvulus), brain (Paragonimus sp.), and other tissues [6, 7, 8].
Helminths have been affecting human beings throughout the history of mankind and still continue to be major causes of mortality and morbidity [9]. Infections caused by helminthic parasites are among the most widespread infections, affecting a vast population of tropical regions and posing an immense risk to health [10, 11]. In these warm regions, STH are endemic [5].
Ancylostoma duodenale, Ascaris lumbricoides, Necator americanus, and Trichuris trichiura [5], referred to as STH, are the four most important human gastrointestinal nematodes. Infections with STH occur after embryonic eggs or tissues of another host containing larval forms of nematodes are ingested. Eggs passed through feces take about 3 weeks to mature in the soil before they are infectious, hence the name soil-transmitted. Consequently, there is no direct person-to-person transmission, or infection from fresh feces and reinfections occur only as a result of contact with infective stages in the environment [1, 4, 5]. STH is one of the important infections from neglected tropical diseases where 8 out of 20 diseases are caused by helminths [12].
Almost 2 billion people (about a quarter of the world’s population) are infected with soil-transmitted helminthes worldwide. Approximately 270 million preschool children and more than 550 million school-age children live in areas where these parasites are extensively transmitted. Approximately 250 million girls and adult women are living in areas that are endemic for STH. Infections are widely distributed, with the greatest numbers occurring in sub-Saharan Africa, the Americas and Asia. [5].
These infections are chronic, mostly asymptomatic, which makes treatment and eradication of the diseases tricky. It can take years for existing infections to resolve, while at the same time, superinfections or reinfections are fairly common occurrences for people who live in endemic communities [13, 14]. According to Wakelin (1996), worms trigger different parasite-mediated immune regulations in the host [2]. Helminthes also evade host immune systems via various strategies including motility [15].
In animals, parasitic diseases cause substantial morbidity and mortality worldwide, as well as considerable losses in food production [16]. These diseases are the prime causes of poor livestock productivity in many developing countries [17, 18, 19]. In areas where extensive grazing is practiced, helminthic infections are a serious threat to small ruminants resulting in substantial economic losses [20]. Among helminths, nematodes are the most important parasite group of poultry [21], ruminants [16, 19], equids [18, 22, 23], and domestic animals [24].
This chapter discusses the medications in use for STH as well as compounds in the pipeline—preclinical and clinical candidates. Also, it gives insight into the efforts and advances made in the development of vaccines.
Proper hygiene maintenance is one of the most important measures to prevent helminthic infections [25]. At present, the most popular pharmacological means for controlling the disease is the use of anthelmintic drugs [26]. Anthelmintics are drugs that destroy or expel parasitic intestinal worms from the body, by either stunting (vermifuges) or killing (vermicides) [6]. As in all antibiotic drugs, the anthelmintic drugs are expected at metabolic targets that are present in the parasite, but are either absent from or have diverse characteristics than those of the host [4].
Almost all drugs that are used to treat human helminth infections started out as veterinary medication. Antinematoda drugs against pinworm, whipworm, hookworms, ascarids and strongyloides include piperazine, benzimidazoles, imidazothiazoles, tetrahydropyrimidines, macrocyclic lactones, amino-acetonitrile derivatives, spiroindoles, cyclooctadepsipeptides, aminophenylamidines, and organophosphates.
Of the antinematoda medications, the ones used for the treatment of STH are reviewed briefly (Table 1 and Figure 2). Albendazole (1), Mebendazole (2), Levamisole (3), Pyrantel pamoate (4), and Ivermectin (5) are drugs used in the prevention, treatment, and eradication of STH at different capacities and places. In endemic areas (prevalence >50%), WHO recommends annual/biannual intervention with 1 and 2. The cure rate for the intervention with benzimidazoles against Ascariasis is high while it is less efficient with Trichiuriasis.
Epidemiology and treatment options of soil-transmitted helmintiasis.
Figure 2.
Chemical structures of anthelmintics used for STH treatment.
2.1 Benzimidazoles
Benzimidazoles are Benzo derivatives of Immidazole. The name benzimidazole is the most popular yet the terms benziminazole, benzoglyoxaline, and 1,3-benzdiazole are also used to describe the compound class. This pharmacophore is found in lots of bioactive compounds with different biological activities. Since the mid-1990s, the therapeutic potential of the class has been and continues to be explored. A range of compounds are approved and available for varied clinical uses with this heterocyclic nucleus. The different derivatives with their varied uses (antimicrobial, antiparasitic, antihypertensive, anti-inflammatory, anticancer, and antiulcer) and their modes of action are compiled and available in a number of publications [29, 30, 31, 32].
One of the benzimidazoles approved clinical uses is as anthelmintic drugs. They are the only true broad-spectrum antibiotics active against nematodes, trematodes, and to some extent cestodes. The discovery of thiabendazole in 1961 [33] and its approval as anthelmintic revolutionized treatment. In the years that followed, hundreds of benzimidazoles were synthesized but only a few evolved to be drugs.
Shortly after its discovery, it was found that thiabendazole undergoes enzymatic hydroxylation which renders it inactive [34]. To overcome this problem, investigators began to prepare second-generation benzimidazoles with structural modifications that might prevent metabolic inactivation. Combinations of the modifications at positions 2- and 5- of the molecule have provided the most active drugs [35]. Albendazole (1) and mebendazole (2) are among the successful compounds of the class.
The mode of action of these drugs is inhibition of microtubule polymerization [36, 37]. This is believed to be a result of the pseudo irreversible binding of the monomer tubulin which prohibits aggregation. This results in the observed effects, including inhibition of cellular transport and energy metabolism. Inhibition of these secondary events appears to play an essential role in the lethal effect on worms. Benzimidazoles progressively deplete energy reserves and inhibit the excretion of waste products and protective factors from parasite cells.
As these changes coincided with the disappearance of cytoplasmic microtubules, it was suggested that benzimidazoles act by inhibiting the microtubule-mediated transport of secretory vesicles in the helminth absorptive tissues with the released digestive enzymes being responsible for the observed tissue damage. The safety of these drugs is astounding considering tubulin is a ubiquitous protein. The principle of the high selective toxicity of benzimidazole anthelmintics is not entirely clear but it appears primarily to be due to the much stronger and irreversible binding interaction of the drugs with helminth as compared with mammalian tubulins [36]. Unfortunately, animal parasites with mutations in the β-tubulin gene have become resistant to benzimidazoles and other anthelmintics.
2.2 Imidazothiazole
The imidazothiazole nucleus is active against a broad range of nematodes yet does not have any efficacy toward flukes or tapeworms. The first of this class is the racemic mixture tetramisole. Later, it was found that the L-isomer, Levamisole (3), was much more active than both the racemic mixture and the D-isomer. To date, it is the only one of the classes to be used for clinical use [38].
The imidazothiazoles are nicotinic anthelmintics that act as agonists at nicotinic acetylcholine receptors (nACHR) of nematodes. Their anthelmintic activity is mainly attributed to their ganglion-stimulant (cholinomimetic) activity, whereby they stimulate ganglion-like structures in somatic muscle cells of nematodes. This stimulation first results in sustained muscle contractions, followed by a neuromuscular depolarizing blockade resulting in paralysis. The spastic paralysis of the worm results in its expulsion from the host. The detailed mode of action for 3 was investigated using the patch-clamp technique that at the single-channel level in Ascaris suum muscles, it causes activation of cation-selective channels, in addition to voltage-sensitive open channel-block and desensitization [39, 40, 41].
After the discovery, 3 has seen success over the years as an anthelmintic treatment both for veterinary and human use. The compound also has an immunomodulatory effect and has been approved as adjuvant therapy for cancer treatment [38]. Despite the compound’s efficacy for various conditions, it has a variety of side effects. The US FDA has dropped the drug from the market in the USA because of the side effects, yet it continues to be a treatment option in many countries as an anthelmintic.
2.3 Tetrahydropyrimidines
The first compound of this class, pyrantel (4), was introduced in 1966 as an anthelmintic. It however did not possess activity against whipworm [42]. To tackle this lack of efficacy derivatives of the compound were synthesized [43].
This group of antinematoda drugs shares the mode of action of imidazothiazoles. They are nicotinic agonists [44] possibly at the same receptor. Compounds of this class including 4, like 3 activate the L-subtype nAChRs in A. suum while some preferentially activate the N-subtype. Because of their levamisole-type pharmacological action, these groups of compounds also share the toxicity of imidazothiazoles.
2.4 Macrocyclic lactones
Avermectins and milbemycins (which are deglycosylated analogs) are the anthelmintic macrocyclic lactones. The avermectins and milbemycins are the macrolides produced through fermentation by soil-dwelling microorganism Streptomyces avermitilis [39]. MLs were introduced in the 1980s as antiparasitic agents with broad spectrum activity against nematodes and arthropods. It is a unique combination of killing both endo and ectoparasites affording them the name “edectocides” [44, 45]. Ivermectin (5), the semisynthetic derivative of abamectin, is one of the commercially available avermectin and the first and only approved endectocide for human use.
The macrocyclic lactones induce a reduction in motor activity and paralysis in both arthropods and nematodes. The parasitic effects are mediated through GABA and/or glutamate-gated chloride channels (GluCl), collectively known as ligand-gated chloride channels [46]. The endectocides cause paralysis and death of both arthropod and nematode parasites due to their paralytic effects on the pharyngeal pump which affects nutrient ingestion, and on the parasite somatic musculature limiting its ability to remain at the site of predilection in the host. In addition, MLs cause inhibitory effects on the female reproductive system and cause reductions in parasite egg production [40, 41, 47, 48].
Anthelmintic pharmacologic treatment options are few. Albeit very successful until recently, the chemicals used in the group of diseases are limited in number. The continuous and long-term reliance on these small range of compounds has led to the development of drug resistance in many helminthic strains [11, 18, 48, 49]. Resistance is observed in all classes of antinematoda drugs in animals.
Though resistance to STH and other nematode infections in humans has not been reported, reduced efficacy and low cure rates are observed in some endemic parts of the world. Cross-resistance, which is helminths developing resistance to two or more drugs with similar modes of action without direct previous exposure and side-resistance, where resistance develops for the same chemical family although belonging to different chemical groups, are common occurrences [50]. Hence, “resistance is inevitable” and better detection of the emergence of resistant helminths and devised strategies to cope with them once they do appear, should be in place [51].
Additionally, for a certain set of patients, such as pregnant and lactating mothers, certain anthelmintic medicines are contraindicated. These medications should also be used with caution in patients with hepatitis and in children under 2 years of age [11]. Although safety profiles for anthelmintic drugs are compelling, there still remains a lot unknown about their teratogenicity and embryotoxicity. Hence, there is no drug approved for treatment or prevention in the first trimester of pregnancy. There also exists ambiguity in the ethics of exposing women of reproductive age to such drugs [52]. To combat the above-stated challenges in anthelmintic treatment, the availability of new anthelmintic therapy will be essential over the next few years.
Development of more effective medicines and medicine to improve patient outcomes and in case of drug resistance of STH is stated as one of three critical actions in the roadmap to ending the neglect to attain the sustainable development goals [12]. Therefore, considerable efforts have been devoted to the development of new anthelmintic drugs, especially those with more pronounced efficacy in nematodes resistant to classical anthelmintics. The efforts, routes explored, promising results, challenges, and opportunities along the path of anthelmintic drug discovery are discussed in reviews [53, 54]. Drug discovery and approval of anthelmintic medication that can be used for human use have lagged behind for the past two decades except for the approval of two compounds (Figure 3).
Figure 3.
Timeline of approval of anthelmintics used for nematode infections in human.
Various approaches are used to this end. The synthetic approach has been the most successful in the past in particular with anthelmintic compounds. It is still continues to be one of the mainstays of drug discovery. The other route is finding effective treatment options from natural remedies and compounds from natural products. Drug repurposing from veterinary anthelmintics and medications for other indications, and combinations of existing anthelmintic medication are the other endeavors affording the promise of better control.
4.1 Natural products
Nature is a farm of unique compounds. A number of inimitable bioactive molecules have been isolated from natural sources. In the past few decades, however, natural product drug discovery has taken a backseat. According to Jayawardene et al. difficulties in access and supply, complexities of natural product chemistry, concerns about intellectual property rights, and greater optimism of success with collections of compounds prepared by combinatorial chemistry methods are the main reasons [55].
Recently, the interest in natural products as drug leads is being revitalized since technological and scientific developments are addressing some of the challenges [56]. In terms of anthelmintic drug discovery, the discovery and success of ivermectin hugely impacted the research in favor of natural products [57]. Over the past two decades, a vast number of plant species have been tested against parasitic nematodes such as Haemonchus contortus, A. suum, A. lumbricoides, and non-parasitic free-living nematodes like Caenorhabditis elegans and Pheretima posthuman [55]. Compounds from natural compounds with promising antinematoda activity (Figure 4) are discussed.
Figure 4.
Natural compounds with anthelmintic activity.
Screening of 7500 plant extracts from a library resulted in four αpyrones from two active plant extracts. Goniothalamin (6) from Cryptocarya novoguineensis and three kavalactones from Piper methysticum namely dihydrokavain (7), desmethoxyyangonin (8), and yangonin (9), were purified. All four compounds affected H. contortus in an irreversible manner at different stages of the nematode [58]. In a follow-up study, the latter two kavalactones were synthesized with 17 analogs to study the structure–activity relationships. Four of synthesized analogs showed activities far greater than either of the parent compounds. All the synthesized compounds including the original kavalactones did not show toxicity against human HepG2 hepatoma cells invitro with the most potent derivative showing the most selectivity [59].
A diverse set of natural compounds with prodigious potential to drug discovery is marine compounds. Fromiamycalin (10) from Monanchora unguiculata, halaminol A (11) from Haliclona sp. [60], phorioadenine A (12) from Phoriospongia sp. [61], and echinobetaine B (13) from Echinodictyum sp. [62] are anthelmintic compounds from marine sponges. The preliminary SAR of the two latter nematicides revealed the importance of the N-acyl side chain in compound 12 and the importance of 2-OMe and stereopurity of the pharmacophore.
4.2 Synthetic compounds
The synthesis of new compounds is a fruitful undertaking in terms of discovering new therapeutic options with novel mode of action [63]. Promising compounds from this undertaking are discussed (Figure 5). High throughput screenings of synthetic compounds and libraries have afforded a number of actives. Though this process of drug development is lengthy and expensive, it is still one of the most rewarding strategies.
Figure 5.
Synthetic compounds with anthelmintic activity.
Screening of molecules from compound libraries has afforded “Hit” compounds for further development and optimization. Discussed below are the promising compounds under development from this venture. Screening of 67,012 compounds in one non-parasitic, two parasitic nematode species, and two vertebrate models (HEK293 cells and zebrafish), identified 30 structurally distinct anthelmintic lead molecules. The family labeled Wact-11 was found to inhibit complex II at the Q-site with nematode specificity and nanomolar potency [64].
The ChemBridge DIVERset and Maybridge Hitfinder compound libraries of 26,000 compounds were screened affording 14 compounds anthelmintic actives with 5 of them having high nematode specificity [63]. Of the nematode selective compounds, CID 2747322 (14) was shown to act in a different biochemical pathway than benzimidazole, levamisole, ivermectin, and amino-acetonitrile derivatives. Following this, a structure–activity relationship study established the complex II inhibition action of the compound class, benzamide analogs [65, 66]. The study highlighted the relevance of the amide group for nematicide activity [66].
The “Open Scaffolds” library was screened for anthelmintic activity and the compound 1-methyl-1H-pyrazole-5-carboxamide, called SN00797439 (15), was identified as a “hit” compound exhibiting broad range activity [67]. Following this discovery, structural optimization of the hit compound SN00797439, resulted in the discovery of a pyrrolidine-oxadiazole series with the potential to become a novel class of anthelmintics because their potency is already on the level of commercial anthelmintics, with a significant cytotoxicity window and evidence that a broad anthelmintic spectrum is achievable. Current efforts are directed toward progressing the best compounds and assessing their efficacy and toxicity in vivo [68, 69, 70].
Screening of the “Kruz box,” 236 compounds from diverse chemical classes, afforded two compounds designated BLK127 (16) and HBK4 (17) that induced phenotypic changes in infective larval stages of H. contortus. Interestingly, compound BLK127 exerted a phenotype that was similar to a recently described lethal evisceration phenotype. HBK4, a benzimidaxole derivative, was markedly more potent on L4s than L3s [71]. In a consequent study, BLK127 was found to decrease the viability of adult H. contortus both in sensitive and resistant strains and showed no hepatotoxic effect, even at the highest concentration tested while HBK4 had no impact on the viability of adults and exhibited significant hepatotoxicity. The benzyloxy amide was more extensively metabolized with a glycine conjugate of 4-(pentyloxy)benzoic acid as the main BLK127 metabolite in ovine liver yet the biotransformation was found to be low in both strains of the nematode with no significant difference [63].
Five compounds, with scaffolds not described as nematicidal prior, were found to be active against C. elegans in testing a library of 175 compounds. One of the five actives, (1E,2E)-1,2-bis(thiophen-3-ylmethylene)hydrazine (18), was active as a nematicide, but innocuous to the vertebrate model zebrafish. Conjugation of an unsaturation (one or two double bonds) with an electronegative atom in the center of the molecule (N, O, or S) and an aromatic ring were observed patterns in 26 of 28 active compounds indicating that this type of structure constitutes a scaffold for future optimization. It is also important to highlight that five out of the six most potent nematicides were symmetric, with five-atom aromatic heterocycles as substituents [72].
Screening of 480 small-molecule compound libraries (Chemistry Research Laboratory, University of Oxford) against both eggs and adults of Trichuris parasites revealed two active chemotypes, one with a diaminothienopyrimidine scaffold [73]. OX02926 (19), 2,4-diaminothieno[3,2-d] pyrimidine, and three close neighbors exhibited activity. Though the compound reaches the activity threshold for lead compounds for drug development against the microfilarial nematode its small selectivity window of their activity against the parasite compared to cytotoxicity in a mammalian cell line needs particular attention. Other thienopyrimidines have broad utility in medicinal chemistry, but have not previously been described as having an anthelmintic activity which could mitigate the cost of drug development [73].
The other chemotype with the dihydrobenzoxazepinone scaffold, OX02983 (20), was effective at reducing the ability of eggs to establish infection in vivo, thus pointing the way to a potential environmental treatment for trichuriasis [74]. In efforts of improving efficacy, dihydrobenzoxazepinones analogs of OX02983 were studied affording an understanding of the SAR of the chemical group. From the study dihydrobenzoquinolinones are suggested as possible candidates for further improvement. It was demonstrated that the class of compounds and related compounds were active against multiple helminths across different phyla: nematodes and trematodes. The improvement of potency is still a point of progress [75].
Two 6-arylquinolines (21 and 22) showed activity comparable in potency to the nematicide levamisole against susceptible strains of H. contortus. These compounds were also active against the various drug-resistant strains. Evidence of activity against the important parasitic nematodes T. colubriformis and O. circumcincta was also reported [76]. 7-fluoro-(23), 7-chloro-(24), 7-bromo-(25) derivatives of benzopyrano[2,3-c]pyrazol-4(2H)-one also showed potent anthelmintic activities against the model nematode C. elegans. Although the compounds were not -cidal they strongly inhibited the development of nematodes, with the majority of larvae never progressing past the L1 stage. They also showed favorable toxicity toward the worms than human cell lines [77].
4.3 Drug repurposing and modification of existing drugs
Drug repurposing (also called drug repositioning, drug re-profiling, drug re-tasking, and therapeutic switching) is the process of developing new indications for existing drugs to achieve optimal potential and maximize the value of a therapeutic drug. Repositioned drugs include marketed drugs that are still under patent or patents that have expired, drugs that have moved through development and fallen at clinical or regulatory hurdles, and stereoisomers or metabolites of existing compounds. Drug repurposing accelerates the drug discovery and development process with relatively lower costs and reduced risks of failure since the molecules have existing clinical and/or preclinical data [78, 79]. Though the strategy is expected to let the most use out of the already known compounds a lot of hurdles like resources and access to information keep us from reaping the full benefits; the challenges and opportunities toward this undertaking are reported in Pushpakom et al.
In anthelmintic drug repurposing the main effort is to prove the efficacy of known anthelmintics for other helminth species in hopes of broader spectrum activity and cross-over development of veterinary anthelmintics for human use (Figure 6) [80]. A review by panic et al. reported the ongoing efforts for the approval of the benzimidazoles (flubendazole (26), fenbendazole (27), oxibendazole (28)), emodepsin (29), oxantel pamoate (30), tribendimidine (31), doramectin (32), and melbemycin (33) for human STH. The review also gives insight to the repositioning efforts of nitrazoxanide (34) and cyclosporine (35).
Figure 6.
Veterinary anthelmintics investigated for repurposing to human anthelmintics.
Emodepsin, the antnematoda cyclodepsipeptide approved for use in cats, has been shown to be effective in human models for STH. In nematodes, the over-activation of the SLO-1 receptors by 29 is likely to induce a potassium efflux triggering a hyperpolarization of the neurons that results in a decreased synaptic transmission and muscle contraction, leading notably to a paralysis of the worm pharynx [81]. The drug is currently in clinical trials for T. trichiura and Hookworm infections in adults (ClinicalTrials.gov).
Furthermore, 29 and its precursor, PF1022A (36), were found to be fully effective against benzimidazole-, levamisole- and ivermectin-resistant populations of H. contortus in sheep as well as an ivermectin-resistant C. oncophora population in cattle which reinforces endeavor [82]. Compound 36, isolated from cultured mycelia of Mycelia sterilia is described to have a different mode of action from the known anthelmintics which makes it ideal for the development of new medication [83, 84]. The compound is also shown to be effective in human STH models [85]. PF1022H (37) is a bis-hydroxy derivative of 36, which perhaps represents an interesting precursor for new related anthelmintics [86].
In the effort for repurposing other compounds active for various other conditions are investigated for their anthelmintic activities and proved effective (Figure 7). Sertraline (38), paroxetine (39), and chlorpromazine (40), are antidepressant and antipsychotic medications that exhibited anthelmintic activity across a broad range of nematode (both free-living and parasitic) and trematode species. The drugs were active on nematodes resistant to existing anthelmintics that target ion channels and microtubules. Furthermore, mutations in the genes responsible for these drugs’ anti-depressant or anti-psychotic effects in humans did not eliminate their anthelmintic actions. The findings suggest the modes of anthelmintic action of the compounds might perhaps be novel, which warrants further investigation [87].
Figure 7.
Drugs and compounds of other indications investigated for repurposing to anthelmintics.
SNS-032 (41) and AG-1295 (42) are kinase inhibitors identified for their anthelmintic activities against H. contortus while screening the “stasis box.” Compound 41 is cyclin-dependent kinase (CDK)-2, −7, and -9 inhibitor and entered phase I clinical trials. Compound 42, a 6,7-dimethyl-2-phenylquinoxaline, is a protein tyrosine kinase (PTK) inhibitor targeting the platelet-derived growth factor (PDGF) receptor kinase. Both compounds showed comparable activities but the former has a higher toxicity profile [88]. Hence, SAR study of tetrahydroquinoxaline chemical series, 42 and its 14 analogs, was attempted. All compounds were shown to have inhibitory effects on larval motility, development, and growth, and induced evisceration through the excretory pore in xL3s. Though the typical kinase (PTK) was not characterized in the test nematode the results point to a mode of action involving dysregulation of morphogenetic processes during a critical time frame, in agreement with the expected behavior of a tyrosine kinase inhibitor [89]. Currently, the metabolism, resistance level, and mechanism of action of these candidates are being tested.
A quinoline derivative, ABX464 (43), was found to be active aganist H. contortus and C. elegans from the “pandemic response box.” The potent in vitro effect on the most pathogenic and reproductively active stage of H. contortus encourages the optimization of 43via SAR studies and toxicity evaluation of analogs with increased potency. The compound was first reported as a novel anti-HIV molecule [90] and is now undergoing phase 2 clinical trials as an anti-inflammatory compound for the treatment of ulcerative colitis, Crohn’s disease, and rheumatoid arthritis in humans (ClinicalTrials.gov, NIH). Currently, the mechanism of action of the compound in nematodes is unknown, but could be explored using genomic, transcriptomic, and/or proteomic methods [91].
EVP4593 (44) was found to be a promising hit of four hits out of a library 2745 compounds discovered from a repurposing library owing to its potent anthelmintic activity and favorable cytotoxicity. Though no in vivo studies have been reported, considering its novel and unexplored chemical scaffold for anthelmintic activity, the observed broad anthelmintic profile, and its relatively high selectivity index, the compound may be an interesting starting point for further optimization [92].
Screening of 1600 FDA-approved compounds revealed two active compounds, trichlorfon (45) and bitoscanate (46), against hookworm and Trichurus species in vivo. Though the compounds have clear limitations, related pharmacophores could be of value [93]. Thirty-two hit molecules, of which 30 were analogs of the commercial product chlorfenapyr (47), were identified from a library of pesticide analogs. The mode of anthelmintic action is expressed to be similar to the compound class’s insecticidal action which is oxidative phosphorylation. The other two potent inhibitors of H. contortus motility were derivatives of fipronil (48). The latter two had higher cytotoxicity while the arylpyrrole derivatives showed less cytotoxicity [94].
Metronidazole (49) and derivatives exhibited anthelmintic activity comparable with that of albendazole and can be further developed as alternative anthelmintic agents to combat drug resistance that will certainly follow the use of monotherapy in treating helminthiasis [95].
Another approach for drug discovery is the modification of already existing anthelmintic drugs (Figure 8) to improve their efficacy and/or bioavailablity. 1,2,5-tri-substituted benzimidazole derivatives (50), affected adult worm motility more than albendazole. Because of substitution in these compounds would not meet the structure–activity relationships conditions necessary to bind to tubulins at the anthelmintic benzimidazole binding site. These new benzimidazole derivatives could bind tubulins at a different site from 2-methyl-benzimidazole carbamate, or present a different drug target, so further studies should be conducted to identify the pharmacological target of these potential anthelmintic compounds [96]. Another modification on the benzimidazole scaffold, a coumarin-benzimidazole hybrid (51), was found to paralyze earthworms equipotent to albendazole. Also, its mortality activity was marginally greater than the activity of albendazole at all concentrations. The activity was in agreement with prediction of activity spectrum of substances (PASS) projections. In addition, a comparative analysis of calculated Lipinski’s parameters reveals that the compound has the propensity to be orally bioavailable [97]. Similarly, organometallic derivatives of albendazole were synthesized and tested for their anthelmintic activities. T. muris and H. conturtus were the two nematodes in the collection of parasites. Two compounds showed some activity toward the former but none of the analogs were active against the latter [98].
Figure 8.
Modification of already existing anthelmintic drugs for new anthelmintic discovery.
Tenvermectin (52) is a macrolide designed after successful avermectins. It was obtained from a genetically engineered S. avermitilis [99]. The components tenvermectin A and B were found to be effective in expelling Ascaris and Trichuris sp. with tenvermectin A being less toxic than ivermectin [100].
4.4 Combination of existing anthelmintics
Combination of anthelmintics is another approach being investigated to increase the effectiveness of therapies and avoid or delay resistance. Drugs of different classes with different modes of action are combined to achieve better eradication of nematodes. Combination of moxidectin and albendazole for Trichuriasis is in clinical trials (ClinicalTrials.gov). Another combination investigated is oxantel pamoate with albendazole, mebendazole, and ivermectin for the treatment of tricuriasis and hookworm infections [101]. Triple therapy with albendazole, pyrantel pamoate, and oxantel pamoate is also stated to be more efficacious and tolerable in T. trichuria infections [102]. Combination therapies are considered in the condition that there does not exist resistance of all members of the combination.
As the global community strives to meet the target set for neglected tropical diseases in 2030, different strategies are set [12]. In parallel with environmental sanitation and hygiene intervention, mass deworming campaigns are undertaken in endemic areas. Despite making significant progress in reducing the burden of STH, deworming campaigns raise concerns about their long-term viability and the emergence of resistance. In addition, medications available at present fail to offer long-term protection against reinfection [15, 27]. Vaccination presents an attractive alternative for controlling STH infections because it allows for the interruption of infection, disease, and transmission in a single step [27]. The development of anthelmintic vaccines is fraud with hurdles. Selecting lead antigens, selection of adjuvants, mass production, efficacy, immunogenicity, and safety are some of the difficulties. The progress, challenges, lessons learned, and future perspectives of STH-vaccine development are reviewed in multiple articles [15, 103, 104].
Anthelmintic lead selections are more complex compared to vaccines for other anti-infectives because of the multiple life cycle stages of helminths each with stage specific antigen. As reviewed by Zawawi and Else, there are four types of anthelmintic leads [103]. Crude antigen preparations, irradiated extracellular vesicles/secretions, are native parasite molecules which sit at the host–parasite interface that induce immune responses. Recombinant proteins and DNA-based preparations are the other two lead antigens in the works. These are expressed to be safer and more convenient than crude preparations. Two recombinant protein vaccine candidates, Na-APR-1 and Na-GST, against the hookworm N. americanus are currently in clinical trials (ClinicalTrials.gov) for human use.
Epitopes are the fourth lead antigen molecule. They are identified via reversed volcanology approach based on immunological and bioinformatics tools. Antigens identified via these technologies are found to be stage specific and essential for the parasite biological process. MHC-II T-cell epitopes from T. trichiura genome sequence were identified in silico, incorporated into virus-like particles and tested in vivo in murine models. Vaccination results confirm epitope-based vaccines to be promising for development [105]. Another highly anticipated endeavor is the “pan-anthelmintic vaccine” which is to contain a combination of antigen or a consensus of antigens against all four STH as co-infections with two or more of the species is a common occurrence in endemic areas [106].
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Written By
Eyael Tewelde and Solomon Tadesse
Submitted: 17 June 2022Reviewed: 28 July 2022Published: 03 November 2022
Open access peer-reviewed chapter
