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SYNTHESIS AND MOLECULAR MODELING OF THIETHANE-CONTAINING 3-METHOXY-4-OXYPHENYLMETHYLIDENHYDRASIDES 2-[3-METHYLXANTHINYL-8-SULPHANIL]ACETIC ACIDS AS PROMISING PHOSPHODIESTERASE 4 INHIBITORS

DOI: https://doi.org/10.29296/25877313-2023-07-04
Issue: 
7
Year: 
2023

M.A. Urazbaev
Ph.D. (Pharm.), Bashkir State Medical University (Ufa, Russia)
E-mail: great-blood-mak@mail.ru
I.M. Sharipov
Ph.D. (Pharm.), Bashkir State Medical University (Ufa, Russia)
F.A. Khaliullin
Dr.Sc. (Pharm.), Bashkir State Medical University (Ufa, Russia)
E.E. Klen
Dr.Sc. (Pharm.), Bashkir State Medical University (Ufa, Russia)

Objective – to study the parameters of binding of 3-methoxy-4-hydroxyphenylmethylidenehydrazides of 2-[3-methylxanthinyl-8-sulfanyl]-acetic acids with PDE 4A, 4B, 4C, 4D active centers, evaluate the effect of the thietane ring and select the most promising compound for synthesis Material and methods: The objects of study are phosphodiesterase 4 and the structures of derivatives of thietanylxanthine. The studies were carried out by molecular docking. The structure of the synthesized compounds was confirmed by IR and NMR spectroscopy. Results and conclusions. The inhibitory activity of 2-[3-methylxanthinyl-8-sulfanyl]acetic acid 3-methoxy-4-hydroxyphenyl-methylidenehydrazides against phosphodiesterases 4 was studied by molecular modeling. It was found that the studied molecules bind in the same site areas as native ligand roflumilast. Binding energies are comparable to roflumilast and for compound II even surpass it. The influence of the thietane and thietane 1-oxide cycles on the inhibitory activity was studied. The most promising compound II was synthesized.
Keywords: 
thietane
xanthine
arylmethylidenehydrazides
prediction of biological activity
inhibitors of c-AMP phosphodiesterase
molecular docking
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