Synthesis, Identification, and Biological Study for Some Complexes of Azo Dye Having Theophylline.

This article includes the synthesis of heterocyclic azo dye of theophylline by coupling diazonium salt of 4-chloroaniline with theophylline which is, namely, 8-(1-(4-chlorophenyl)azo)theophylline (CPAT). The complexes of cobalt and nickel were prepared by reacting their ions with CPAT ligand in ethanol under 1 : 2 ratio metal-ligand. The CPAT ligand and its complexes were characterized by elemental analysis, infrared spectrometry, electronic absorption spectroscopy, molar conductivity, and magnetic moment. The cobalt and nickel complexes show octahedral geometry having general formula [M(CPAT)2Cl2]. This article addresses the properties of CPAT dye such as photochromic properties. The CPAT dye exhibited obvious and desired changes under irradiation with visible light (405 nm), high sensitive for pH changes which refer to its ability to be analysis indicator. CPAT dye exhibited solvatochromic properties presenting red shift with polar solvent. The CPAT and its complexes show interesting antibiological activities towards Staph. aureus and E. coli bacteria and Aspergillus fungi.

Design, synthesis and biological evaluation of theophylline containing variant acetylene derivatives as α-amylase inhibitors.

A novel pharmacophore with theophylline and acetylene moieties was constructed by using a fragment-based drug design and a series of twenty theophylline containing acetylene conjugates were designed and synthesized, and all the compounds were evaluated by enzyme-based in vitro α-amylase inhibition activity. The in vitro evaluation revealed that most of the compounds displayed good inhibitory activities, and among them nine analogs 13-15, 20, 21 and 24-27 were exhibited more or nearly as equipotent inhibitory activity with IC50 values 1.11 ±â€¯0.07, 1.14 ±â€¯0.17, 1.07 ±â€¯0.01 and 1.21 ±â€¯0.03, 1.33 ±â€¯0.09, 1.17 ±â€¯0.01, 1.05 ±â€¯0.02, 1.61 ±â€¯0.04, 1.02 ±â€¯0.03 µM respectively, as compared with standard, acarbose 1.37 ±â€¯0.26 µM. Further, molecular docking simulation studies were done to identify the interactions and binding mode of synthesized analogs at binding site of α-amylase enzyme (PBD ID: 4GQR). Among the synthesized analogs, two compounds 25 and 27 were selected on the basis of α-amylase inhibition activity and evaluated for in vivo anti-diabetic activity by High Fat Diet-Streptozotocin (HFD-STZ) model in normal rats. At the dose of 10 mg/kg, bw, po these compounds have significantly reduced Plasma Glucose level in rats as compared to pioglitazone. The anti-diabetic activity results showed that the animal treated with the compounds 25 and 27 could better reverse and control the progression of the disease compared to the standard.

Synthesis and Evaluation as a Blood-Brain Barrier-Permeable Probe of 7-N-(PROXYL-3-yl-methyl)theophylline.

The drug-nitroxide radical hybrid-compound 7-N-((2,2,5,5-tetramethylpyrrolidine-1-yloxy(PROXYL))-3-yl-methyl)theophylline (3) was synthesized by coupling 7-N-tosyltheophylline with 3-hydroxymethyl-PROXYL, HMP). The stability of 3 relative to that of HMP was examined in the presence of the anti-oxidant, ascorbic acid (AsA). The initial reduction rate constants of 3 and HMP were 11.9±5.3 and 6.1±5.2 M-1 min-1, respectively. In the presence of glutathione (GSH), these constants increased slightly to 22.3±6.8 and 9.1±2.4 M-1 min-1, respectively. Two-dimensional cranial electron paramagnetic resonance imaging of mice intravenously injected with 3 via the tail vein revealed that probe 3 enters the mouse brain by passing through the blood-brain barrier (BBB).

Synthesis of novel proxyphylline derivatives with dual Anti-Candida albicans and anticancer activity.

Three out of 16 newly synthesized 1,3-dimethylxanthine derivatives (proxyphylline analogues) exhibited consistencies between antifungal and anticancer properties. Proxyphylline possessing 1-(10H-phenothiazin-10-yl)propan-2-yl (6) and polybrominated benzimidazole (41) or benzotriazole moiety (42) remained selectively cidal against Candida albicans (lg R ≥ 3 at conc. of 31, 36 and 20 µM, respectively) however not against normal mammalian Vero cell line in vitro (IC50 ≥ 280 µM) and Galleria mellonella in vivo. These compounds also displayed moderate antineoplastic activity against human breast adenocarcinoma (MCF-7) cell line (EC50 = 80 µM) and high against peripheral blood T lymphoblast (CCRF-CEM) (EC50 = 6.3-6.5 µM). In addition, 6 and 42 exerted: (1) dual activity against fungal adhesion and damage mature biofilm; (2) necrosis of planktonic cells due to loss of membrane function and of structural integrity; (3) biochemical (inhibition of sessile cell respiration) and morphological changes in cell wall polysaccharide contents. Therefore, leading proxyphylline derivatives can be employed to prevent cancer-associated biofilm Candida infections.

Inline UV/Vis spectroscopy as PAT tool for hot-melt extrusion.

Hot-melt extrusion on co-rotating twin screw extruders is a focused technology for the production of pharmaceuticals in the context of Quality by Design. Since it is a continuous process, the potential for minimizing product quality fluctuation is enhanced. A typical application of hot-melt extrusion is the production of solid dispersions, where an active pharmaceutical ingredient (API) is distributed within a polymer matrix carrier. For this dosage form, the product quality is related amongst others to the drug content. This can be monitored on- or inline as critical quality attribute by a process analytical technology (PAT) in order to meet the specific requirements of Quality by Design. In this study, an inline UV/Vis spectrometer from ColVisTec was implemented in an early development twin screw extruder and the performance tested in accordance to the ICH Q2 guideline. Therefore, two API (carbamazepine and theophylline) and one polymer matrix (copovidone) were considered with the main focus on the quantification of the drug load. The obtained results revealed the suitability of the implemented PAT tool to quantify the drug load in a typical range for pharmaceutical applications. The effort for data evaluation was minimal due to univariate data analysis, and in combination with a measurement frequency of 1 Hz, the system is sufficient for real-time data acquisition.

Chemoenzymatic Synthesis of Proxyphylline Enantiomers.

A novel synthetic route for preparation of proxyphylline enantiomers using a kinetic resolution (KR) procedure as the key step is presented. The reactions were catalyzed by immobilized Candida antarctica lipase B in acetonitrile. Three types of reactions were examined: (i) enantioselective transesterification of racemic proxyphylline with vinyl acetate as well as (ii) hydrolysis and (iii) methanolysis of its esters. The influence of reaction conditions on the substrate conversion and enantiomeric purity of the products were investigated. Studies on analytical scale reactions revealed that the titled API enantiomers could be successfully obtained with excellent enantiomeric excess (up to >99% ee). The process was easily conducted on a 5 g scale at 100 g/L. In a preparative-scale reaction, unreacted (S)-(+)-butanoate (97% ee) and (R)-(-)-alcohol (96% ee) were obtained after 2 days in yields of 45% and 46%, respectively. When the reaction time was extended to 6 days, (S)-(+)-butanoate was isolated in >99% ee and acceptable high enantioselectivity (E = 90). Importantly, the KR's products could be conveniently isolated by exploiting varying solubility of the ester/alcohol in acetonitrile at room temperature. In addition, a chiral preference of the CAL-B active site for the R-enantiomer was rationalized by in sillico docking studies.

Design, Synthesis, and Antimycobacterial Activity of Novel Theophylline-7-Acetic Acid Derivatives With Amino Acid Moieties.

The theophylline-7-acetic acid (7-TAA) scaffold is a promising novel lead compound for antimycobacterial activity. Here, we derive a model for antitubercular activity prediction based on 14 7-TAA derivatives with amino acid moieties and their methyl esters. The model is applied to a combinatorial library, consisting of 40 amino acid and methyl ester derivatives of 7-TAA. The best three predicted compounds are synthesized and tested against Mycobacterium tuberculosis H37Rv. All of them are stable, non-toxic against human cells and show antimycobacterial activity in the nanomolar range being 60 times more active than ethambutol.

Theophylline-7-acetic acid derivatives with amino acids as anti-tuberculosis agents.

A series of amides were synthesized by condensation of theophylline-7-acetic acid and eight commercially available amino acid methyl ester hydrochlorides. Consecutive hydrolysis of six of the amido-esters resulted in the formation of corresponding amido-acids. The newly synthesized compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv. The activity varied depending on the amino acid fragments and in seven cases exerted excellent values with MICs 0.46-0.26 µM. Assessment of the cytotoxicity revealed that the compounds were not cytotoxic against the human embryonal kidney cell line HEK-293T. The theophylline-7-acetamides containing amino acid moieties appear to be promising lead compounds for the development of antimycobacterial agents.

Synthesis and pharmacological evaluation of novel tricyclic[2,1-f]theophylline derivatives.

The multireceptor strategy was implemented to obtain potential antipsychotics and/or antidepressants in a series of long-chain arylpiperazines bearing a tricyclic theophylline fragment. Their binding profile toward monoaminergic receptors (α1, 5-HT(1A), 5-HT(2A), 5-HT6, 5-HT7, D2, D3) was determined as well. The selected compounds 7 and 9 were tested in functional in vivo models and showed, like atypical antipsychotic drugs, presynaptic 5-HT(1A) receptor agonistic and postsynaptic 5-HT(1A), 5-HT(2A), and D2 receptor antagonistic activity.

Prodrugs of theophylline incorporating ethyleneoxy groups in the promoiety: synthesis, characterization, and transdermal delivery.

Two different types of derivatives of theophylline (Th-H) incorporating ethyleneoxy groups into the promoiety have been synthesized. One is a soft alkyl type where N-methyl-N-methoxyethyleneoxycarbonylaminomethyl chlorides have been used to alkylate Th-H in the 7 position. The other is in an acyl type where methoxyethyleneoxycarbonyl chlorides have been used to acylate Th-H in the 7 position. All of the prodrugs were more soluble in the lipid isopropyl myristate (IPM) than Th-H, and three were more soluble in water (AQ) than Th-H. The most water-soluble prodrug gave the highest maximum delivery of total species containing Th-H through hairless mouse skin from IPM (maximum flux, J(MMIPM))-more than seven times that of Th-H, while the other two gave more than three times that of Th-H. The acyl-type prodrugs delivered only Th-H, while the soft alkyl types delivered 60-70% Th-H plus intact prodrug. The Roberts-Sloan equation was able to predict the best performer for each type with an average of the absolute difference between the experimental log J (MMIPM) and calculated log J (MMIPM) (Δlog J (MMIPM)) of 0.253 log units. The values for the present prodrugs and previously reported prodrugs that had not been previously included in the Roberts-Sloan data base (n = 23) were included in the previous n = 71 data base to give n = 94. New coefficients for the Roberts-Sloan equation have been obtained.

Water-soluble Cp ruthenium complex containing 1,3,5-triaza-7-phosphaadamantane and 8-thiotheophylline derivatives: synthesis, characterization, and antiproliferative activity.

The new water-soluble ruthenium(II) mononuclear complexes [RuCp(X)(PTA)(L)] (X = 8-thio-theophyllinate (TTH(-)), L = PTA (1), L = PPh(3) (7)); (X = 8-methylthio-theophyllinate (8-MTT(-)), L = PTA (2), L = PPh(3) (8)), (X = 8-benzylthio-theophyllinate (8-BzTT(-)), L = PTA (3), L = PPh(3) (9)) and binuclear complexes [{RuCp(PTA)(L)}(2)-µ-(Y-κN7,N'7)] (Y = bis(S-8-thiotheophyllinate)methane (MBTT(2-)), L = PTA (4), L = PPh(3) (10)), (Y = 1,2-bis(S-8-thiotheophyllinate)ethane (EBTT(2-)), L = PTA (5), L = PPh(3) (11)), (Y = 1,3-bis(S-8-thiotheophyllinate)propane (PBTT(2-)); L = PTA (6), L = PPh(3) (12)) have been synthesized and characterized by NMR, IR spectroscopy and elemental analysis. The single crystal X-ray structure of [RuCp(8-MTT-κS)(PTA)(2)] (2) was also obtained. The antiproliferative activity of the complexes on cisplatin-sensitive T2 and cisplatin-resistant SKOV3 cell lines has been evaluated.

Synthesis of theophylline derivatives and study of their activity as antagonists at adenosine receptors.

The synthesis of oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 and/or 8 is described. The binding activity at adenosine receptors of selected derivatives was studied. Compound 2 showed high affinity for human A(2B) receptor (K(i) = 4.16 nM) with a selectivity K(iA2A)/K(iA2B) of 24.1, and a solubility in water of 1 mM. The alkenyl substituent in some of the theophylline derivatives allows for covalent attachment of them onto hydrogen-terminated silicon substrate surfaces via hydrosilylation. Alternatively, an azido group was incorporated to an oligo(ethylene glycol)theophylline derivative as an anchor for tethering the molecules on ethynyl presenting surfaces via click reaction.

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.

Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels.

Epidemiological evidence suggests that caffeine or its metabolites reduce the risk of developing Parkinson's disease, possibly by protecting dopaminergic neurons, but the underlying mechanism is not clearly understood. Here, we show that the primary metabolite of caffeine, paraxanthine (PX; 1, 7-dimethylxanthine), was strongly protective against neurodegeneration and loss of synaptic function in a culture system of selective dopaminergic cell death. In contrast, caffeine itself afforded only marginal protection. The survival effect of PX was highly specific to dopaminergic neurons and independent of glial cell line-derived neurotrophic factor (GDNF). Nevertheless, PX had the potential to rescue dopaminergic neurons that had matured initially with and were then deprived of GDNF. The protective effect of PX was not mediated by blockade of adenosine receptors or by elevation of intracellular cAMP levels, two pharmacological effects typical of methylxanthine derivatives. Instead, it was attributable to a moderate increase in free cytosolic calcium via the activation of reticulum endoplasmic ryanodine receptor (RyR) channels. Consistent with these observations, PX and also ryanodine, the preferential agonist of RyRs, were protective in an unrelated paradigm of mitochondrial toxin-induced dopaminergic cell death. In conclusion, our data suggest that PX has a neuroprotective potential for diseased dopaminergic neurons.

Synthesis of new mannosyl, galactosyl and glucosyl theophylline nucleosides with potential activity as antagonists of adenosine receptors. DEMA-induced cyclization of glycosylideneiminouracils.

The synthesis of D-mannosyl, D-galactosyl and D-glucosyl theophylline nucleosides by diethoxymethyl acetate (DEMA)-induced cyclization of 4-amino-5-glycosylideneimino-1,3-dimethyluracil is reported. 8-Methyltheophylline derivatives of the same sugars were also prepared by Ac(2)O/H(+)-induced cyclization of their imine precursors. This approach has allowed beta-D-mannopyranosyl-, alpha-D-galactofuranosyl- and beta-D-glucofuranosyltheophylline nucleosides to be synthesized for the first time. The inhibition of specific binding at A(1), A(2A), A(2B) and A(3) adenosine receptors in the mannose derivatives is also reported.

Phosphinic platinum complexes with 8-thiotheophylline derivatives: synthesis, characterization, and antiproliferative activity.

The platinum mixed-phosphine complexes (SP-4,2)-[PtCl(8-MTT)(PPh3)(PTA)] (2) and cis-[Pt(8-MTT)2(PPh3)(PTA)] (3) (MTTH2 = 8-(methylthio)theophylline, PTA = 1,3,5-triaza-7-phosphaadamantane) have been prepared from the precursor cis-[PtCl2(PPh3)(PTA)] (1), which has been fully characterized by X-ray diffraction determination. Antiproliferative activity tests indicated that the presence of one lipophilic PPh3 and one hydrophilic PTA makes 1-3 more active than the analogues bearing two PPh3 or two PTA. The reactivity of cis-[PtCl2(PPh3)2], cis-[PtCl2(PTA)2], and cis-[PtCl2(PPh3)(PTA)] with the bis(thiopurines) bis(S-8-thiotheophylline)methane (MBTTH2), 1,2-bis(S-8-thiotheophylline)ethane (EBTTH2), and 1,3-bis(S-8-thiotheophylline)propane (PBTTH2) has also been investigated. New binuclear complexes have been prepared and identified by spectroscopic techniques and their antiproliferative activities on T2 and SKOV3 cell lines evaluated.

Topical delivery of N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of theophylline (ThH).

N(7)-(N-Alkyl-N-alkyloxycarbonyl) aminomethyl (NANAOCAM) prodrugs of theophylline (ThH) have been synthesized and characterized by their solubilities in isopropyl myristate (S(IPM)), solubilities in water (S(AQ)), partition coefficients between IPM and pH 4.0 buffer (K(IPM:4.0)) and by their ability to penetrate hairless mouse skin from IPM (J(MIPM)). The most lipid soluble and water soluble member, N-methyl-N-ethyloxy-carbonylaminomethyltheophylline, gave the highest flux through hairless mouse skin from IPM compared to ThH. The flux of NANAOCAM prodrugs of ThH can be accurately predicted by the Roberts-Sloan (RS) equation.

Novel 1,3-disubstituted 8-(1-benzyl-1H-pyrazol-4-yl) xanthines: high affinity and selective A2B adenosine receptor antagonists.

Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is believed to be an A(2B) adenosine receptor (AdoR) mediated pathway. We hypothesize that a selective, high-affinity A(2B) AdoR antagonist may provide therapeutic benefit in the treatment of asthma. In an attempt to identify a high-affinity, selective antagonist for the A(2B) AdoR, we synthesized 8-(C-4-pyrazolyl) xanthines. Compound 22, 8-(1H-pyrazol-4-yl)-1,3-dipropyl xanthine, is a N-1 unsubstituted pyrazole derivative that has favorable binding affinity (K(i) = 9 nM) for the A(2B) AdoR, but it is only 2-fold selective versus the A(1) AdoR. Introduction of a benzyl group at the N-1-pyrazole position of 22 resulted in 19, which had moderate selectivity. The initial focus of the SAR study was on the preparation of substituted benzyl derivatives of 19 because the corresponding phenyl, phenethyl, and phenpropyl derivatives showed a decrease in A(2B) AdoR affinity and selectivity relative to 19. The preferred substitution on the phenyl ring of 19 contains an electron-withdrawing group, specifically F or CF(3) at the m-position, as in 33 and 36 respectively, increases the selectivity while retaining the affinity for the A(2B) AdoR. Exploring disubstitutions on the phenyl ring of derivatives 33 and36 led to the 2-chloro-5-trifluoromethylphenyl derivative 50, which retained the A(2B) AdoR affinity but enhanced the selectivity relative to 36. After optimization of the substitution on the 8-pyrazole xanthine, 1,3-disubstitution of the xanthine core was explored with methyl, ethyl, butyl, and isobutyl groups. In comparison to the corresponding dipropyl analogues, the smaller 1,3-dialkyl groups (methyl and ethyl) increased the A(2B) AdoR binding selectivity of the xanthine derivatives while retaining the affinity. However, the larger 1,3-dialkyl groups (isobutyl and butyl) resulted in a decrease in both A(2B) AdoR affinity and selectivity. This final SAR optimization led to the discovery of 1,3-dimethyl derivative 60, 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl xanthine, a high-affinity (K(i) = 1 nM) A(2B) AdoR antagonist with high selectivity (990-, 690-, and 1,000-) for the human A(1), A(2A,) and A(3) AdoRs.

Synthesis and 5-HT1A/5-HT2A activity of some butyl analogs in the group of phenylpiperazine alkyl pyrimido[2,1-f]theophyllines.

New arylpiperazines with a four-methylene spacer containing a terminal pyrimido[2,1-f] theophylline fragment were synthesized, and their 5-HT1A and 5-HT2A receptor affinities were determined. All these compounds displayed a high affinity for 5-HT1A receptors (Ki=0.5-21.5 nM), and low affinity for 5-HT2A ones. The results of in vivo experiments showed that compounds revealed potential agonistic activity at presynaptic 5-HT1A receptors, whereas their functional activity at postsynaptic 5-HT1A sites was diversified. In fact, compounds and behaved like partial agonists, antagonists or agonists of postsynaptic 5-HT1A receptors, respectively. The pharmacological properties of the tested compounds were discussed in comparison with those of the three methylene-analogs described earlier.

Design of a microporous controlled delivery system for theophylline tablets.

The aim of present work was to develop a microporous-controlled delivery system for theophylline via coating a blend of PCL and PEG on the surface of tablets, where PCL was the major component of film coating material and PEG was acted as a leachable pore-forming agent when contacting with an aqueous medium. The influences of the type of solvent, the amount of PEG, and the thickness of films on the mechanical and thermal properties of coating films and drug release performance were investigated. The DSC thermograms and FTIR spectra indicated both PCL and PEG remained independently in the blended films. The mechanical data showed a decrease tendency as increase in the amount of PEG in the blends due to highly crystalline character of PEG. Slower evaporation rate of acetone than dichloromethane enhanced phase separation between PCL and PEG during film formation, and resulted in the pore size in films prepared from acetone larger than from dichloromethane. The release rate of coated tablets were increased by increasing the amount of pore-forming agent, and the corresponding values from tablets coated in dichloromethane were less than in acetone. Much denser structure and smaller pore size of films formed from dichloromethane contributed to this result. The release of drug from tablets coated in acetone showed a profile more close to a zero-order constant release profile. The penetration of water into drug core played an important role in influencing drug release pattern.