WO2023021496A2 - Novel urea analogues containing 5-amino uracil: one-pot green synthesis and in vitro biological evaluation - Google Patents
Novel urea analogues containing 5-amino uracil: one-pot green synthesis and in vitro biological evaluation Download PDFInfo
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- WO2023021496A2 WO2023021496A2 PCT/IB2022/062058 IB2022062058W WO2023021496A2 WO 2023021496 A2 WO2023021496 A2 WO 2023021496A2 IB 2022062058 W IB2022062058 W IB 2022062058W WO 2023021496 A2 WO2023021496 A2 WO 2023021496A2
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- urea
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the current invention discloses the novel urea analogues containing 5-amino uracil via one- pot, two-component green method. Furthermore, antioxidant studies have been evaluated for all the four synthesized compounds 3(a-d).
- Urea is synthesized in the body of many organisms as part of the urea cycle. Urea production occurs in the liver and found in the urine of mammals, dissolved in blood, plants, birds, yeast and many microorganisms.
- Aromatic urea derivatives such as N-phenyl-N-(2-chloroethyl) urea and hetero cyclic urea derivatives show good anti-cancer activity due to their good inhibitory activity against receptor tyrosine kinases (RTKs).
- Urea has widespread applications in agriculture, industries, antiviral, antiinflammatory, anti-HIV, antimalarial, antioxidant, antimicrobial, catalysts in chemical reactions, laboratories, automobiles, fertilizers, urinetherapy, medicines, and enzyme urease.
- Diphenyl urea derivatives are inhibitors of transketolase.
- Urea derivatives show good biological activities such as antimicrobial, anticancer and anaplastic lymphoma kinase (ALK) inhibitors.
- ALK aplastic lymphoma kinase
- Uracil containing scaffolds has noteworthy importance in anti-cancer, drug delivery, nucleic acid replication process, anti-HIV, and pharmaceuticals. Uracil's use in the body is to help carry out the synthesis of many enzymes necessary for cell function through bonding with riboses and phosphates.
- Urea is synthesized in the body of many organisms as part of the urea cycle. Urea production occurs in the liver and found in the urine of mammals, dissolved in blood, plants, birds, yeast and many microorganisms.
- Aromatic urea derivatives such as N-phenyl-N-(2-chloroethyl) urea and heterocyclic urea derivatives show good anti-cancer activity due to their good inhibitory activity against receptor tyrosine kinases(RTKs).
- RTKs receptor tyrosine kinases
- Urea has widespread applications in agriculture, industries, antiviral, anti-inflammatory, anti-HIV, antimalarial, antioxidant, antimicrobial, catalysts in chemical reactions, laboratories, automobiles, fertilizers, medicines, urinetherapy and enzyme urease.
- Diphenyl urea derivatives are inhibitors of transketolase.
- Urea analogues show good biological activities such as antimicrobial, anticancer and anaplastic lymphoma kinas
- uracil containing scaffolds has significant importance in drug delivery, anticancer, nucleic acid replication process, and pharmaceuticals.
- Uracil's use in the body is to help carry out the synthesis of many enzymes necessary for cell function through bonding with riboses and phosphates.
- DPPH 2, 2- diphenyl- 1 -picrylhydrazyl
- Hydrogen peroxide radical scavenging activity of the newly synthesized compounds 3(a-d) were determined according to the method of Ruch et al.
- a solution of hydrogen peroxide (40 mM) was prepared in phosphate buffer at pH 7.4. -7.5 and 100 pg/mL concentrations of the test compound in 3.4 mL of phosphate buffer were added to H2O2 solution (0.6 mL, 40 mM).
- the test tubes were incubated for 30 min in dark with occasional shaking.
- the absorbance of the test samples and phosphate buffer without hydrogen peroxide were measured at 230 nm using UV spectrophotometer. Ascorbic acid was used as the standard.
- the percentage of hydrogen peroxide radical scavenging activity was calculated using the given formula.
- the experiments were evaluated in triplicate and mean values were summarized in Table 2.
- Abs con troi was the absorbance of the standard H2O2
- Abs sam ie was the absorbance in the presence of the sample and standard H2O2.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Anti-Oxidant Or Stabilizer Compositions (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The current invention offers a one-pot, two-component green synthetic protocol as potent antioxidant drug candidates of novel synthesized urea analogues. All the compounds were evaluated for in vitro antioxidant studies by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydrogen peroxide (H2O2) methods. In both DPPH and in H2O2 methods, compounds 3a, and 3c exhibited noteworthy antioxidant activity compared with the standard drug ascorbic acid at various concentrations of 25, 50, 75, and 100 µg/mL. The protocol has various advantages such as green synthetic route, short reaction times, excellent yields, simple work-up procedure, no column chromatography, and potential antioxidant agents.
Description
NOVEL UREA ANALOGUES CONTAINING 5-AMINO URACIL: ONE-POT GREEN SYNTHESIS AND IN VITRO BIOLOGICAL EVALUATION
TECHNICAL FIELD OF THE INVENTION
The current invention discloses the novel urea analogues containing 5-amino uracil via one- pot, two-component green method. Furthermore, antioxidant studies have been evaluated for all the four synthesized compounds 3(a-d). Urea is synthesized in the body of many organisms as part of the urea cycle. Urea production occurs in the liver and found in the urine of mammals, dissolved in blood, plants, birds, yeast and many microorganisms. Aromatic urea derivatives such as N-phenyl-N-(2-chloroethyl) urea and hetero cyclic urea derivatives show good anti-cancer activity due to their good inhibitory activity against receptor tyrosine kinases (RTKs). Urea has widespread applications in agriculture, industries, antiviral, antiinflammatory, anti-HIV, antimalarial, antioxidant, antimicrobial, catalysts in chemical reactions, laboratories, automobiles, fertilizers, urinetherapy, medicines, and enzyme urease. Diphenyl urea derivatives are inhibitors of transketolase. Urea derivatives show good biological activities such as antimicrobial, anticancer and anaplastic lymphoma kinase (ALK) inhibitors.
Uracil containing scaffolds has noteworthy importance in anti-cancer, drug delivery, nucleic acid replication process, anti-HIV, and pharmaceuticals. Uracil's use in the body is to help carry out the synthesis of many enzymes necessary for cell function through bonding with riboses and phosphates.
BACKGROUND AND PRIOR ART
Urea is synthesized in the body of many organisms as part of the urea cycle. Urea production occurs in the liver and found in the urine of mammals, dissolved in blood, plants, birds, yeast and many microorganisms. Aromatic urea derivatives such as N-phenyl-N-(2-chloroethyl) urea and heterocyclic urea derivatives show good anti-cancer activity due to their good inhibitory activity against receptor tyrosine kinases(RTKs). Urea has widespread applications in agriculture, industries, antiviral, anti-inflammatory, anti-HIV, antimalarial, antioxidant, antimicrobial, catalysts in chemical reactions, laboratories, automobiles, fertilizers, medicines, urinetherapy and enzyme urease. Diphenyl urea derivatives are inhibitors of transketolase.
Urea analogues show good biological activities such as antimicrobial, anticancer and anaplastic lymphoma kinase (ALK) inhibitors.
In such search, uracil containing scaffolds has significant importance in drug delivery, anticancer, nucleic acid replication process, and pharmaceuticals. Uracil's use in the body is to help carry out the synthesis of many enzymes necessary for cell function through bonding with riboses and phosphates.
In this connection, we synthesized a novel urea analogues containing 5-amino uracil via one- pot, two-component method. Furthermore, antioxidant studies have been evaluated for all the four synthesized compounds.
STATEMENT OF INVENTION
In the present invention, we have synthesized a one-pot, green synthetic, novelurea tethered 5-amino uracilanalogues. In addition, compounds 3a, and 3c shown significant antioxidant activity.
DETAILED DESCRIPTION OF THE INVENTION
All the urea analogues are novel and displayed a potential antioxidant activity.
A simple 2, 2- diphenyl- 1 -picrylhydrazyl (DPPH) radical assay was used to study the free radical scavenging activity of the synthesized compounds 3(a-d). Ascorbic acid was used for comparing the antioxidant activity of the title compounds as positive control. DPPH (4 mg) was dissolved in methanol 100 mL to obtain 0.004% concentration of DPPH solution. Different concentrations (25, 50, 75, and 100 pg/mL) of title compounds were prepared by diluting with methanol. 1 mL of these test solutions were added to 4 mL of DPPH: methanol solution containing in a set of test tubes and then incubated for 30 min in dark with occasional shaking. Absorbance of the incubated test samples were measured at 517 nm using UV- Visible spectrophotometer. The percentage of DPPH radical scavenging activity was calculated by following formula. The experiments were evaluated in triplicate and mean values were summarized in Table 1.
Where ‘Abscontroi’ represents the absorbance of the DPPH solution and ‘Abssam ie’ represents
the absorbance of the sample and DPPH solution.
Hydrogen peroxide radical scavenging activity of the newly synthesized compounds 3(a-d) were determined according to the method of Ruch et al. A solution of hydrogen peroxide (40 mM) was prepared in phosphate buffer at pH 7.4. -7.5 and 100 pg/mL concentrations of the test compound in 3.4 mL of phosphate buffer were added to H2O2 solution (0.6 mL, 40 mM). The test tubes were incubated for 30 min in dark with occasional shaking. The absorbance of the test samples and phosphate buffer without hydrogen peroxide were measured at 230 nm using UV spectrophotometer. Ascorbic acid was used as the standard. The percentage of hydrogen peroxide radical scavenging activity was calculated using the given formula. The experiments were evaluated in triplicate and mean values were summarized in Table 2.
Where, Abscontroi was the absorbance of the standard H2O2; Abssam ie was the absorbance in the presence of the sample and standard H2O2.
1 2(a-d) 3(a-d)
Scheme 1. Synthesis of novel urea analogues containing 5-amino uracil 3(a-d)
GENERAL PROCEDURE FOR THE SYNTHESIS OF NOVEL UREA ANALOGUES
To a 50 mL round-bottom flask, 5-amino uracil (0.001 mol) (1) was added with various isocyantobenzene (0.001 mol) 2(a-d) in the presence ofpolyethylene glycol (PEG-400) as a solvent and catalyst allowed to stir for 2-3 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). After the completion of the reaction, the resultant solid was purified by passing through a column of silica gel using hexane: ethylacetate (7:3) as an eluent to obtainnovel urea analogues3(a-d) (Scheme 1) in good to excellent yields (87-96%).
TABLES
Table 1. DPPH radical scavenging activity of synthesized compounds 3(a-d)
DPPH scavenging activity
Compounds _
25pg/mL 50 pg/mL 75 pg/mL 100 pg/mL
3a 68.20 79.14 80. 16 81.42
3b 62.13 71.15 78.43 80.22
3c 67.16 78.65 79.36 84.82
3d 63.22 73.74 77.53 79.61
Standard 74.65 82.50 90.15 94.50
Blank — — — —
Standard: Ascorbic acid; Blank: DMSO
Table 2. H2O2 radical scavenging activity of synthesized compounds 3(a-d)
H2O2 scavenging activity
Compounds _
25pg/mL 50 pg/mL 75 pg/mL 100 pg/mL
3a 69.21 76.41 78.12 85.42
3b 62.12 72.13 74.13 80.15
3c 67.46 77.61 75.22 84.81
3d 63.12 70.74 71.52 79.50
Standard 74.84 81.68 88.14 92.42
Blank — — — —
Standard: Ascorbic acid; Blank: DMSO
Claims
1. The invention provides one-pot, two-component protocol for the green synthesis of novel urea analogues with formula 3(a-d).
2. The method as claim 1, where said compound formula 3(a-d) are l-(2,4-diozo- l,2,3,4-tetrahydropyrimidin-5-yl)-3-(3-nitrophenyl)urea(3a),l-(3-chlorophenyl)-3- (2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)urea(3b), l-(4-bromophenyl)-3-(2,4- dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)urea(3c), and l-(4-fluorophenyl)-3-(2,4- dioxo- 1 ,2,3,4-tetrahydropyrimidin-5-yl)urea(3d).
3. The method as claim 1, where the synthesis of new urea analogues are the potential antioxidant agents.
4. The method as claim 1, where the synthesis of new urea analogues utilizes polyethylene glycol (PEG-400).
5. The method as claim 1, where the synthesis of urea containing 5 -amino uracil and antioxidant activity is the first report.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2022/062058 WO2023021496A2 (en) | 2022-12-12 | 2022-12-12 | Novel urea analogues containing 5-amino uracil: one-pot green synthesis and in vitro biological evaluation |
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| PCT/IB2022/062058 WO2023021496A2 (en) | 2022-12-12 | 2022-12-12 | Novel urea analogues containing 5-amino uracil: one-pot green synthesis and in vitro biological evaluation |
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| WO2023021496A2 true WO2023021496A2 (en) | 2023-02-23 |
| WO2023021496A3 WO2023021496A3 (en) | 2023-04-13 |
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| PCT/IB2022/062058 Ceased WO2023021496A2 (en) | 2022-12-12 | 2022-12-12 | Novel urea analogues containing 5-amino uracil: one-pot green synthesis and in vitro biological evaluation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| SE9903894D0 (en) * | 1999-10-28 | 1999-10-28 | New Pharma Research Ab | Novel compounds |
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