SYNTHESIS, COMPUTATIONAL STUDY AND ANTIOXIDANT ACTIVITY OF FURAN DERIVATIVE

Abstract

This invention presents a novel furan derivative with antioxidant properties was synthesized through a reaction between (E)-1-(furan-2-yl)-3-(4-hydroxy-3-methoxyphenyl) prop-2-en-1-one and 2-chloro-N-(3-methoxyphenyl) acetamide, using anhydrous potassium carbonate and potassium iodide in dry acetone. The mixture was refluxed for 22 hours, precipitated, filtered, and recrystallized in ethanol, yielding a compound with approximately 51.58% efficiency. Structural confirmation was achieved through IR and NMR spectroscopy, revealing characteristic peaks for aromatic C=C, C=O, and methoxy groups. Computational analysis via Swiss ADME indicated high gastrointestinal absorption and drug-likeness, aligning with Lipinski’s rule of five. Antioxidant efficacy was validated using a DPPH radical scavenging assay, where the compound showed 39.10% inhibition at 50 µg/ml and 70.01% inhibition at 250 µg/ml, indicating moderate antioxidant activity compared to ascorbic acid. This furan derivative demonstrates potential for applications targeting oxidative stress-related conditions.

Specification

Description:IELD OF INVENTION
The present invention relates to the field of medicinal chemistry and the synthesis of heterocyclic compounds with potential therapeutic applications, specifically antioxidant properties useful in combating oxidative stress-related diseases.

BACKGROUND OF THE INVENTION
Oxidative stress, caused by an overproduction of reactive oxygen species (ROS), contributes to the damage of cellular components like lipids, proteins, and DNA, leading to various diseases including neurodegenerative disorders, cardiovascular diseases, diabetes, and certain cancers. Conventional antioxidant therapies, although widely used, face significant limitations that reduce their effectiveness in mitigating oxidative damage. Many natural antioxidants, such as vitamins C and E, along with polyphenols, suffer from low bioavailability, making it difficult for them to reach effective therapeutic levels within target cells, especially in chronic conditions where sustained antioxidant activity is necessary. Moreover, stability issues further limit their use, as antioxidants like vitamin C are highly sensitive to light, heat, and oxygen, leading to rapid degradation and diminished efficacy. Synthetic antioxidants, including compounds like butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), while potent, have raised concerns about toxicity, especially at high doses over extended periods, restricting their suitability for long-term therapeutic use. Additionally, many existing antioxidants lack specificity, reducing their efficacy in complex oxidative environments, and are often cost-prohibitive for large-scale pharmaceutical applications. Given these challenges, there is a pressing need for novel antioxidant compounds that are bioavailable, stable, and safe for extended use. In this context, heterocyclic compounds, particularly those with furan rings, present a promising avenue for developing effective antioxidants with improved pharmacokinetic properties. This invention introduces a novel furan derivative designed to address the drawbacks of conventional antioxidants by providing enhanced stability, bioavailability, and targeted antioxidant activity, making it a valuable candidate for therapeutic applications aimed at combating oxidative stress-related diseases..
OBJECTS OF THE INVENTION
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows.
It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative
An object of the present disclosure is to provide a synthesis, computational study and antioxidant activity of furan derivative.
Another object of the present disclosure is to synthesize a novel furan derivative with enhanced antioxidant properties, aimed at mitigating oxidative stress by effectively neutralizing reactive oxygen species (ROS).
Another object of the present disclosure is to improve bioavailability and stability over conventional antioxidant compounds, ensuring that the synthesized furan derivative remains active under physiological conditions for prolonged periods.
Another object of the present disclosure is to minimize toxicity risks associated with long-term antioxidant use, by developing a compound that is effective at lower concentrations and safe for extended therapeutic applications.
Another object of the present disclosure is to achieve high specificity and efficacy in antioxidant action, targeting specific ROS types and reducing cellular oxidative damage more precisely, especially in complex oxidative environments.
Another object of the present disclosure is to establish the pharmacokinetic suitability of the synthesized compound for therapeutic use through computational studies, ensuring it meets drug-likeness criteria for potential pharmaceutical applications.
Another object of the present disclosure is to validate the antioxidant efficacy of the furan derivative through in vitro assays, providing quantitative data to support its potential for use in preventing or treating ROS-related diseases.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY OF THE INVENTION
The following presents a simplified summary of the invention in order to provide a basic understanding of some aspects of the invention. This summary is not an extensive overview of the present invention. It is not intended to identify the key/critical elements of the invention or to delineate the scope of the invention. Its sole purpose is to present some concept of the invention in a simplified form as a prelude to a more detailed description of the invention presented later.
The present invention involves a systematic approach to synthesizing a specific furan derivative with targeted antioxidant properties. By employing specific reaction conditions and in silico analyses, the synthesized compound exhibits favorable physicochemical properties, demonstrating its potential as an effective antioxidant agent. Experimental antioxidant activity further corroborates its capability, supporting applications in therapeutic contexts.
DETAILED DESCRIPTION OF THE INVENTION
The following description is of exemplary embodiments only and is not intended to limit the scope, applicability or configuration of the invention in any way. Rather, the following description provides a convenient illustration for implementing exemplary embodiments of the invention. Various changes to the described embodiments may be made in the function and arrangement of the elements described without departing from the scope of the invention.
The present invention pertains to a new synthetic pathway for producing furan derivatives that demonstrate antioxidant activity. By employing a specific reaction mechanism and computational verification, the resultant compound has been shown to possess favorable physicochemical properties for potential medicinal use. Additionally, the antioxidant efficacy of this furan derivative was evaluated, and although it showed lower efficacy compared to ascorbic acid, it presents a basis for further development.
The invention relates to an synthesizing a novel furan derivative through a carefully designed synthetic procedure. The process began by combining equimolar amounts of (E)-1-(furan-2-yl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one and 2-chloro-N-(3-methoxyphenyl)acetamide, with anhydrous potassium carbonate as the base and potassium iodide as a catalyst in dry acetone. Refluxed for 22 hours, the reaction progress was monitored using thin-layer chromatography (TLC), and the product was purified through recrystallization with ethanol. Structural characterization included infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy, confirming the presence of functional groups and structural integrity. Computational analysis using Swiss ADME predicted favorable pharmacokinetic properties, with high gastrointestinal absorption and adherence to Lipinski's rule of five, suggesting drug-likeness. Furthermore, the furan derivative was tested for antioxidant potential via a DPPH radical scavenging assay, showing moderate activity compared to ascorbic acid. The overall yield of the synthesized compound was 51.58%, and while it exhibited some radical scavenging ability, its antioxidant capacity was lower than the standard control.

Example 2: Scheme of Reaction Synthesis
Synthesis of (E)-2-(4-(3-(furan-2-yl)-3-oxoprop-1-en-1-yl)-2-methoxyphenoxy)-N-(3-methoxyphenyl) acetamide

Procedure: Equimolar quantities of (E)-1-(furan-2-yl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one (1) (0.01 mol) and 2-chloro-N-(3-methoxyphenyl)acetamide (0.01 mol) in presence of anhydrous potassium carbonate (0.01 mol) and catalytic amount of potassium iodide in dry acetone were refluxed for 22 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with distilled water and allowed to stand at room temperature for precipitation. Precipitated solid was filtered and recrystallized from absolute alcohol.
% Yield=51.58%; M.P. =88-90; Rf = 0.69; IR (KBr) cm-1: 1494 (C-C Str. Ar.), 1470 (C=C Str. Ar.), 3055 (C-H Str. Ar.), 1747 (C=O Str.), 1636 (C=O Str.), 1073 (C-O-C Str.), 3474 (N-H Str.); 1H-NMR (500 MHz) (ppm): 3.93 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 6.30 (s, 2H, CH2), 6.32 (s, 2H, CH), 7.16 (d, 2H, Ar.), 7.18 (d, 2H, Ar.), 7.02 (d, 2H, Ar.), 7.44 (d, 1H, Ar.), 7.66 (d, 4H, Ar.), 9.28 (s, 1H, NH); 8.27 (3H, Furan); 13CNMR (500MHz): 187.74, 170.35, 151.86, 132.22, 118.89, 117.90, 107.32, 79.52, 55.05
In Silico Drug Likeness : This prediction directs users towards treatment effectiveness and provides insights into whether the ligands being examined exhibit traits indicative of oral bioactivity. This prediction is based on Lipinski's rule of five, a well-established concept formulated by Lipinski et al. The compounds' chemical structures were transformed into their canonical simplified molecular input line entry system (SMILES) and submitted to the SwissADME tool to estimate in silico pharmacokinetic parameters. SwissADME predictor offers data regarding the quantity of hydrogen donors, hydrogen acceptors, rotatable bonds, and the total polar surface area of a chemical. The ligands were evaluated according to Lipinski et al. and analyzed using SwissADME .
EXAMPLE 3: Antioxidant Activity
DPPH radical scavenging activity
The in vitro antioxidant activity of the synthesized compound was quantitatively assessed using the DPPH radical scavenging test. DPPH is a stable free radical at ambient temperature that accepts an electron or hydrogen radical to transform into a stable diamagnetic molecule. The DPPH radical is neutralized by antioxidants via proton donation, resulting in decreased DPPH. Solutions of the synthesized furan derivative were produced in 100% ethanol at concentrations of 50, 100, 150, 200, and 250 µg/ml. A DPPH blank was created without the chemical, utilizing ethanol for baseline correction. The renowned antioxidant, ascorbic acid, was utilized for comparison or as a positive control. The DPPH solution was produced daily and stored in the dark at 4°C between measurements. In summary, 2 ml of each chemical solution with varying concentrations (50-250 µg/ml) were placed in separate test tubes, to which 2 ml of a 0.1 mM ethanol solution of DPPH was added and mixed violently. The tubes were subsequently incubated at 37°C for 30 minutes. Absorbance alterations were quantified at 517 nm utilizing a UV/Vis spectrophotometer, and the residual DPPH was computed. Measurement was performed in triplicate. The radical scavenging activity was expressed as percentage inhibition of DPPH and was calculated using the equation:

Radical scavenging activity (%) = [(A0 - A1)/A0] ×100.
Where, A0 is the absorbance of the control (blank, without compound) and A1 is the absorbance of the compound. The radical scavenging activity of ascorbic acid at various concentrations was also measured and compared with those of the newly synthesized compounds.

The furan derivative namely (E)-2-(4-(3-(furan-2-yl)-3-oxoprop-1-en-1-yl)-2-methoxyphenoxy)-N-(3-methoxyphenyl) acetamide was synthesized by reacting (E)-1-(furan-2-yl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one with 2-chloro-N-(3-methoxyphenyl)acetamide in presence of anhydrous potassium carbonate and catalytic amount of potassium iodide in dry acetone. The structure of synthesized compound was confirmed by IR and NMR spectroscopy. Computational study was tested using SwissADME and results are presented in table 1, 2 and 3. The synthesized compound has high GI absorption. The compound is found to be non-substrates of P-gp. The compound was found to be substrates of CYP1A2. Antioxidant activity was tested by Free Radical Scavenging Potential by DPPH method. The synthesized compound demonstrated less antioxidant effect than standard drug.
Table 1. Drug likeness predictions of compounds AT-2.
S. No. Compound Mol. Wt. NHD NHA NRB TPSA Log P (iLOGP)
lipophilicity Log S (ESOL)
water
solubility Synthetic
accessibility Lipinski's rule of five with zero violations
2 AT-2 407.42 1 6 10 87.00 3.45 -4.59 3.46 0

Table 2: Predicted distribution parameters in ADME of compounds AT-2.
S. No. Compound GI absorption BBB permeant Log Kp (cm/s)
2 AT-2 High No -6.01
Table 3: Predicted metabolism parameters in ADME of compounds AT-2.
S. No Compound P-gp CYP1A2 inhibitor CYP2C19 inhibitor CYP2C9 inhibitor CYP2D6 inhibitor CYP3A4 inhibitor
2 AT-2 No Yes Yes Yes Yes Yes

Table 4: DPPH radical scavenging activity of Synthesized Compounds

Concentration of compounds (µg/ml) % Inhibition
AT-2 Ascorbic Acid
0 0 0
50 39.10 50.26
100 42.11 63.24
150 50.23 71.93
200 59.99 79.23
250 70.01 93.35
, Claims:1. A method for synthesizing a furan derivative with antioxidant properties, comprising:
reacting equimolar quantities of (E)-1-(furan-2-yl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one and 2-chloro-N-(3-methoxyphenyl)acetamide in the presence of anhydrous potassium carbonate and potassium iodide in dry acetone;
refluxing the reaction mixture for approximately 22 hours;
precipitating the product by dilution with distilled water;
isolating the precipitate through filtration;
purifying the product by recrystallization in ethanol,
wherein the resulting furan derivative exhibits antioxidant activity measured by a DPPH radical scavenging assay.
2. The method as claimed in claim 1, wherein the furan derivative achieves a yield of approximately 51.58% after recrystallization.
3. The method as claimed in claim 1, wherein the antioxidant activity of the furan derivative is characterized by radical scavenging activity measured at concentrations between 50 and 250 µg/ml, resulting in 39.10% inhibition at 50 µg/ml and 70.01% inhibition at 250 µg/ml.
4. The method as claimed in claim 1, wherein the structure of the compound is confirmed by infrared (IR) spectroscopy showing absorption peaks indicative of C=C and C=O groups, and by nuclear magnetic resonance (NMR) spectroscopy, identifying methoxy and furan ring structures.
5. The method as claimed in claim 1, wherein the compound shows high gastrointestinal absorption and satisfies Lipinski's rule of five, indicating its suitability as a drug candidate.
Dated this 6 November 2024

Dr. Amrish Chandra
Agent of the Application
IN/PA-2959

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