Theophylline Analogues Research Articles

Thiosemicarbazide binds with the dicopper center in the competitive inhibition of mushroom tyrosinase enzyme: Synthesis and molecular modeling of theophylline analogues

Theophylline is long known for its anti-ageing and anti-oxidative properties. Moreover, Tyrosinase is a crucial enzyme that regulates the melanin synthetic pathway, which is involved in various physiological metabolic processes including aging. The current paper describes the synthesis of various heterocyclic systems coupled with theophylline moiety along with their tyrosinase inhibition activity in view to identify the potent nucleus. Around 19 compounds were synthesized and screened for enzyme inhibition. Based on the current study, it is suggested that compound 18 having thiosemicarbazide has strong enzyme inhibition potential. The enzyme kinetics and docking studies provide important insights into how the compound interacts with the mushroom tyrosinase active site. The work will provide clue to developing new, potent tyrosinase inhibitors for drug development.

Design, synthesis, anticancer activity and docking studies of theophylline containing 1,2,3-triazoles with variant amide derivatives.

A new series of theophylline analogues containing 1,2,3-triazoles with different amide groups (22-41) has been designed and synthesized, and their biological activities have been evaluated as potential anticancer agents. The anticancer activities of the synthesized compounds were studied in four cancer cell lines viz. lung (A549), colon (HT-29), breast (MCF-7) and melanoma (A375). Furthermore, these compounds were screened for computational ADME and Lipinski's analysis followed by molecular docking and binding energy calculations against the various therapeutic targets involved in cell proliferation. The in vitro results demonstrate that compounds 22, 27, 36 and 40 have pivotal anticancer activity. Among these, compounds 22 and 27 have significant cytotoxic activity in all three cell lines; the in silico docking studies also reveal that compounds 22, 27 and 36 have good dock scores, binding affinities and binding energies towards human epidermal growth factor receptor 2. This is the first report to demonstrate theophylline hybrids containing 1,2,3-triazoles as potential anticancer agents.

8-Alkylthio-6-thio-substituted theophylline analogues as selective noncompetitive progesterone receptor antagonists

The progesterone receptor (PR) plays a key role in reproduction and is important in cancers of the reproductive tract. Current PR antagonists usually compete for progestin binding in the PR ligand-binding pocket and often exhibit cross-binding with other members of the steroid receptor family. Using stably transfected cells expressing reporter genes, a set of ∼150 theophylline analogues were screened for their ability to inhibit progesterone, estrogen, glucocorticoid and androgen signaling. The structure–activity studies presented here identify branched 8-alkylthio-6-thio-substitutions of theophylline as selective PR inhibitors. 6-Thio-8-(2-ethylbutyl)thiotheophylline (51), the most extensively studied derivative, does not act by competing with progestins for binding in the ligand-binding pocket of PR. It demonstrated the ability to inhibit the mouse mammary tumor virus (MMTV)-luciferase reporter and endogenous PR-regulated alkaline phosphatase activity in T47D breast cancer cells. Compound 51 is the lead member of a novel class of PR inhibitors that act outside the PR ligand-binding pocket, thus serving as a novel probe to investigate PR action and a lead for further development.

8-Alkylthio-6-thio-substituted theophylline analogues as selective noncompetitive progesterone receptor antagonists

8-Alkylthio-6-thio-substituted theophylline analogues as selective noncompetitive progesterone receptor antagonists

Synthesis and structure–activity relationship studies of theophylline analogs on population responses in the rat hippocampus in vitro

We synthesized several theophylline analogs and tested the hypothesis that these compounds may be nootropic or cognitive enhancers by examining their effects on evoked population spikes recorded extracellularly in the CA1 region of the rat hippocampus. Whereas the length of the carbon chain on N7 had no effect, different size of the terminal lactam ring strongly influenced neuroactivity. Our results suggest that hexahydroazepin-2-one analogs have potential for further development as cognitive enhancers.

Towards the design of highly selective recognition sites into molecular imprinting polymers: A computational approach

A computational approach to simulate the formation of possible imprinted polymers in acetonitrile solution for theophylline (THO) is proposed, using combined molecular dynamics (MD), molecular mechanics (MM), docking and site mapping computational techniques. Methacrylic acid (MAA) and methylmethacrylate (MMA) monomers are used to simulate possible homo and copolymer structures. The model is able predict binding affinity and selectivity when considering THO analogues, such as caffeine, theobromine, xanthine and 3-methylxanthine. Comparison with available experimental data is proposed.

Free energy calculations for theophylline binding to an RNA aptamer: Comparison of MM-PBSA and thermodynamic integration methods.

We have applied the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method (J. Srinivasan, T. E. Cheatham, P. Cieplak, P. A. Kollman, and D. A. Case, Journal of the American Chemical Society, 1998, Vol. 120, pp. 9401-9409) to study the interaction of an RNA aptamer with theophylline and its analogs. The MM-PBSA free energy analysis provides a reasonable absolute binding free energy for the RNA aptamer-theophylline complex formation. Energetic analysis reveals that the van der Waals interaction and the nonpolar contribution to solvation provide the basis for the favorable absolute free energy of complex. This trend is similar to other protein-ligand interactions studied previously. The MM-PBSA method also ranks the relative binding energies of five theophylline analogs approximately correctly, but not as well as the more conventional thermodynamic integration calculations, which were carried out to convert theophylline into its analogs. The comparison of MM-PBSA with TI suggests that the MM-PBSA method has some difficulties with the first-solvation-shell energetics.

Activities of caffeine, theophylline, and enprofylline analogs as tracheal relaxants

A variety of xanthines cause tracheal relaxation, an activity predictive of antiasthmatic potential. Structural analogs of caffeine, theophylline, and enprofylline were examined for their abilities to relax carbamylcholine-stimulated guinea pig trachea in vitro. All caffeine analogs tested were more potent than caffeine ( ec 50 = 551 ± 81 μM) except the 8- p-sulfophenyl analog. 1,3,7-Tripropylxanthine and 1,3,7-tripropargylxanthine were among the more potent analogs with ec 50 values of 12 ± 1.3 and 65 ± 11 μM respectively. Increasing the polarity at the 1- or 3-position by substituting a propargyl group for an n-propyl group decreased relaxant activity, an effect not observed at the 7-position. The 8-cyclohexyl-, 8-cyclopentyl- and 8-phenyl-derivatives of caffeine were relatively potent (ec 50 = approximately 75 μM). The theophylline analog 1,3-di- n-propylxanthine was approximately two times more active than theophylline ( ec 50 = 162 ± 17 μM). 3-Isobutyl-1-methylxanthine ( ec 50 = 7.1 ± 1.8 μM) and 1-isoamyl-3-isobutylxanthine ( ec 50 = 37 ± 4.2 μM) were among the most potent tracheal relaxants. The 8-substituted theophylline analogs were weak or inactive relaxants except for 8-cyclopentyl- and 8-cyclohexyltheophylline, which were more potent or as potent as theophylline. In contrast to enprofylline ( ec 50 = 56 ± 9 μM), 8-substituted enprofylline analogs were weak or inactive as relaxants with the exception of the 8-cyclohexyl analog. The potency of xanthines as tracheal relaxants was unrelated to potency as adenosine receptor antagonists and may reflect activity as phosphodiesterase inhibitors.

Caffeine and theophylline analogues: Correlation of behavioral effects with activity as adenosine receptor antagonists and as phosphodiesterase inhibitors

The behavioral stimulant effects of xanthines, such as caffeine and theophylline, appear to involve blockade of central adenosine receptors. However, 3-isobutyl-1-methylxanthine (IBMX), a potent phosphodiesterase (PDE) inhibitor, produces behavioral depression. The effects of caffeine analogs on open field behavior of mice and potencies as antagonists of adenosine receptors and as inhibitors of three classes of brain PDE have been compared. 1,7-Dimethyl-3-propargylxanthine, 1,3,7-tripropargylxanthine, and 3,7-dimethyl-1-propargylxanthine, which have high affinity for adenosine receptors and weaker activity as PDE inhibitors, all increase behavioral activity. In contrast, 1,3,7-tripropylxanthine, a more potent inhibitor of the brain calcium-independent (Ca-indep) PDEs than 1,3,7-tripropargylxanthine, produces behavioral depression, even though both analogues are potent adenosine receptor antagonists. 7-Benzyl-IBMX, an active receptor antagonist and selective inhibitor of a brain calcium-dependent (Ca-dep) PDE, produces a slight behavioral activation. Xanthines that are potent adenosine receptor antagonists and relatively weak inhibitors of the Ca-indep PDEs reverse the depressant effects of N 6-cyclohexyladenosine, while xanthines, such as 1,3,7-tripropylxanthine, that are potent inhibitors of the Ca-indep PDEs, do not. The results suggest that the behavioral effects of xanthines may be determined primarily by relative activity as adenosine receptor antagonists and as inhibitors of brain Ca-indep PDEs.