SYNTHESIS AND MOLECULAR MODELING OF INHIBITORS OF C-AMP PHOSPHODIESTERASE 4A IN SERIES OF HYDRAZINE DERIVATIVES OF 2-[3-METHYL-7-(THIETANYL-3)XANTHINYL-1]ACETIC AND 2-[3-METHYL-7- (THIETANYL-3)XANTHINYL-8-THIO]ACETIC ACIDS

Reactions of ethyl 2-[8-bromo-3-methyl-7-(thietanyl-3)xanthinyl-1]acetate (1) and ethyl 2-[1-benzyl-3-methyl-7-(thietanyl-3)xanthinyl-8-thio]acetate (4) with hydrazine were investigated and hydrazine 2 and hydrazide 6 derivatives were synthesized. Reactions hydrazine 2 and hydrazide 6 with aromatic carbonyl compounds arylmethylenehydrazides 3а,b и 7а,b were obtained. The structure of the synthesized compounds was confirmed by spectroscopy. Based on the prediction of biological activity of the synthesized compounds in the PASS program we selected promising inhibitors of c-AMP phosphodiesterase, and their molecular docking with an active cAMP phosphodiesterase 4A binding site was performed. The calculated inhibition constant of cAMP phosphodiesterase 4A by compounds 2 and 7a is lower than that of pentoxifylline by 15 and 253 times, respectively, which confirms the prospectivity of the search for cAMP inhibitors of phosphodiesterase 4A in the series of hydrazine derivatives of 2-[3-methyl-7-(thietanyl-3)xanthinyl-1]acetic and 2-[3-methyl-7-(thietanyl-3)xanthinyl-8-thio]acetic acids.

тиетан, ксантин, арилметилиденгидразины, прогноз биологической активности, ингибиторы цАМФ фосфодиэстеразы 4А, молекулярный докинг, thietane, xanthine, arylmethylidenehydrazines, prediction of biological activity, inhibitors of c-AMP phos- phodiesterase 4A, molecular docking

1. Gresele, P. Anti-platelet therapy: phosphodiesterase inhibitors/ P. Gresele, [et al.] //Br. J. Clin. Pharmacol. - 2011. - 72(4). - P. 634-46

2. Spina, D. PDE4 inhibitors: current status/ D. Spina // Br. J. Pharmacol. -2008. - Vol. 155, № 3. - P. 308-315

3. Drugs. com [Электронный ресурс]. URL: https://www.drugs.com/ (дата обращения 1.04.2018)

4. Синтез и гемореологическая активность 8-аминозамещенных 3-метил-7-(1,1-диоксотиетанил-3)-1-этилксантинов / Ю.В. Шабалина [и др.] // Вопросы биологической, медицинской и фармацевтической химии. - 2014. - № 5. - С. 20-23

5. Небогатова, В.А. Взаимодействие 8-замещенных 3-метил-7-(тиетанил-3)ксантинов с этилхлорацетатом / В.А. Небогатова [и др.] // Тезисы докладов II Всероссийской молодежной конференции «Проблемы и достижения химии кислород- и азотсодержащих биологически активных соединений». - Уфа, 2017. - С.90-91

6. Халиуллин, Ф.А. Синтез солей 2-[1-бензил-3-метил-7-(тиетанил-3)-ксантинил-8-тио]уксусной кислоты / Ф.А. Халиуллин, М.А. Уразбаев //Башкирский химический журнал. - 2016. - Т. 23,№ 3. - С. 53-55

7. PassOnline [Электронный ресурс]. URL: www.pharmaexpert.ru/passonline/ (дата обращения 1.04.2018)

8. Osiris Datawarrior [Электронный ресурс]. URL: www.organic-chemistry.org/prog/peo/ (дата обращения 1.04.2018)

9. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility/ G.M. Morris [et al.] // J. Comput. Chem. - 2009. - Vol. 30. - P. 2785-2791

10. Protein Data Bank [Электронный ресурс]. URL: http://www.rcsb.org/structure/3TVX (дата обращения 1.04.2018)

11. Recht M. I. [et al.] Fragment-Based Screening for Inhibitors of PDE4A Using Enthalpy Arrays and X-ray Crystallography/ M. I. Recht [et al.] // Journal of Biomolecular Screening. - Vol. 17, №4. - P. 469-480