Synthesis and molecular modeling of thiethane-containing 3-methoxy-4-oxyphenylmethylidenhydrasides 2-[3-methylxanthinyl-8-sulphanil]acetic acids as promising phosphodiesterase 4 inhibitors
- Authors: Urazbaev M.A.1, Sharipov I.M.1, Khaliullin F.A.1, Klen E.E.1
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Affiliations:
- Bashkir State Medical University
- Issue: Vol 26, No 7 (2023)
- Pages: 26-33
- Section: Pharmaceutical chemistry
- URL: https://journals.eco-vector.com/1560-9596/article/view/568656
- DOI: https://doi.org/10.29296/25877313-2023-07-04
- ID: 568656
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Abstract
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.
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About the authors
M. A. Urazbaev
Bashkir State Medical University
Author for correspondence.
Email: great-blood-mak@mail.ru
Ph.D. (Pharm.)
Russian Federation, UfaI. M. Sharipov
Bashkir State Medical University
Email: great-blood-mak@mail.ru
Ph.D. (Pharm.)
Russian Federation, UfaF. A. Khaliullin
Bashkir State Medical University
Email: great-blood-mak@mail.ru
Dr.Sc. (Pharm.)
Russian Federation, UfaE. E. Klen
Bashkir State Medical University
Email: great-blood-mak@mail.ru
Dr.Sc. (Pharm.)
Russian Federation, UfaReferences
- Hronicheskaja obstruktivnaja bolezn' legkih (HOBL)https://www.who.int/ru/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd). Accessed 14 Apr. 2023.
- Singh D., Lea S., Mathioudakis A.G. Inhaled Phosphodieste-rase Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease. Drugs. 2021; 81: 1821–30.
- Hatzelmann A., Morcillo E.J., Lungarella G., et al. The preclinical pharmacology of roflumilast – A selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulmonary Pharmacology & Therapeutics. 2010; 23: 235–256.
- Card G.L., England B.P., Suzuki Y., et al. Structural Basis for the Activity of Drugs that Inhibit Phosphodiesterases. Structure. 2004; 12: 2233–2247.
- Leiva-Fernández J., Leiva-Fernández F., García-Ruiz A., et al. Efficacy of a multifactorial intervention on therapeutic adhe-rence in patients with chronic obstructive pulmonary disease (COPD): a randomized controlled trial. BMC Pulm Med. 2014; 14: 70.
- Yasui K., Komiyama A. New clinical applications of xanthine derivatives: Modulatory actions on leukocyte survival and function. Int J Hematol. 2001; 73: 87–92.
- Zygmunt M., Chłoń-Rzepa G., Sapa J., et al. Analgesic ac-tivity of new 8-methoxy-1,3-dimethyl-2,6-dioxo-purin-7-yl derivatives with carboxylic, ester or amide moieties. Pharmacological Reports. 2015; 67: 9–16.
- Zygmunt M., Chłoń-Rzepa G., Sapa J. Analgesic and anti-inflammatory activity of 7-substituted purine-2,6-diones. Pharmacological Reports. 2014; 66: 996–1002.
- Nebogatova V.A., Urazbaev M.A., Klen E.Je. i dr. Sintez i molekuljarnoe modelirovanie ingibitorov camf- fosfodijesterazy 4a v rjadu gidrazinoproizvodnyh 2-[3-metil-7-(tietanil-3)ksantinil-1]uksusnoj i 2-[3-metil-7-(tietanil- 3)ksantinil-8-tio]uksusnoj kislot. Medicinskij vestnik Bashkortostana. 2018; 13: 54–59.
- Filimonov D.A., Lagunin A.A., Gloriozova T.A., et al. Prediction of biological activity spectra of organic compo-unds using web-resource PASS online. Chemistry of Hetero-cyclic Compounds. 2014; 3: 483–499.
- Trott O., Olson A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem. 2010; 31: 455–461.
- Halgren T.A. MMFF VI. MMFF94s option for energy minimization studies. Journal of Computational Chemistry. 1999; 20: 720–729.
- Recht M.I., Sridhar V., Badger J., et al. Fragment-Based Screening for Inhibitors of PDE4A Using Enthalpy Arrays and X-ray Crystallography. J. Biomol. Screen. 2012; 17: 469–480.
- Wang H., Peng M.-S., Chen Y., et al. Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors. Biochemical Journal. 2007; 408: 193–201.
- Burgin A.B., Magnusson O.T., Singh J., et al. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol. 2010; 28: 63–70.
- Shabalina Yu.V., Khaliullin F.A., Spasov A.A., et al. Synthesis and Antiaggregant Activity of 8-Substituted 1-Alkyl-3-methyl-7-(1-oxothietan-3-yl)xanthines. Pharm Chem J. 2013; 47: 151–153.
- Haliullin F.A., Urazbaev M.A. Sintez solej 2-[1-benzil-3-metil-7-(tietanil-3)-ksantinil-8-tio]uksusnoj kisloty. Bashkirskij himicheskij zhurnal. 2016; 23(3): 53–55.
- Barlow J.H., Hall C.R., Russell D.R., et al. Stereochemical assignment of 3-substituted thietan 1-oxides. The crystal structures of cis- and trans-3-p-bromophenylthietan 1-oxides. J. Chem. Soc., Chem. Commun. 1975: 133.
- Uciechowska U., Schemies J., Scharfe M., et al. Binding free energy calculations and biological testing of novel thiobar-biturates as inhibitors of the human NAD+ dependent histone deacetylase Sirt2. Med Chem Commun. 2012; 3: 167–173.
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