Synthesis and biological properties of 7-(2-hydroxy-3-m-ethylphenoxypropyl-1-)theophilline derivatives

  • D. G. Ivanchenko Zaporizhzhia State Medical University
Keywords: synthesis, theophilline, NMR-spectroscopy, antibacterial activity, biological action


Various origin antibiotics and many other chemotherapeutic agents, which are based on the heterocyclic compound, found wide application in the treatment of infectious diseases. Purine derivatives have long been used in medical practice as antiviral agents (acyclovir, gancyclovir, etc.), and further research to find new antimicrobial and antiviral agents in the row of purine derivatives are justified and perspective.

The aim of this paper is to elaborate simple laboratory methods of 7,8-disubstituted theophylline synthesis, unspecified in scientific papers earlier, and to study their physical and chemical properties.

The melting point has been determined by open capillary method on the device PTP (M). Elemental analysis has been performed on the device Elementar Vario L cube. NMR spectra have been taken using spectrometer Bruker SF-400.

For the initial screening study of the newly-synthesized substances benchmark testing-cultures of both gram-positive and gram-negative bacteria have been used, which belong to clinically significant groups of infections agents which are differing by their morpho-physiological properties.

Heating of 8-bromotheophilline with m-ethylphenoxymethyloxyrane in propanol-1 environment results in formation of 8-bromo-7-(2-hydroxy-3-m-ethylphenoxypropyl-1-)theophylline. Its reactions with primary and secondary amines proceed at boiling in aqueous dioxane environment to form the corresponding 8-aminoderivatives. The heating of initial syntone with 2-ethylpiperidine leads to the formation of oxazoline xanthine.

By applying such computer programs as ALOGPS, DRAGON, GUSAR and ACD/Percepta Platform was established viability of further biological and toxicological in vitro and in vivo research.

Simple laboratory method has been elaborated to synthesize 8-bromo-7-(2-hydroxy-3-m-ethylphenoxypropyl-1-)theophylline, which is initial compound for further synthesis of various theophylline N-, O-, S-substituted.

Reactions of 8-bromo-7-(2-hydroxy-3-m-ethylphenoxypropyl-1-)theophylline with primary and secondary amines have been investigated. As a result 8-aminosubstituted of 7-(2-hydroxy-3-m-ethylphenoxypropyl-1-)theophylline and 6,8-dimethyl-2-m-ethylphenoxymethyl-2,3-dihydro-1,3-oxazolo[2,3-f]theophylline have been synthesized. NMR-spectral characteristics of new synthesized compounds have been studied.

Molecular and pharmacological descriptors (LogP, TPSA, A) to forecast properties of the obtained substances have been calculated, in addition to acute toxicity index. The perspective of the obtained substances using as antistaphylococcal and antifungal agents has been shown.


1. Moriarty T. F., Zaat S. A. J., Busscher H. J. Biomaterials associated with infection: immunological aspects and antimicrobial strategies. - NY: Springer, London: Heidelberg Dordrecht, 2013. - 566 p.
2. Mashkovsky M. D. Medicines. Izd. 16th, transfiguration, correction and add - M .: OOO "Publishing house Nova wola", 2012. - 1216 p.
3. Kireev IV, Investigation of antibacterial and fungistatic activity of substituted and annelled xanthine derivatives // Vysn. Sumy state un-th Series Medicine. - 2009. - No. 1. - P. 22-29.
4. Hayallah AM, Talhoun A. A., Alim A. A. M. A. Design and Synthesis of New 8-Anilide Theophylline Derivatives as Bronchodilators and Antibacterial Agents // Arch. Pharm Res - 2012. - V. 35, N 8. - P. 1355-1368.
5. Voynikova Yu., Valchevab V., Momekova G., Peikova P., Stavrakova G. Theophylline-7-acetic acid derivatives with amino acids as anti-tuberculosis agents // Bioorg. Med. Chem Lett - 2014. - V. 24, N 14. - P. 3043-3045.
6. Pat. to utility model No. 94707. 7-n-Butyl-8-diethylaminoethylamino-3-methylxanthin, which exhibits antibacterial and antifungal activity / D.G. Ivanchenko, M.I. Romanenko, A.M. Kamishnyi, N. M. Polischuk , M.V. Nazarenko - Declared. June 16, 2014; Pubwished Nov 25, 2013, Bul. No. 22
7. Romanenko MI, Nazarenko MV, Ivanchenko D.G., Kamyshny O.M., Polyshuk N.M. Synthesis, physicochemical and biological properties of 8-amino derivative 7-alkyl-3-methylxanthines / / Pharmacist journ - 2015. - No. 6. - P. 50-55.
8. Eckstein M., Gorczyca M., Zlyc A. Uber die oxidative bromiation of methylxantinene // Acta Pharm. Yugoslav - 1972. - N 4. - P. 133-136.
9. Volyansky Yu.L., Gritsenko I.S., Shirobokov V.P. and others. Study of specific activity of antimicrobial drugs: Method. river - K .: State Pharmacological Center MoH Ukraine, 2004. - 38 p.
10. Lipinski Ch. A., Lombardo F., Dominy B. W., Feeney P. J. Experimental and computational approaches to the estimation of solubility and permeability in drug discovery and development settings // Adv. Drug Del. Rev. - 2001. - N 46. - P. 3-26.
11. Ghose A. K., Viswanadhan VN, Wendoloski J. J. A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. 1. A Qualitative and Quantitative Characterization of the Known Drug Databases // J. Comb. Chem - 1999. - N 1. - P. 55-68.
How to Cite
Ivanchenko, D. G. (2018). Synthesis and biological properties of 7-(2-hydroxy-3-m-ethylphenoxypropyl-1-)theophilline derivatives. Farmatsevtychnyi Zhurnal, (3-4), 42-49.
Synthesis and analysis of biologically active compounds