Advances in Pharmacology and Pharmacy 2(2): 30-45, 2014 http://www.hrpub.org DOI: 10.13189/app.2014.020203

Ecological, Physiological and Biochemical Adaptation in Helminth: Trends in Evolution of Anthelminthic Chemical Agents

M.Kh. Dzhafarov*, F.I. Vasilevich

K.I. Skryabin Moscow State Academy of Veterinary Medicine and biotechnology, 109472 Moscow, ul. Akademika Skryabina, 23 *Corresponding Author: [email protected]

Copyright © 2014 Horizon Research Publishing All rights reserved.

Abstract This review discusses the landmark market (both single- and multi- multicomponent), with anthelminthic substances – traditional medicine components, narrow to broad activity ranges, are based on compounds different categories of pluripotential synthetic and naturally belonging to a limited set of relatively safe and highly occurring compounds. Much attention is paid to the sections efficient active ingredients (substances) [1,2]. Anthelminthic devoted to recent discoveries (Emodepside, Monepantel, substances are synthetic non-organic and organic or natural Derquantel, Tribendimidine) and to some promising works. compounds. In the latter case, compounds are largely the The review is also focused on some aspects of molecular products of secondary bacterial, fungal and plant metabolism mechanisms of action of anthelminthic substances and of and may be used both in native and in chemically modified helminth adaptation to anthelminthic substances, and on form [3]. alternative worming treatment options. Based on the However, the intensive administration of anthelminthic systemic analysis of particular features of the chemical preparations leads to development of resistance, which is one structure of anthelminthic substances, the hypothesis on the of the ways of biochemical adaptation of helmiths to the viability of the targeted search for such compounds among first- and second-order environmental changes (the host and the derivatives of conditionally progenitor cyclic ecological niche occupied by the host, where certain stages hydrocarbons – benzene, indene, naphthalene, of the complex-cycle helminth metamorphoses take place), 1Н-cyclopenth [a]-naphthalene , anthracene and which necessitates regular renewal of the range of chemical phenanthrene – by alternating absolutely unsaturated and agents, among different measures. saturated structures, including heterocyclic analogues This review is aiming to classify anthelminthic substances containing nitrogen, oxygen and sulfur and different by their origin and to outline the prospects of search for new substitutes and functional groups, was voiced. anthelminthic chemical formulas, besides alternative Keywords Anthelmintic Substances, Folk Medicine, anthelminthic treatment methods. Non-Organic and Organic Anthelminthic Substances, Avermectins, Emodepside, Monepantel, Derquantel, Tribendimidine, Biological Methods of Helminthoses 2. Evolution in Chemotherapy of Control Helminthosis

2.1. Remedies of Traditional (Ethnic) Medicine 1. Introduction Traditional medicine has long tested many minerals, mushrooms, plants, animal tissues and biological substances It is well-known that humans occupy a certain niche in the of animal origin, e.g. snake and spider venom, milk [4], and ecosystem and, standing at the top of the food chain, they also animals themselves (e.g. leeches, bees etc.) to make interact constantly with environmental pathogenic micro- powders, infusions, ointments, extracts, mixtures etc. to treat and macro-organisms. Human evolution involved fighting various diseases [5], including helminthoses [6]. different diseases, including helminthoses. Even now Anthelminthic (anti-helminthic) substances as agents against helminthoses are still dangerous parasitoses of humans, parasite worms were initially called vermifuges (from Latin animals and plants. Chemotherapy and prevention are of vermus meaning worm, and fugere meaning to expel) [6]. high priority in control of these diseases. Numerous folk remedies [7] were created and included The entire variety of anthelminthic drugs available on the into reference books of ancient and medieval philosophers Advances in Pharmacology and Pharmacy 2(2): 30-45, 2014 31

and healers. For instance, the Ancient Egyptian papyrus of The anthelminthic effect of the wormseed sage (Artemisia Ebers (dated approx. 1550 B.C.) contains information on cinae) is due to the natural compound of santonin. It is a human snail fever and helminthes [6]. Hippocrates described sesquiterpenic lactone first extracted in 1830 by German some worms in his works (dated approx. 500 B.C.) and pharmacist Kahler (known as "apotheker Kahler") and introduced the terms of helminthos and ascaridos (in Greek, pharmaceutical student J.A. Alms from raw materials of the diseases caused by helminthes and ascarids, respectively) Russian origin [11], and introduced into medical practice in [8]. Ancient Roman physician Galen (approx. 129-200 A.C.), 1838 [12]. However, it was not until 1963 that its chemical one of the founders of pharmacology, suggested the methods structure was established [13]. Many other plants to make infusions and ointments (e.g. with plant extracts) (pomegranate, European aspen, male fern, tansy, certain called Galenic drugs; he also introduced the notion of active chamomiles, tobacco, pumpkin, garlic) were found to substances [9]. Avicenna’s Canon of Medicine (980-1037 possess anthelminthic properties [9, 14, 15]. For example, A.C.) mention malaria and many helminths, e.g. filixan for treatment of cestodiases is derived from the male Dracunculus [10]. These reference books abound in fern root extract (Dryopteris filixmas) [1]. Structural recommendations as to healing diseases caused by parasite formulas of some anthelminthic vegetal substances are worms, e.g. administration of wormseed sage in ascaridosis. provided below:

2.2. Inception of the Planned Chemotherapy The idea of using chemical compounds to treat animals and humans was proposed by hermetists (in the 4th to 16th centuries), in particular, by iatrochemists (iatrochemistry, or therapeutic chemistry, from the Greek iatrós, meaning physician) who were engaged in drug search and preparation (16th/ 18th centuries), applying the chemical substances known at that time [16], mostly the derivatives of Hg, As, Sb, Cu, Zn, Fe, S. For instance, Glauber’s sault (Na2SO410H2O) is still used in certain cases as a laxative, to expel intestinal worms [17]. The scientific foundations of chemotherapy of parasitoses (including helminthoses) were laid at the turn of the 20th century, as a result of establishment of the structural theory of organic and non-organic substances. P. Erlich, Nobel prize winner in 1908, having studied over 600 arsenic compounds, showed the possibility of targeted synthesis of drugs capable of influencing the infinitesimal organisms and proposed the term of ‘chemotherapy’. In 1910, as a result of his studies, the arsenic-containing drug of Atoxil [18] against trypanosomiasis (along with salvarsan fighting against syphilis) was put into clinical practice [19]. The beginning of use of suramin, a derivative of urea which can still be prescribed sometimes to patients with onchocercosis and sleeping dropsy (the limitations are due to its high toxicity), goes back to the same period (1916) [1]: 32 Ecological, Physiological and Biochemical Adaptation in Helminth: Trends in Evolution of Anthelminthic Chemical Agents

th Early in the 20 century, the simplest chlorine organic compounds, carbon tetrachloride CCl4 (1921) and hexachlorethane C2Cl6 (1928), started to be used against Fasciola hepatica [1]. Due to their toxicity for mammls, they have been mostly cancelled. However, hexichol (paraxylene chlorine derivative introduced in the USSR in 1964) remains in the list of anthelminthic substances in certain republics of the former USSR and in China (efficient against adult maritas) [20]:

Till the mid-20th century, non-organic compounds of arsenic (As), tin (Sn), stibium (Sb), fluor (F), hydrogen peroxide (H2O2), sulfur (S), oxygen О2, metallic arsenates – arsenate aluminum and dyad metals (Са, Сu, Zn, Sn), Fe (dyad and triad iron) were widely used as anthelminthic substances, despite the explosive growth in organic substances synthesis. For instance, against mature and immature helminthes, the efficient dose of copper acetoarsenite and calcium arsenate Ca3(AsO4)2 for lambs came to 0.3-0.5 g/capita [21], and the dose of copper sulfate (CuSO4 5H2O) for buffalo calves, 112 mg/kg of live weight [22]. At present, non-organics are not used as anthelminthic substances, due to their high toxicity and emergence of more efficient organic substances, e.g. albendazole, phenbendazole, praziquantel etc., which are used against monieziasis of ruminant and other parasitoses [6]. However, certain organoelemental (e.g. organometallic) compounds (e.g. sodium thioacetarsamid and As3+ based melarsomin) are used in dogs’ heartworm disease (caused by Dirofilaria immitis) [23]. Structural formulas of certain arsenic and stibium-containing substances are provided below [24,25]:

Chlorine, copper sulfate, and slack lime are still in the toolbox of veterinarians, cattle breeders and sanitary services for desinfection of reservoirs, stalls and other facilities. Studies are underway to create composite anthelminthic substances, e.g. albendazole and copper pectinate (II) (n = 20-30, molecular weight = 17,000-25,000 Da) [26]:

Advances in Pharmacology and Pharmacy 2(2): 30-45, 2014 33

2.3. Modern Anthelmintics 2.3.1. Phenothiazines and piperazines The breakthrough in chemotherapy of helminthoses occurred in the 1940/1950’s, with introduction of synthetic organic chemicals – phenothiazine (1940; the first phenothiazine, methylene blue, was applied as fabric dye) [27] and piperazine (1953) [28] – in nematodosis treatment:

Veterinarians still administer them, e.g. piperazine and its salts (adipinate, sulfate, phosphate) and phenothiazine are used in fur-farming, pig farming and aviculture as ascaridosis treatment, and DEC, in nematodoses (toxocariasis, filariasis, etc.) [1]. 2.3.2. Benzimidazoles and other heterocyclic anthelminthics The 1960’s saw introduction of efficient pluripotential anthelminthic drugs — benzimidazoles (the most numerous substances), imidazole thiazoles and tetrahydropirimidines into the clinical practice, for treatment of intestinal and non-intestinal nematodoses as well as cestodiases:

Thiabendazole (1961), albendazole (since 1972, it has been released for treatment of animal and human echinococcosis) [29], levamisole (1966) [30] and pyrantel (1966) [31] were the first representatives of the named anthelminthic substances. Some of them are still in use (often as part of multi-component anthelminthic substances) [1, 2]. Other nitrogen-containing heterocyclic substances emerged in the 1970’s, the most important of which were pyrazine isochinolines, e.g. prasiquantel (biltricide, discovered in 1977) administered for treatment of cestodiasis and trematodoses [32]. Prasiquantel showed excellent results and remains in the list of animal and human anti-schistosomiasis drugs [1,2,33]:

2.3.3. Salicylanilides This important anthelminthic class was discovered when searching for biocide properties in phenol compounds (phenols, biphenols, tiophenols etc.) administered as antimicrobial and fungicide agents (the well-known example is carbolic acid) (Lister J.,1867). These were niclozamide (Hecht G. et al., 1960), tribromsalan (Boray J.C.et al., 1965), clioxanide (Boray J.C. 34 Ecological, Physiological and Biochemical Adaptation in Helminth: Trends in Evolution of Anthelminthic Chemical Agents et al, 1965). More efficient substances were developed later: oxiclozanide (Broome A.W. et al., 1966), clozantel (Janssen M.A.C. et al., 1973) and rafoxanide (Mrozik H. et al., 1969), which are important in distomiasis control [47]:

2.3.4. Macrolides The 1980’s were the beginning of the era of natural avermectins (abamectin, doramectin) produced by soil bacteria Streptomyces avermitilis, and their pluripotential semi-synthetic derivatives (ivermectin, selamectin, etc.) against nematodes, insects and mites at very low doses (0.2-0.3 mg/kg) (Table 1) [34].

Table 1. Structural features of 16-membered anthelminthic macrolides

Substance 1 2 3 4 5

R(5), Н(5) R(4) R(13) R(25) С(22)-С(23)

Hypothetic elementary structure: “avermectin type” lacton nucleus Two homologues: Milbemycins, e.g. А , А 3 4 ОН, Н - Н СН -, С Н - single bond (native) 3 2 5 Respectively Oxim milbemycin А /А 3 4 =NOH the same the same the same the same (semi-synthetic) Nemadectin One homologue: 22-Н,23-hydrox ОН, Н the same the same (native) Isopenten-2-il-2 i-derivative Moxidectin 23-methoxym ОН, Н the same the same the same (semi-synthetic) (=NOСН3) Two homologues: Abamectin 4-(-L-oleandrozyl)- ОН, Н ОН sec-butyl, double bond (native) -L-oleandrozyl residual iso-propyl

Emamectin the same the same the same the same (semi-synthetic)

Eprinomectin the same the same the same the same (semi-synthetic)

Ivermectin the same ОН the same the same single bond (semi-synthetic) One homologue: Doramectin the same ОН the same double bond (native, in specific conditions)

NONE: Selamectin The residual of one (4-О-desoleandrosyl-5-deoxi-5-hydroxyli oleandrose molecule min-22,23-dihydrodoramectin) – =NOH ОН the same single bond (hydrolyzed deglycosilyzed di-saccharide semi-synthetic doramectin analogue 1,4-glycoside bond) Advances in Pharmacology and Pharmacy 2(2): 30-45, 2014 35

Several years prior to introduction of avermectins, representatives of another sub-group of 16-membered macrolides, milbemycins produced by actinomycetes S.hygroscopicus (Ssp. aureolacrimosus) as a mixture of compounds, were discovered. They are characterized by an absence of di-saccharine lateral chain at the С(13) position and by a presence of methyl (milbemycin А3), ethyl (milbemycin А4), isopropyl (milbemycin D) and secondary butyl (13-desoxi-22,23-dihydroavermectin В1а) groups as well as a saturated 22,23-connection (as with ivermectin) (1972) [35]. Semi-synthetic 5-oximins of А3 and А4 milbemycins are used as pesticides. Late in the 1980’s, nemadectins, congenerous with milbemycins, from S. hygroscopicus (ssp.noncyanogenus) with a hydroxyl group at С(23), unsaturated hydrocarbon radical at С(25) and, like with milbemycins, without a di-saccharine lateral chain at С(13), were discovered. Nemadectin is a raw material for deriving moxidectin (the active substance of the veterinary drug of cidectin for treatment and prevention of endoectoparasitoses: psoroptic scab, dictyocaulosis, intestinal strongylatosis, pediculation, oestrosis, hypodermosis [35]) (Table 1). Anti-parasitic effect is typical of all 16-membered macrolides having a structural nucleus with double bonds at 4,6,10 positions of the hypothetic parent saturated 16-membered lacton butadecenolide (8,10,14 positions, respectively, according to the adopted nomenclature of avermectins/milbemicyns), fragments of 1-oxahydrinden-5 and spiroacetal 1,7-dioxaspyro [5.5]undecan (or undecen-4) type and 7a-ОН-group, which we conventionally called the "avermectin lactone nucleus". The substituents at positions of 5, 13, 22, 23 and 25 macrolides just modulate the anti-parasite activity: one way or another, all of them show sufficient biological activity and found practical application. Therefore, avermectins / milbemycins are a suitable raw material for deriving new substances through their chemical modification, and when some particular substrate is selected, preference is given to the already available effective producing strain. This thesis is confirmed by introduction of semi-synthetic ivermectin (1979) [36, 37], doramectin (1993) [34], eprinomectin (1998) [38], selamectin (2000) [34]. Introduction of other newly discovered substances is expected [39, 40]. 2.3.4.1. Biological Activities of Avermectins The diversity of avermectins’ properties (in addition to anthelminthic, insecticidal and acaricidal activities) arouses interest in searchers [41]. Ivermectin blocks CANCER1-dependent growth in cells of benign and malignant tumors (type II neurofibromatosis, ovarian carcinoma etc.) resulting from inactivation of р21-protein-dependent kinase (CANCER1) [42, 43]. Inhibition of the yellow fever virus replication [44] and sporogony in Plasmodium falciparum and Anopheles gambiae by ivermectin has been recently discovered [45]; the anti-TB effect of avermectins was also established [46]. In light of these discoveries, obtaining and study of biological properties of new semi-synthetic derivatives of 16-membered lactones seems to be promising in search for new medicinal substances of different pharmacological groups. 2.3.5. Other Substances Besides the above basic anthelminthic classes, numerous substances of different chemical origin were obtained: e.g. hygromycin (aminoglycoside antibiotic and anthelminthic agent produced by Streptomyces hygroscopicus) [48], and organophosphoric drugs (metriphonate, citioate, etc.) [1], application of which is limited by low efficiency or significant side effects [6]:

2.4. Modes of Action Availability of a broad range of anthelminthic agents is due to the variety of hosts, heltminths, development of their drugs resistance and some other factors. The processes, in which the anthelminthic substance is involved from its getting into a patient’s body to producing the treatment effect, can be consolidated into two groups. The first includes physic-chemical and chemical interaction of the substance with environmental factors (рН, temperature, enzymes etc.) when it moves to the helminth’s location in the host’s body (Fig. 1), with the respective biochemical and physiological consequences. For instance, 36 Ecological, Physiological and Biochemical Adaptation in Helminth: Trends in Evolution of Anthelminthic Chemical Agents non-fermentative and fermentative changes are possible, as in case of dichlophos that is capable of spontaneous transformation in water solutions into a more active dichlorvos that interacts with the nicotinic receptor (naChR) (14), or nitazoxanide that quickly (in approx. 6 minutes) turns, in the blood plasma under enzyme impact, into active metabolites of tizoxanide and glucoronide tizoxanide that inhibit pyruvate ferredoxine oxidoreductase and thus undermine the helminth’s energy metabolism [49]. The second group includes the processes that ensure the anthelminthic agent transportation to target cells via investments (cuticle, tegument) or internal cavities (oral, pharyngeal and intestinal cavities) of the helminth and interaction with these cells (see Fig. 1).

Figure 1. Pattern of anthelminthic substance delivery to a helminth in the body and interaction with the target cell. By the nature of their interaction with the targeted cell, all anthelminthic agents can be divided into: quick-acting (2-4 hours, they inhibit ionotropic receptors) and slow-acting (1-4 days, they influence metabolic processes) [50] (Fig. 2). Substances included in the first group act as nAChR agonists (imidazol thiazoles, tetrahydropirimidines, pyrazine isochinolines, amino acetonitril derivatives etc.) and antagonists (phenothiazine, spiroindoles), allosteric modulators of GABAА-receptor and glutamate dependent chloride channels (GluCls) (16-membered macrolides — avermectins and milbemycins), GABA-ergic receptor (piperazine) agonists, Са2+-channel activators (praziquantel) and Са2+-dependent К+-channel SLO-1 activators (emodepside). Slow-acting -tubulin ligands (benzimidazoles) interfere with its polymerization and the microtubular apparatus formation, which leads to degenerative changes and other metabolic disorders in a nematode’s intestinal cells and cuticle. Other drugs of this group are SH-group containing substances (melarsomin); ChEI [carbamates, organophosphoric substances (metriphonate), diphenyl substances (biphenium, nitrozocanate and amoscanate]; cyclo- and lipoxygenases (e.g. DEC that interferes with arachidonic acid metabolism and blocks prostaglandin formation in the host, which leads to capillary constriction and occlusion to microfilaria; it increases microfilaria phagocytosis by vascular walls, lymphocytes and granulocytes; in addition, its effect is obviously related to the inducible NO-syntase); chitinases (in particular, clozantel that also has protone ionophoric activity that is synergic with chitinase inhibition); pyruvate ferredoxin oxidoreductase (nitazoxanide) [50, 51]. Advances in Pharmacology and Pharmacy 2(2): 30-45, 2014 37

Figure 2. Certain targets and transportation of anthelminthic substances to them (description in the text).

2.5. Efficacy The helminthosis chemoprevention and chemotherapy cost efficiency largely depends on correctness and appropriateness of methods used combined with efficiency of anthelminthic agents and with allowance for the helminth development cycle, particular features of the host, climate etc. For instance, mebendazole and thiabendazole act on trichinella intestinal forms, but not on incapsulated forms [33, 51]. Efficiency comparison for anthelminthic agents of different generations suggests that introduction of new substances was accompanied with the dose reduction and reached the bottom in avermectins [52] (Fig. 3).

Figure 3. Doses of critical anthelminthic substances introduced in different years [52] (as amended and supplemented). 2.5.1. Helminth Adaptation and Drug Resistance Intensive administration of anthelminthic agents is not only accompanied with some adverse biochemical consequences for a patient (negative adverse effects) but also leads to appearance and establishment of the biocide-resistant forms in helminth population. This fact was noted by P. Erlich as early as in the beginning of the 20th century, and resistance to frequently used anthelminthic substances is now registered universally [52-63]. The resistance develops as a result of helminth adaptation to anthelminthic effects. While interacting with the target, it 38 Ecological, Physiological and Biochemical Adaptation in Helminth: Trends in Evolution of Anthelminthic Chemical Agents initiates a cascade of physical, chemical and biochemical events (in addition to those related to the expression of anthelminthic effects) that involve intracellular effectors at different levels (up to the genetic apparatus and its functional activity), and therefore, in addition to the initial target, a modified target may appear and be reproduced (see Fig. 2). Reduction in expression of receptor proteins or its subunits (nAChR agonists), increased P-glycoprotein expression ([54] and multiple resistance proteins (GluCl allosteric modulators), single nucleotide polymorphism (b-tubuline ligands) play an important part in resistance development [50, 61]. In particular, it was experimentally shown in C. elegans nematodes that simultaneous mutation of avr-14, avr-15 and glc-1 genes encoding GluCl -subunits is the reason for significant resistance to ivermectin, due to the reduction in affinity of the substance to the chlorine ion channel. On the contrary, mutation of any two genes of the channel either does not lead to resistance or does lead to an insignificant one [62]. Resistance formation may be accelerated by incorrect anthelminthic agent administration [52-55] (Table 2).

2.6. New Anthelminthic Agents Resistance onset in pathogenes encourages the search for new anthelminthic agents with a different action mechanism and/or the one typical of the already existing substances (but more efficient) [64-66]. For instance, in 2000/2010 emodepside, monepantel, derquantel (veterinary science), as well as tribendimidin and nitazoxanid (medicine) emerged (Table 2). Emodepside represents a N-methyl derivative of a 24-membered cyclooctadepsipeptide – the product of Mycelia sterilia fungus fermentation, first extracted from the microbial flora of Japanese camellia leaves by Japanese scientists in 1990 [67]. It is efficient against nematodes in the gastro-intestinal tract and lungs and microfilaria resistant to benzimidazoles, 16-membered macrolides and cholinergic agonists. It is included into newly created drugs recommended for feline and canine nematodosis treatment [68-70]. Structural formulas of substances developed in 2000/2010:

Table 2. Certain most important anthelminthic substances for human and animal helminthosis treatment

Pathogenic group (pathology) Drug, anthelminthic class

Nematodoses Avermectins and milbemicyns, monepantelа, emodepsideа, tribendimidinа, derquantelа, benzimidazoles, morantel, Intestinal nematodes pyrantel, levamizole, clozantel (and halogenized salicylanilides), piperazin Tissue nematodes (filariasis) Diethylcarbamazine, suramine, ivermectin

Trematodoses of different localization Triclabendazol (against all forms), praziquantel, clorsulon, Common liver flukes (fasciolasis) clozantel (and halogenized salycilanilides), oxiclozanide, albendazole (against adult forms) Blood flukes (schistosomiasis) Antimonates,metriphonate, oxamnichin, praziquantel Praziquantel, triclabendazole, niclozamide (alternative), Lung and intestinal flukes albendazole (alternative) Cestodiasis

Tapeworm Benzimidazoles, praziquantel, niclozamide

Note: The superscript (а) marks the substances developed in 2000/2010. Advances in Pharmacology and Pharmacy 2(2): 30-45, 2014 39

The efficiency and the action spectrum of the substances Tribendimidine is an aminophenyl dimidine derivative of administered for anthelminthic treatment depend on many amidantel that was first synthesized in China in 1980 [83] factors: the host (including humans) and the helminth species and was introduced into medical practice there in 2004 (their anatomic, histological and physiologo-biochemical [84-86], it has anti-nematode effect. Tribendimine is properties, e.g. presence of a tegument, body and organ included into the L-subtype of nAChR agonists with the temperature, individual differences); the lifecycle of a bio- or same action mechanism as that of levamizole and pyrantel; geo-helminth and pathogen localization in the intermediate so it is not prescribed in case of levamizole resistance. or definitive host body; the host’s position in the ecosystem’s However, developers recommend administering food chain, its nutrition and living features (climate, lifestyle tribendimidine instead of benzimidazoles or in combination etc.) [71, 118-120]; bioavailability, physical and chemical with them, in case of resistance to the latter [87]. properties of the anthelminthic agent and its interaction with Out of anthelmintic drugs developed during the last the target (receptors, enzymes and other endogenous decade, it is worth mentioning nitazoxanide [49, 88] — a metabolites and cellular elements) etc., which is (or must be) salicylic acid derivative, in which, unlike with salicyl taken into account in the successful anthelminthic treatment anilides, its residual is bound with the nitrothiazole fragment protocol. via an amide bond. As mentioned above, active metabolites Emodepside inhibits muscles function (throat, body and of nitazoxanide inhibit pyruvat ferredoxine oxidoreductase organs involved in egg laying), by increasing conductance of (see also [89]). It has protozoacide, anthelmintic and 2+ + Са -activated К -channels (SLO1) in pre- (obviously, to a anti-bacterial properties and is used in medicine [2]. By its greater extent) and post-synaptic cells of a nematode’s efficiency, nitazoxanide is inferior to benzimidazoles, but it neuromuscular plexus [72] (Fig. 4). However, the sequence can be used against benzimidazole-resistant forms [89]. of events in this case needs to be specified. They also assume Work on chemical modification of known substances that [73], in addition to the above, the slow-acting signal continues. In particular, benzimidazole derivatives, i.e. mechanism (with participation of latrophylin-like benzimidazolyl-chalcones (chalcones are flavonoids with an pre-synapse and Gq-protein receptor) plays a minor part [72, open pyran ring) [90], as well as 5-О-succinoyl avermectin 73]. and Gemacs on its basis [91-93] have been developed. These Monepanthel (S-enantiomer, a synthetic product, was so-called horizontal developments are aimed at obtaining discovered in 2008 and admitted to the market in 2010) is a analogues with improved physical, chemical and so-called amino-acetonitrile derivative (ААDs) [74]. Its pharmacological properties (e.g. reduction in residual most active metabolite is sulphone monepanthel [75, 76], a quantities in milk after administration of drugs in the pluripotential drug against larvae and adult gastro-intestinal lactation period, etc.). helminths that are resistant to the common anthelmintic drugs, is efficient in low doses (2.5-3.5 mg/kg) [77]. The interaction of monepanthel with nemado-specific nAChR 3. Prospects in the Development of Hco-MPTL-1 interfers this receptor function and paralyzes the helminth’s muscles [78, 79]. Derquantel is a Substances semi-synthetic derivative of paragerquamide А found among natural spyroindoles produced by the mildew Penicillium 3.1. Screening Methods paraherquei [80, 81]. Derquantel inhibits nAChr [82], is a pluripotential anthelmintic agent and is applied in Virtual and experimental Screening of known synthetic combination with abamectine for treatment and control of compounds and metabolites of land and marine organisms, different gastro-intestinal nematodoses (including cases of mostly bacteria, fungi, plants but also, possibly, noxious helminths resistance to other drugs), which points to the animals (spider toxins or toad bufotoxin having cardiotonic feasibility of search of anthelmintic agents among such effect), as well as semi-synthetic and synthetic analogues of compounds. the last compounds is still of critical significance. Their chemical nature can be different: mono- and polycyclic (condensed and non-condensed, or poly-phenyl) aromatic (e.g. poly-atom phenols — plant tannins) and heterocyclic (e.g. fervenulin) compounds, flavonoids, alkaloids, lactones, terpenoids, peptides etc. Numerous articles on deriving such substances with anthelminthic properties have been recently published, namely: fungichromine В (28-membered polyene macrolide produced by actinomycete Streptomyces albogriseolus HA10002, it is efficient against tubercular Figure 4. Emodepside effect pattern: KМ-Cа2+ — Cа2+-binding protein of nematodes) [104], fervenuline (103], nafuredine (produced calmodulin, SLO1 — Са2+-activated К+-channels, RCK— domain by Aspergillus niger FT-0554) [105), bacterial protein + regulating К -conductance, Gq — G-protein involved in transmitting an Cry5B (Bacillus thuringiensis) [106], cysteine proteinase of extracellular signal perceived by membrane receptors and leading to S phospholipase (FL-S) activation (description is available in the text; [73]). the pipeapple, papaya, other plants [107], ross alcaloids 40 Ecological, Physiological and Biochemical Adaptation in Helminth: Trends in Evolution of Anthelminthic Chemical Agents

[108], other substances [109]: is yet to be found out. Anthelminthic effect was found in other synthetic steroid compounds (data will be published in the respective patents).

3.3. Alternative Methods for the Helminthosis Control Biological treatment methods destroying helminth eggs applicable for pastures (nematophagous fungus Duddingtonia flagrans) [94], reservoirs (ascomycete Caryospora callicarpa YMF1.01026) [95], gastro-intestinal tract (nematophagous fungus Pochonia chlamydosporia) [96], immune system reinforcement [97], selection of helminth-resistant breeds and lines should be regarded as 3.2. Some Considerations for Synthetic Search alternative approaches to helminthoses control in animals. With discovery of so-called pattern recognition receptors The search for synthetic anthelminthic substances among (PRR) that are capable of specific interaction with nematode the derivatives of conditionally parent hydrocarbons, such as and flatworm antigens in the inherent and adaptive immune benzene, indene, naphthalene, 1Н-cyclopent[a]-naphtnalene system of mammals, there are prospects to develop vaccines and phenanthrene, by modifying the structure, from based on resistant helminth tissues [98]. Filariasis treatment absolutely unsaturated to saturated forms, including using agents acting on Wolbachia pipientis bacteria heterocyclic forms containing N, O, and S atoms, different (cytoplasm symbiont of nematodes) [99], e.g. tetracycline substituents and functional groups, seems promising. This antibiotics such as doxicycline [100] and others, may also be can be illustrated by classical anthelminthic agents, such as used as a helminthoses prevention and treatment method biphenyl, biphenium, and recently discovered substances of [101]. It is noteworthy that endo-symbionts were found in monepanthel and tribendimin that contain two and three more than 90 % of studied nematodes [50, 102]. benzene residuals, respectively. Different saturated and unsaturated cys-hydrindan derivatives (including conditionally heterocyclic analogues, 4. Conclusion e.g. benzimidazoles) in the form of the CD-fragment of aglycons of cardiac steroids (see section 3.2.1), the divalent Chemotherapy is central in fighting animal and human residual of cys-1-oxahydrinden-4,5 within 16-membered helminthoses. Pathogen resistance to known anthelminthic macrolide anthelminthic agents, the BC-fragment of the substances necessitates their constant renewal. tricyclic 1Н-cyclopent [a]-naphthalene (e.g. in the form of A new substance development, be it designing a new santonin containing the condensed 5-membered lactone ring) compound or identification of properties of any existing are hypothetically attractive. In this connection 8,14-[115], compounds, is a time-consuming and expensive process. 9,10- and 9,11-secosteroids, e.g. analogues of Torgov Application of the diversification (different types of seco-diketone, vitamin D2 [116], 6,7- secoecdysteroids and compounds) and the focused (related compounds) screenings, others may also be promising. software-based evaluation of anthelminthic activity in silico [117], chemical and genetic trials on model small animals 3.2.1. Cardioactive steroids: New Posiblities? (nematodes Artemia salina, Caenorhabditis elegans, etc.) Interestingly, anthelminthic properties were found in are intended to accelerate introduction of new substances [50, certain cardioactive steroids (natural cardenolides and 118]. Further knowledge in molecular action mechanisms of bufadienolides, as well as synthetic 14β-hydroxy-derivatives anthelminthic agents and in resistance development would of estrogens), e.g. asperozide of Streblus asper [110] plant improve planning of helminthoses control protocols. bark and synthetic 14-metoxy-18-methyl-estron [111]. As it In our opinion based on codification of known substances is known, positive inotropic effect of cardioactive steroids is by chemical structure, the target search among the associated with inhibition of the membrane Na,K-АТPase derivatives of conditionally parent hydrocarbons – benzene, [112], but they were also found to produce anti-tumour effect indene, naphthalene, 1Н-cyclopent[a]-naphthalene, recently [113]. At the same time, modulation of anthracene and phenanthrene by structure variation from GABAА-receptor activity by neuro-steroids [114] was unsaturated to saturated forms, including their heterocyclic described. Therefore, the anthelminthic effect of these analogues containing nitrogen, oxygen, sulfur, different compounds (through Na,K-ATPase inhibition or otherwise) substituents and functional groups, may be promising: Advances in Pharmacology and Pharmacy 2(2): 30-45, 2014 41

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