Promising GABAA receptor modulators based on avermectins modified with an imidazo[1,2-a]pyridine fragment were synthesized at the ZIOC

4 july 2022 г.

Avermectins are polycyclic compounds produced by the soil microorganism Streptomyces avermitilis and known throughout the world as pesticides against endo- and ectoparasites of humans, plants, and animals. In recent decades, avermectins have been extensively studied, and in addition to their antiparasitic activity, they have been found to have a wide range of beneficial biological properties, including antiviral, antibacterial, anti-inflammatory, and anticancer activity. The widespread use of avermectins over the past 20 years as antiparasitic agents has led to the development of resistance in many important parasite species in ruminants and horses. For these reasons, the development of new synthetic derivatives of avermectin with higher activity and a broad spectrum of action is very important.

Scientists from the Laboratory of Chemistry of Steroid Compounds of the ZIOC have developed a method for the synthesis of avermectin derivatives containing an imidazo[1,2-a]pyridine fragment. The resulting compounds showed activity as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors, the main pharmacological target for the treatment of neurological disorders, as well as a target for insecticides, antihelmintic, and anticonvulsant drugs. Studies have been carried out both in vitro and in vivo using zebrafish as animal models. The most active synthesized hybrid molecules have nanomolar activity against the GABA benzodiazepine site. Thus, the resulting structures can serve as a starting point for the development of improved drugs for the treatment of neurological disorders and potent antiparasitic agents.

Source:

Yulia A. Volkova, Irina V. Rassokhina, Eugeny A. Kondrakhin, Alexey V. Rossokhin, Sergey N. Kolbaev, Tatiana B. Tihonova, Mamedsalim Kh. Dzhafarov, Marina A. Schetinina, Elena I. Chernoburova, Ekaterina V. Vasileva, Andrey S. Dmitrenok, Georgy I. Kovalev, Irina N. Sharonova, Igor V. Zavarzin Synthesis and evaluation of avermectin–imidazo[1,2-a]pyridine hybrids as potent GABAA receptor modulators Bioorg. Chem., 2022, 127, 105904. DOI: 10.1016/j.bioorg.2022.105904.