The γ-aminobutyric acid type A (GABAA) receptors are pentameric transmembrane protein complexes. They have attracted extensive attention from the scientific community due to their significant pharmacological potential. Here we report the first synthesis of avermectin-imidazo[1,2-a]pyridine hybrids promising as GABAA receptor positive allosteric modulators (PAMs). An efficient multi-step protocol was elaborated for the installation of the 6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine pendant to the Avermectin B1a and Ivermectin skeletons through a linker. A variety of linkers were used in order to study the effect of disturbances in the hybrid structure on the GABAA receptor affinity. In vitro experiments showed that the lead compounds exhibited high potency (IC50 = 207 and 359 nM) for binding at the benzodiazepine site of GABAA receptors. In silico studies suggest that the hybrids are able to bind at the Ivermectin binding site of the GABAA receptor. The functional properties of the highest-affinity hybrid (compound 15e) as GABAAR PAM were evaluated by patch-clamp electrophysiological recordings of GABA-mediated currents in rat cerebellar Purkinje neurons. The results obtained suggest that the potentiating effect of hybrid compound 15e is due to its interaction both with benzodiazepine- and Ivermectin-binding sites of GABAARs. Drug-induced behavioral responses in adult zebrafish for hybrids correlate with an alternative mode of action of avermectin and imidazo[1,2-a]pyridine pharmacophores. The investigation of avermectin-imidazo[1,2-a]pyridine hybrid molecules with activity as GABAA receptor modulators is important for the discovery of safe and effective drugs for the treatment of neurological disorders and pest control agents.

One half of the 2015 Nobel Prize in Physiology or Medicine was awarded to Satoshi Omura and William Campbell for the discovery of natural avermectins in 1976, which has revolutionized the treatment of endo- and ectoparasitic diseases. The published reviews on avermectins are primarily concerned with their biological activity and applications. This is the first review that analyzes the main advances and trends in the development of avermectin chemistry. The strategies for the total synthesis of natural avermectins are described. Considerable attention is given to the methods of chemical modification of avermectins giving new semisynthetic derivatives. The established structure–biological activity relationships for the products are discussed. The review considers the optimal strategies for chemical modification of avermectins in order to increase their biological activity and stability, reduce toxicity for warm-blooded animals and expand their field of application. The bibliography includes 241 references.

Parasitic diseases are a serious problem for medicine and the agro-industrial complex. The most effective antiparasitic compounds are avermectins, for the discovery of which Satoshi Omura and William Campbell were awarded the 2015 Nobel Prize in Physiology or Medicine. For the first time, the monograph summarizes and analyzes the achievements in the chemistry of avermectins and milbemycins, as well as analyzes the possible directions and patterns of chemical modification of these compounds. In addition, the analysis of data on the relationship «structure-property» allows a more conscious approach to the modification of these compounds in order to increase their biological activity, stability, etc. The monograph is intended for wide range of specialists in the field of chemistry of natural compounds and biologically active substances.

Reaction of avermectin B 1 with succinic acid monoethyl ester chloride under catalysis of 2,6-lutidine provided hitherto unknown 5- O -mono- and 4″,5- O, O -bis-derivatives with ethyl succinoyl moiety that are potential antiparasitics.

Reaction of 4″ O ,5 O -bis(chloroacetyl)ivermectin with amines in the presence of sulfur provided the corresponding bis(2-amino-2-thioxoacetyl) derivatives that are potential antiparasitics.

Acylation of ivermectin 5-oxime was first studied. Procedures for selective acylation of ivermectin 5-oxime either selectively at 5-oxime group or at both 5-oxime group and 4″-hydroxy group to give, respectively, mono- and diacyl derivatives were developed. The synthesized compounds exhibit antifungal activity.

Reaction of avermectin B1 hemisuccinate with N-hydroxysuccinimide and N,N’-dicyclohexylcarbodiimide followed by amination provided succinic monoamide avermectine esters that are potential antiparasitics.

New ivermectin-4″,5-diyl[bis(N-methylcarbamate)] was synthesized by the MoO2Cl2(DMF)2-catalyzed reaction of ivermectin with methyl isocyanate. The synthesized compound could find application as antiparasitic agent.

Treatment of ivermectin with sulfuric acid–acetic anhydride in pyridine gives sodium 5-sulfate-ivermectin and disodium 4″,5-disulfate-ivermectin. The synthesized salts are water-soluble compounds with promising antiparasitic activity.

Searching for antiparasitics with a different mode of action than existing drugs, and (or) with the same but much more effective mechanisms is necessary to periodically update the applicable protection chemicals.For the first time we here present data on the biocidal action of new semisynthetic derivatives of avermectin B1 that we have synthetized earlier.These are the 16-membered macrocyclic lactones, the representatives of an important class of anthelmintics.In 2015 S. Omura (Japan) and W. Campbell (USA) who discovered this avermectin group, were awarded the Nobel Prize in physiology and medicine.In our study the oligochaetes Tubificidal tubifex were used as a test-object.The original chemicals and synthetized derivatives tested were avermectin B1 (abamectin), ivermectin, monosaccharide analogues of abamectin and ivermectin, namely abamectin, ivermectin, 5-O-succinyl avermectin B1, methyl ester of 5-O-succinyl avermectin B1, ethyl ester of 5-O-succinyl avermectin B1, diethyl ester of 5,4-di-O-succinyl avermectin B1, ethyl ester of 5-Omalonyl avermectin B1, diethyl ester of 5,4-di-O-dimalonyl avermectin B1, monosaccharide hemisuccinate of avermectin B1 (5-O-succinyl-4´-dezoleandrozyl-4´-hydroxyavermectin B1), ethyl ester of 5-O-succinyl-4-O-chloroacetyl avermectin B1, 5-O-succinyl ivermectin, ethyl ester of 5-O-succinoyl ivermectin, 5,4-di-O-succinyl ivermectin, diethyl ester of 5,4-di-O-succinyl-ivermectin, ethyl ester of 5-O-malonylivermectin, diethyl ester of 5,4-di-O-dimalonyl ivermectin, monoavermectin-5-yl ester of 4-[2-(4-nitrophenyl)-2-oxoethoxy]-4-oxobutanoic acid, monoavermectin-5-yl ester of 4-[2-(4-chlorophenyl)-2-oxoethoxy]-4-oxobutanoic acid, monoavermectin-5-yl ester of 4-[(4-nitrophenyl)-methoxy]-butanoic acid, monoavermectin-5-yl ester of 4-[1-methyl-2-(4-methylphenyl)-2-oxoethoxy]-4-oxobutanoic acid, monoavermectin-5-yl ester of 4-[2-(4-chlorophenyl)-1-methyl-2oxoethoxy]-4-oxobutanoic acid, monoavermectin-5-yl ester of 4-[3-chloro-1-(4-сhlorbenzoil)-propoxy]-4-oxobutanoic acid, monoavermectin-5-yl ester of 4-{2-[(4-methylphenyl)-amino]-2-oxoeth-oxy}-4-oxobutanoic acid and monoavermectin-5-yl ester of 4-{2-[(4-bromophenyl)-amino]-2-oxo-ethoxy}-4-oxobutanoic acid.The acute toxicity (LD 50 ) of the most effective ones, 5-O-succinyl avermectin B1, 5-O-ethylsuccinyl avermectin B1 and 5,4-di-О-ethylsuccinyl avermectin B1, for intraperitoneally challenged white mice was 37.85; 41.37 and 45.82 mg/kg, respectively.We also used membrane preparations of rat brain as in vitro model for screening and studying activity of natural and semi-synthetic avermectins.A radioligand [G-3H]SR 95531 binding assay of avermectin B1, ivermectin, and 5-O-succinyl avermectin B1 interaction with GABA-receptors (the biotargets for these compounds) showed a 30 % increase of maximal inhibition (Imax) of specific binding by hemisuccinate derivative of avermectin B1 when compared to original avermectin B1.

Esters of bile acids and avermectin B 1 were obtained for the first time by the reaction of avermectin B 1 with bile acid anhydrides.

An approach to the synthesis of earlier unknown androstano[17,16-d]pyrazoles containing a monothiooxamide fragment at the nitrogen atom of the pyrazole ring has been suggested. The method is based on the reaction of NH-unsubstituted androstano[17,16-d]pyrazole with chloroacetyl chloride with subsequent involvement of the obtained N-chloroacetylpyrazole into the reaction with elementary sulfur in the presence of aromatic amines. The synthesized androstano[17,16-d]pyrazoles containing a monothiooxamide fragment at the nitrogen atom of the pyrazole ring exhibit high antiparasitic activity.

A reaction of 5-O-succinoylavermectin B-1 with alkylating agents, namely phenacyl halides, bromoacetanilides, and benzyl bromides, was studied. Esters of 5-O-succinoylavermectin B-1 were obtained for the first time, which are of interest as potential antiparasitic agents.

A reaction of avermectin B1 with succinic anhydride at ultrahigh pressure (10 kbar) gave previously unavailable 5,4″-di-O-succinoylavermectin B1, which is of interest as potential antiparasitic agent.

Acylation of avermectin B 1 with vicinal 1,2-dicarboxylic acid anhydrides leads only to 5-O-acyl derivatives in high yields. Avermectin 4″-O-acyl derivatives were obtained under similar conditions from avermectin B 1 5-O-TBS-derivatives in good yields. The compounds obtained are of interest as antiparasitic agents.

The attention is focused on the main classes of anthelmintics. Mode of action of the anthelmintics and the anthelmintic resistance, and alternative methods for dehelminthization are discussed. A targeted search for new anthelmintic substances in the series of speculative parental hydrocarbons (benzene, indene, naphthalene, 1 H1-cyclopenta [a]-naphthalene and phenanthrene) is suggested to be prospective on the basis of variation in their structure from the fully unsaturated to saturated forms, including those containing heteroatoms (N, O, S), various functional groups and substituents:

This review discusses the landmark anthelminthic substances - traditional medicine components, different categories of pluripotential synthetic and naturally occurring compounds. Much attention is paid to the sections devoted to recent discoveries (Emodepside, Monepantel, Derquantel, Tribendimidine) and to some promising works. The review is also focused on some aspects of molecular mechanisms of action of anthelminthic substances and of helminth adaptation to anthelminthic substances, and on alternative worming treatment options. Based on the systemic analysis of particular features of the chemical structure of anthelminthic substances, the hypothesis on the viability of the targeted search for such compounds among the derivatives of conditionally progenitor cyclic hydrocarbons - benzene, indene, naphthalene, 1H-cyclopenth [a]-naphthalene, anthracene and phenanthrene - by alternating absolutely unsaturated and saturated structures, including heterocyclic analogues containing nitrogen, oxygen and sulfur and different substitutes and functional groups, was voiced.