N- (Substituted Aryl) Acryloyl Theophylline Derivatives are a class of compounds that involve the combination of theophylline, a known methylxanthine derivative, with acryloyl groups and substituted aryl groups. These derivatives are of interest in medicinal chemistry due to their potential bioactivity, which could include stimulating effects on the central nervous system, bronchodilation (opening of airways), or other therapeutic activities. When attached to theophylline, the acryloyl group can modify the molecule’s solubility, bioavailability, and pharmacokinetics, potentially improving its therapeutic efficacy. The aryl group refers to an aromatic ring structure, such as a benzene ring, attached to the molecule. The presence of substituted aryl groups means that the aromatic ring has one or more functional groups (like methoxy, hydroxyl, chloro etc.) attached to it. These substitutions can influence the molecule’s lipophilicity, polarizability, and binding affinity for biological targets. The study of N-(substituted aryl) acryloyl theophylline derivativesis an exciting area in medicinal chemistry, aiming to leverage the therapeutic benefits of theophylline while modifying its structure to improve drug delivery, pharmacodynamics, and targeting. The combination of theophylline, acryloyl, and aryl substitutions offers the potential for more efficient, controlled, and targeted therapies, particularly for respiratory conditions or related disorders [1-12] (anti-microbial, anti-inflammatory effects).

2. Materials and Methods

All chemicals used were of commercially available reagent grade and were used without further purification. The major chemicals were purchased from Aldrich Chemical Corporation. The melting points were determined in open capillary tubes and were uncorrected. The reaction’s progress was monitored by Aluminum sheets precoated with silica gel plates of 0.25 mm thickness. Spots were visualized by using UV lamp and Iodine. Infrared (IR) spectra were recorded as a KBr disc using a Shimadzu FT-IR. The data are given in (cm−1). ¹H NMR spectra were determined in DMSO-d6 and recorded on Bruker ¹H NMR spectrophotometer (500 MHz). The chemical shifts are expressed as δ values (ppm) relative to the internal standard, tetramethyl silane (TMS). Signals are indicated by the following abbreviations: s = singlet, d = doublet and m = multiplet. The J constants were given in (Hz). Elemental analysis was performed by using ChemSketch software.

2.1. Synthesis and Characterization

of several bioactive heterocyclic compounds.

Many common medicines available for different

diseases are found to containing 1,2,4-triazole

as heterocyclic moiety. The examples include

Ribavirin which is antiviraldrug, Rizatriptan

is used to cure migrain, Estazolam and

Alprazolam are anxiolytic, Letrozole and

Anastrozole are anticancer drugs. Triazole

derivatives found in drugs like Itraconazole,

Fluconazole, Posaconazole are useful for

the treatment of fungal infections where as

Ruconamide is well known anticonvulsant [8-

19].Triazole derivatives also found to possess

moderate to good antibacterial and antifungal

activities [20]. Many methods are reported for

the preparation of bioactive triazole derivatives.

One of them is Biginelli reaction which

involves condensation of 1,2,4-triazole-5-

amine and β-keto ester with different aldehydes.

Looking to the pharmacological importance we

have synthesized a new series of compounds

containing triazole and dihydropyrimidine

moieties in one frame work using reported

method [21, 22].

Materials and methods:

General:  All the chemicals required are

obtained from Spectrochem, Finar and Sigma

Aldrich. Merck Kieselgel 60 F254 plates were

recorded in DMSO d6 solution in 5 mm tubes

at room temperature, on a BRUKER 400 MHz

FT-NMR, with TMS as internal standard. IR

Spectra were recorded on SHIMADZU FT-IR

8400 using potassium bromide pallets. Mass

spectra were recorded on SHIMADZU QP-

2010. The antimicrobial activity was carried

out using broth dilution method to determine

minimum inhibitory concentration (MIC)

2.1.1. Synthesis of sodium salt of 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1)

To theophylline (0.04mol or 7.3gm) in a stoppered conical flask, was added sodium metal (0.04mol 0.88gm), little by little, till effervescence ceased. Solid separation on cooling was used as such for the next step.

2.1.2. Synthesis of 7-acetyl-1, 3dimethyl-3, 7 dihydro-1H purine-2, 6-dione (2)

The sodium salt of theophylline (1) (0.03mol or 5.2 gm) was suspended in acetone and acetyl chloride (0.03mol, 2.5ml) while stirring and cooling. It was stirred for 1 hr. and K₂CO₃ (0.2mol or 28gms) was added as a base. It was further stirred for another 10hr. The progress and completion of the reaction were confirmed by TLC (Mobile Phase 7.5:2:0.5 Toluene: Methanol: Ammonia). A solid was obtained after the distillation of acetone and recrystallized by ethanol.

2.1.3. Synthesis of 1,3-dimethyl-7-(-3-aryl substituted prop-2-enoyl)-3,7-dihydro-1H-purine-2,6-dione 3(a-e)

N-acetyl theophylline (2) (0.01mol, 2.23.grm) was added in different aromatic aldehydes in 20ml of ethanol and added 40% sodium hydroxide solution. The mixture was stirred for 24hrs at room temperature. The contents were poured on crushed ice with 10% HCl. The progress and completion of the reaction were confirmed by TLC (Mobile Phase 9:1 Chloroform: Methanol). The reaction mixture was then poured on crushed ice with 10% HCl and the solid product formed was filtered. The product was re-crystallized from aqueous ethanol. The synthesis of target compounds 3a-3e was accomplished using the pathways illustrated in Scheme 1.

2.1.4. Physical Characterization:

2.1.5. Spectral Characterization:

3. Evaluation of pharmacological activities

3.1. In vitro anti-microbial screening

The antibacterial activity of synthesized compounds was carried out by the Kirby – Bauer Disc Diffusion Method¹³. The antibacterial activity was tested against both Gram +ve (Bacillus subtilis) and Gram – ve (Escherichia coli) bacteria. Nutrient agar (1g of beef extract, 1g peptone, 0.5 g NaCl dissolved in 100 ml of double-distilled water) was used to cultivate bacteria. The media was autoclaved and cooled. The media was poured into the petri dish and kept for 30 minutes for solidification. After 30 minutes, the fresh overnight cultures of the inoculum of four different strains were spread onto solidified nutrient agar plates. Sterile paper discs made of Whatman filter paper of 5 mm diameter were dipped in synthesized compounds at different concentrations of 1,2.5,5,10 mg and a standard solution (20μg) was placed in each plate. Ciprofloxacin was used as a standard. The cultured agar plates were incubated at 37°C for 24 h. The Zone of inhibition was calculated by measuring the diameters of the inhibition zone around the well.

For B. subtilis (Gram-positive), the zone of inhibition increased with the concentration of the compounds, with phenyl (3a) showing the largest zone of inhibition at 10 mg (15 mm). For E. coli (Gram-negative), phenyl (3a) and 4-chloro phenyl (3b) also exhibited substantial activity, with phenyl reaching the largest zone of inhibition (23 mm) at 10 mg. Some compounds, like 2-hydroxy phenyl (3c) and 2-furyl (3e), showed minimal to no activity at lower concentrations but exhibited larger inhibition zones as the concentration increased.

For Aspergillus niger, all compounds showed a dose-dependent increase in the zone of inhibition as concentration increased. The compound 2-hydroxy phenyl (3c) exhibited the largest inhibition zone (25 mm) at 10 mg. For Penicillium italicum, the compounds also demonstrated increased inhibition zones with higher concentrations. Again, 2-hydroxy phenyl (3c) showed the greatest activity at 10 mg, with a zone of inhibition of 20 mm. Compounds like phenyl (3a) and 4-chloro phenyl (3b) were also effective but did not reach the level of 2-hydroxy phenyl (3c), especially at higher concentrations. The control did not show any zone of inhibition, confirming the activity is due to the compounds being tested. Phenyl (3a), 4-chloro phenyl(3b), 2- hydroxyphenyl (3c),) and substituted at C7 showed significant activity against Aspergillus Niger and Penicillium italicum fungal except for 4-hydroxy 3-methoxy phenyl (3d) and furan-2-yl(3e). 2- hydroxyphenyl (3c), 4-chloro phenyl(3b) and 4-hydroxy 3-methoxy phenyl (3d), substituted at C7 displayed remarkable activity against Aspergillus Niger) and phenyl (3a), 2- hydroxyphenyl (3c) and 4-hydroxy 3-methoxy phenyl (3d) substituted at C7 displayed remarkable activity against Penicillium italicum.

3.2. Anti-inflammatory activity – Carrageenan-Induced Edema test

Carrageenan-induced hind paw edema test [14,15] according to the most commonly used animal model to evaluate the anti-inflammatory by calculating percentage inhibition of the inflammation, following subplantar administration of 0.1 ml carrageenan (1% suspension of carrageenan (0.1 ml) using 2% gum acacia as a suspending agent in normal saline). After 1 hr, acute inflammation was induced in the right hind paw of rats by subplantar injection of 0.1 ml carrageenan. Indomethacin sodium (IND 50 mg/kg p.o) dissolved in 0.5% CMC used as the standard drug. The paw volume was measured at 0, 3, and 5 hr plethysmometrically after the carrageenan injection by using Vernier calipers.

Drugs and chemicals

Indomethacin sodium (Merck), Carrageenan (Sigma Aldrich Chemical Co.), 0.1% solution of SCMC, 2% gum acacia, normal saline, and 0.5% CMC were used in this study.

Materials and Methods

The anti-inflammatory was treated with the test compounds 3(a-e) at the doses of 50 mg/kg, p.o. was evaluated by Carrageenan acetic in rat injected subplantar administration with a dose of 1% (0.1ml/ body weight). Indomethacin sodium (25 mg/kg) p.o used as a standard. Statistical analysis was carried out by one-way analysis of variance followed by Dunnett’s test.

Procedure

The male rats (120-190g) were divided into four groups (n = 6) and fasted overnight before the experiment with free access to water. Group I: control group animals received 0.1% solution of SCMC only. Group II: standard group animals received Indomethacin sodium (IND 50 mg/kg p.o) dissolved in 0.5% CMC. Group III:  The synthesized compounds 3(a-e) were suspended in 0.1% carboxymethylcellulose (SCMC) at doses of 50 mg/kg orally. After 1 hr, acute inflammation was produced by the subplantar administration of 0.1 ml of 1% suspension of Carrageenan (in SCMC w/v) into the plantar tissue of the right hind paw of the rats. After Carrageenan injection, the paw thickness was measured at 0hr,4hr (0h -4h) by using Vernier calipers. The animals were pretreated with the drug 1 hour before the administration of Carrageenan. Anti-inflammatory activity was expressed as a percentage of inhibition of the inflammation when compared with the vehicle control group. The results obtained are tabulated in the table.

The percentage inhibition of the inflammation was determined by the formula;

                                % I = 1–(dt/dc) × 100

Where “dt” is the difference in paw volume in the drug-treated group and “dc” is the difference in paw volume in the control group. Furthermore, “I” stands for inhibition of inflammation.

The % inflammation at 0 hoursshows the initial inflammation level in the animal groups, with the vehicle control group showing the highest value (3.61±0.016). After 4 hours, the inflammation decreased in all experimental groups, with varying degrees of effectiveness. The % inhibition of inflammation was calculated based on the reduction in inflammation compared to the control group, and phenyl (3a) exhibited the highest inhibition (71.80%), followed by 4-chloro phenyl (3b) (64.78%).

3.2. Bronchodilator activity -Histamine-induced bronchospasm in guinea pigs (Anti asthmatic paradigms)

Antihistaminic studies [16-21]were conducted on guinea pigs (350-500 gm) of either sex. All the experimental animals were fed on a commercial pellet diet. They were group housed under standard conditions of temperature (22±20℃), and relative humidity (60±5%) and a 12:12 light/dark cycle was maintained. They were divided into groups of six animals each. Group 1 was the saline fed group that served as control Group 2 was treated with a standard pheniramine maleate drug. Group 3 was synthesized compound 3 (a) 10 mg/kg. Before experimentation, the animals were kept on fast for 24 hours but water was given ab de libitum. During experiments, animals were also observed for any alteration in their general behavior

Materials and Methods

Synthesized compound 3(a) was suspended in 1% SCMC in distilled water and administered orally. The control animals were given an equivalent volume of SCMC vehicle. The standard group received pheniramine maleate.

Procedure

The guinea pigs fasted for 24 hours and were exposed to a 0.2% histamine dihydrochloride aerosol (dissolved in normal saline) using a nebulizer with a pressure of 300 mmHg in the histamine chamber (24×14×24 cm, made of perplex glass). Guinea pigs which were exposed to histamine aerosol showed progressive signs of difficulty in breathing, followed by convulsions, asphyxia and death. The time required for the development of convulsion is called pre-convulsion time (PCD).^11-13 Preconvulsion time can be judge accurately by experience and observation. When the animal reached to pre-convulsion time, the animal was removed from the chamber and placed in fresh air to recover. In this experiment, the criterion used was time for onset of dyspnoea and the percentage protection from convulsant was calculated by the percentage protection offered by the standard and test drug against asphyxia, using the formula: Percentage protection = [(T2-T1)/T2] ×100. Three days before the experiment screening was done and the animals that developed asthma within 3 minutes of histamine were selected for the experiment, along with it we were also given habituation practice to retain them in a histamine chamber. Animals were divided into groups of six animals each. Pheniramine maleate (1 mg/kg) was administered intraperitoneally and synthesized compounds 3(a) 10 mg/kg were administered orally 30 minutes before exposure. Animals, which did not develop typical asthma within 6 minutes, were taken as protected.

Presenting data from an experiment assessing the effects of synthesized compound 3(a) on histamine-induced convulsions in guinea pigs, comparing it to a control and pheniramine maleate, a known antihistamine. The p-value is <0.01, meaning the differences between the groups (control, pheniramine, and synthesized compound 3(a)) are statistically significant.

Results and Discussion

Synthesis and Characterization

Five novel 7-chalcone-1, 3-dimethyl-3, 7-dihydro-1H-purine-2, 6-dione with different substitution patterns were successfully synthesized via the conventional Claisen–Schmidt condensation reaction in an alkaline medium. The percentage yield of the synthesized 7-chalcone-1, 3 dimethyl-3, 7 dihydro-1h purine-2, 6-dione ranged from 65 to 79%. Thin-layer chromatography (TLC) was used to monitor the progress and completion of the reaction. The synthesized 7-chalcone-1, 3-dimethyl-3, 7-dihydro-1H-purine-2, 6-dione was purified by recrystallization method from aqueous ethanol. The structures of the 7-chalcone-1, 3-dimethyl-3, 7-dihydro-1H-purine-2, 6-dione were successfully characterized and confirmed by ¹H NMR, mass spectroscopic and spectrometric techniques. Infra-red (FT-IR) spectroscopy measures the vibrations of the molecules When the effects of all the different functional groups are taken together, the results are a unique molecular “fingerprint region” that can be used to confirm the identity of the sample. The FT-IR in the KBr spectrum of compound (3a-3e) exhibited absorption bands in the region at 3511, 3460 cm^-1 (the broadband belongs to the OH stretching). The absorption bands are between 3088, 3086, 3060 and 3005 cm^-1 (aromatic C-H Stretching). The absorption bands are between 2815, 2811 and 2808 cm^-1 (aliphatic N-CH₃ Stretching). The absorption bands are between 1781,1771,1716,1683 and 1681 cm^-1 (aliphatic C=C Stretching). The peaks which splits to two branches are between 1681, 1670, 1660 and 1637, 1627, 1624 cm^-1 (C=N Stretching, C=0 Stretching). The absorption band at 1172 and 1172 cm^-1 is caused by the valency vibration of C-O-C Stretching, the peak at 1332, 1315 cm^-1 corresponds to C-N stretching. Finally, the peaks at 744 cm^-1 correspond to the mono-substitution C-Cl of the aromatic ring. For ¹H NMR, spectra of the synthesized compounds were found to be consistence with the suggested structures. Furthermore, the number of integrated protons in the spectra matched the expected number of aromatic protons in each case. The Compound 3a-3e spectra showed two singlets at δ 2.77 ppm, and δ 2.97 ppm, integrated to three protons most likely assigning the –CH₃ proton. Compound 3a-3e spectra displayed a multiplet at δ 7.95-6.46 (3H, 4H, 5H m), ppm integrated to four to five protons corresponding to the aromatic ring respectively. A highly deshielded singlet at 9.95 for compound 3b, corresponding to phenolic OH was observed.

Antibacterial activity

The data clearly show a dose-dependent increase in the zone of inhibition for both B. subtilis and E. coli. Higher concentrations of the compounds generally resulted in larger inhibition zones, indicating an increase in antimicrobial activity with higher compound concentrations. This aligns with typical antimicrobial testing where an increased concentration of an antimicrobial agent often results in greater effectiveness. Among the compounds tested, phenyl (3a) was the most effective against both B. subtilis and E. coli, showing the largest zones of inhibition, especially at 10 mg. The presence of the phenyl group may contribute to its antimicrobial activity, possibly due to its ability to interact with bacterial cell membranes or enzymes, disrupting their function. This is consistent with studies where phenyl derivatives have shown antimicrobial potential.4-chloro phenyl (3b) also exhibited strong antibacterial activity, especially against B. subtilis, with a significant increase in zone of inhibition at 10 mg. However, its activity against E. coli was lower compared to phenyl (3a). The addition of a chlorine atom could enhance the compound’s ability to penetrate bacterial cells, but the activity was less pronounced in E. coli, possibly due to the differences in membrane structures between Gram-positive and Gram-negative bacteria. Compounds like 2-hydroxy phenyl (3c) and 2-furyl (3e) showed delayed responses in terms of effectiveness, with stronger activity only seen at 5 mg and 10 mg concentrations. The hydrophobic nature of the furan and hydroxy groups may explain their relatively delayed onset of activity, as they could require higher concentrations to reach an effective concentration in the bacterial environment. The Gram-positive bacteria B. subtilis appeared to be more susceptible to all tested compounds, showing clear zones of inhibition even at lower concentrations. This is likely due to the simpler cell wall structure of Gram-positive bacteria, which is more susceptible to disruption by antimicrobial compounds. On the other hand, E. coli, a Gram-negative bacterium, showed less susceptibility overall. The outer membrane of E. coli provides an additional barrier to the diffusion of antimicrobial agents, making Gram-negative bacteria more resistant to many types of antimicrobial compounds. This could explain why the compounds required higher concentrations to show significant inhibition against E. coli. The control did not show any zone of inhibition, confirming that the observed antibacterial activity is solely due to the tested compounds and not any external factors. This experiment demonstrates the antimicrobial potential of the tested phenyl derivatives, with the phenyl compound (3a) showing the most promise. However, further studies, including testing with different concentrations and more bacterial strains, are needed to confirm the broad-spectrum activity and explore the mechanism behind the antibacterial effects of these compounds.

Antifungal activity

The zone of inhibition increased with the concentration of the tested compounds for both Aspergillus nigerand Penicillium italicum, indicating a dose-dependent effect. This is consistent with typical antimicrobial or antifungal tests, where increasing the concentration of an active agent results in a larger area of inhibition. Higher concentrations of the compounds lead to greater interaction with fungal cell walls and metabolic pathways, thus enhancing antifungal activity. Among the tested compounds, 2-hydroxyphenyl (3c) was the most effective against both Aspergillus nigerand Penicillium italicum, with the largest inhibition zones observed at the highest concentrations (25 mm forAspergillus niger and 20 mm for Penicillium italicum). The presence of a hydroxyl group in2-hydroxyphenyl might contribute to its strong antifungal activity by affecting the fungal cell membrane or enzymatic processes, as phenolic compounds are known to have potent antimicrobial and antifungal properties.  Phenyl (3a) and 4-chloro phenyl (3b)also showed significant antifungal activity, but their maximum inhibition zones were slightly smaller than that of 2-hydroxy phenyl (3c), with the highest being 23 mm for Aspergillus niger at 10 mg for 4-chloro phenyl (3b). The addition of a chlorine atom in 4-chloro phenyl may have enhanced its ability to interact with fungal cells, but the increased activity was still not as high as that observed with 2-hydroxy phenyl.4-hydroxy 3-methoxy phenyl (3d) demonstrated moderate activity against Aspergillus niger with a maximum zone of inhibition of 21 mm at 10 mg, but was less effective against Penicillium italicum, with only a slight increase in activity observed with increasing concentration.2-furyl (3e) showed moderate activity as well, especially against Aspergillus niger, where the zone of inhibition increased from 7 mm at 2.5 mg to 15 mm at 10 mg. It was somewhat less effective against Penicillium italicum but still demonstrated a clear antifungal effect. Both Aspergillus niger and Penicillium italicumshowed varying susceptibility to the compounds. However, Aspergillus nigergenerally showed larger zones of inhibition at lower concentrations, possibly due to its thinner cell wall structure compared to other fungi. This made it more susceptible to the antifungal effects of the compounds. Penicillium italicum, with its more complex cell wall and resistance mechanisms, showed less sensitivity at the lower concentrations. The control treatment, with no compounds, did not produce any zone of inhibition, which confirms that the observed antifungal effects are directly attributable to the tested compounds. The results indicate that 2-hydroxy phenyl (3c) exhibited the strongest antifungal activity against both Aspergillus nigerand Penicillium italicumacross all concentrations tested, particularly at 10 mg. Other compounds like phenyl (3a), 4-chloro phenyl (3b), and 4-hydroxy 3-methoxy phenyl (3d) also showed varying degrees of antifungal activity, while 2-furyl (3e) showed moderate but promising results. Further studies are needed to explore the mechanisms of action of these compounds and to assess their potential for use in antifungal treatments.

Anti-inflammatory activity

All compounds showed a significant reduction in inflammation after 4 hours, with the most notable decrease observed in phenyl (3a), which exhibited the highest % inhibition of inflammation (71.80%). This suggests that phenyl (3a) has potent anti-inflammatory properties, more effective than the other synthesized compounds. The 4-chloro phenyl (3b) compound followed closely with an inhibition of 64.78%, indicating its strong anti-inflammatory activity, though slightly less effective than 3a.2-hydroxy phenyl (3c), 4-hydroxy 3-methoxy phenyl (3d), and 2-furyl (3e) also exhibited anti-inflammatory effects, with % inhibition values of 58.87%, 52.55%, and 49.87%, respectively. These compounds show moderate anti-inflammatory properties, suggesting that the presence of specific functional groups on the phenyl ring might be influencing the effectiveness of the compounds. The vehicle control group had the highest inflammation level at 4 hours (4.72±0.025), confirming that inflammation naturally progressed in the absence of anti-inflammatory agents. The standard (Indomethacin sodium) showed the highest reduction in inflammation (79.82% inhibition), as expected, since indomethacin is a well-known anti-inflammatory agent. This sets a benchmark for comparing the efficacy of the synthesized compounds. The results suggest that the phenyl group (3a), in particular, is very effective in reducing inflammation. This could be due to the structural characteristics of the compound, which might enable it to interact effectively with inflammatory pathways or enzymes involved in the inflammatory process. The presence of additional functional groups like chloro, hydroxy, and methoxy in compounds like 4-chloro phenyl (3b) and 4-hydroxy 3-methoxy phenyl (3d) appears to modulate the anti-inflammatory activity, with 3b being notably more effective than 3d. This suggests that the nature of substitution on the phenyl ring may impact the compound’s anti-inflammatory potential. Compounds like 2-furyl (3e), while still showing significant anti-inflammatory effects, were less potent than the others, indicating that the furan ring may be less effective than phenyl-based groups in this context. The data for phenyl (3a) and 4-chloro phenyl (3b) show statistically significant reductions in inflammation at 4 hours (p < 0.05, as indicated by **** and ** *), highlighting their stronger effects compared to other compounds. This study demonstrates that the synthesized compounds, particularly phenyl (3a), exhibit significant anti-inflammatory activity, with phenyl (3a) showing the highest inhibition of inflammation (71.80%). The presence of specific functional groups on the aromatic ring appears to influence the anti-inflammatory efficacy, with phenyl (3a) and 4-chlorophenyl (3b) being the most effective. Further research could explore the mechanisms through which these compounds exert their anti-inflammatory effects and whether they could be developed as alternative treatments to standard anti-inflammatory drugs like indomethacin.

Bronchodilator activity against histamine

Pheniramine maleate significantly increased the preconvulsion time (20.23 minutes), showing strong protection against convulsions (72.81% protection), as expected for a known antihistamine. Synthesized compound 3(a) also shows a significant effect, with a preconvulsion time of 16.35 minutes, providing 66.36% protection, though it’s somewhat less effective than pheniramine. The control group had the shortest preconvulsion time (5.50 minutes) and no protection against histamine-induced convulsions. The significant p-value (<0.01) indicates that the results are unlikely due to chance and support the conclusion that both pheniramine and synthesized compound 3(a) are effective in protecting against histamine-induced convulsions. This shows that synthesized compounds of 1,3-dimethyl-7-(-3-phenyl prop-2-enoyl)-3,7-dihydro-1H-purine-2,6-dione 3(a) has antihistaminic property. Compound 3a showed an appreciable decrease in the severity of symptoms of asthma and also a simultaneous improvement in lung function parameters. Along with it has significant mast cell stabilizing activity and suggests that, significant bronchodilator activity against histamine.

Conclusion Optional

References

1. Theophylline. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. New York: McGraw-Hill Education; 2018.

2. Patel NB, Shaikh FM. Synthesis and antimicrobial activity of new theophylline derivatives. Saudi Pharm J. 2010;18(3):129–136.

3. Mohamed MS, Kamel MM, Kassem EM, Abotaleb N. Synthesis and biological evaluation of some theophylline derivatives as anti-inflammatory agents. Eur J Med Chem. 2011;46(7):3022–3029.

4. Alagarsamy V, Raja Solomon V, Dhanabal K. Synthesis and pharmacological investigation of novel theophylline derivatives. Biol Pharm Bull. 2007;30(4):653–658.

5. Henry EJ, Bird SJ, Gowland P, Collins M, Cassella JP. Ferrocenyl chalcone derivatives as possible antimicrobial agents. J Antibiot. 2020;73(5):299–308.

6. Benouda H, Bouchal B, Challioui A, Oulmidi A, Harit T, Malek F, Riahi A, Bellaoui M, Bouammali B. Synthesis of a series of chalcones and related flavones and evaluation of their antibacterial and antifungal activities. Lett Drug Des Discov. 2018;16(1):93–100.

7. Okolo EN, Ugwu DI, Ezema BE, Ndefo JC, Eze FU, Ezema CG, Ezugwu JA, Ujam OT. New chalcone derivatives as potential antimicrobial and antioxidant agents. Sci Rep. 2021; 11:21871.

8. Abdullah AA, El-Domany RA, Eldehna WM, Badria FA. Theophylline-based hybrids as acetylcholinesterase inhibitors endowed with anti-inflammatory activity: synthesis, biological evaluation, in silico and preliminary kinetic studies. RSC Adv. 2023; 13:25616–25634.

9. Rollas S, Küçükgüzel ŞG. Biological activities of hydrazone derivatives. Molecules. 2007;12(8):1910–1939.

10. Kappe CO. Controlled microwave heating in modern organic synthesis. Angew Chem Int Ed. 2004;43(46):6250–6284.

11. El-Subbagh HI, Abu-Zaid SM, Mahran MA. Synthesis and biological activity of substituted acryloyl derivatives. Arch Pharm Res. 2000;23(3):236–241.

12. Chhajed SS, Bastikar VA, Bastikar AV. Microwave-assisted synthesis of theophylline analogues and their antimicrobial activity. J Chem Pharm Res. 2012;4(3):1620–1625.

13. Biemer JJ. Antimicrobial susceptibility testing by the Kirby–Bauer disc diffusion method. Ann Clin Lab Sci. 1973;3(2):135–140.

14. Winter CA, Risley EA, Nuss GW. Carrageenan-induced edema in the hind paw of the rat as an assay for anti-inflammatory drugs. Proc Soc Exp Biol Med. 1962; 111:544–547.

15. Kulkarni SK. Handbook of Experimental Pharmacology. 3rd ed. New Delhi: Vallabh Prakashan; 2005.

16. Parmar NS, Prakash S. Screening methods in pharmacology for anti-asthmatic drugs. Indian J Pharmacol. 2006;38(5):313–320.

17. Gupta PP, Singh A, Chauhan SM. Evaluation of bronchodilator activity using histamine-induced bronchospasm in guinea pigs. Int J Pharm Sci Res. 2012;3(7):2108–2112.

18. Kasture SB, Mahadik KR, More HN. Experimental models for evaluation of anti-asthmatic agents. Pharmacology online. 2008; 2:103–114.

19. Armitage AK, Herxheimer H, Rosa L. The protective action of antihistamines against histamine aerosol in guinea pigs. Br J Pharmacol Chemother. 1952;7(4):625–632.

20. Kulshreshtha VK, Singh N, Jaggi AS. Experimental animal models for screening of anti-asthmatic activity. J Pharmacol Toxicol Methods. 2011;64(3):123–129.

21. Biella G, Galli CL. Histamine-induced bronchospasm as a screening model for bronchodilator drugs. Agents Actions. 1979;9(5-6):541–546.