Systematization, symbolization and microbicidal activeness of  3-amino 5,6-dimethoxyl-2-methyl derivatives Via 4H–benzo[d] [1,3]–oxazine–4–one and quinazolin-4-(3H)-one

doi:10.21203/rs.3.rs-2959962/v1

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Systematization, symbolization and microbicidal activeness of 3-amino 5,6-dimethoxyl-2-methyl derivatives Via 4H–benzo[d] [1,3]–oxazine–4–one and quinazolin-4-(3H)-one

https://doi.org/10.21203/rs.3.rs-2959962/v1

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The concentration of 2-amino-methyl-4, 5-dimethoxybenzoate with acetic anhydride yielded the cyclic compound 2-methyl-4, 5-disubstituted-1, 3-benzo-oxazine-4-one which further produce a novel 2,3-disubstituted quinazolin-4 ones via the reaction with hydrazine hydrate. The compounds synthesized were unequivocally confirmed by means of Infrared, Nuclear Magnetic Resonance (¹H and ¹³C), Gas Chromatography Mass Spectrophotometer and Elemental analysis. The synthesized compounds were screened against various strains of microorganism; Staphylococcus aureus, Bacillus species, Escherichia coli, Klebsiella pneumonia, Serratia marcescens, and candida albicans. Compounds 1 and 2 showed significant activity against Staphylococcus aureusand Serratia marcescenswith MIC ranging from 6 – 12 mg/mL.

antibacterial activity

quinazoline-4(3H)-One

6-dimethoxyl 2-methyl 4H–benzo[d] [1

3]–oxazine–4–One

nucleophile

synthesis

3-amino-5

6-dimethoxyl-2-methyl quinazolin-4(3H)-One.

Quinazolinone by–product constitute one of most working classes of compounds dominate a wide scope of biotic activity [1]. During the past five decagram, native, semi-synthetic or synthetic microbicidal agents have been used with great victory against the life threatening diseases. [2].

At the commencement of new renaissance, fast development of antibiotic resistance infections led scientists to continue their efforts to expand new classes of antibiotics [3].

Quinazolinone ring system was compensated as a bright molecule because of its far ranging spectrum of bioactive effectiveness like anti-histaminic [4], anticancer [5, 6], anti-HIV [7], anti-inflammatory, [8]analgesic, [9] anti-diabetic [10], anti-bacterial [11], antifungal [12], anti-oxidant [13], anti-tubercular [14], anti-convulsant[15].

Quinazolinone by–product typify one of the most operative classes of compounds dominate a wide spectrum of botanical activity. They are encyclopedic used in pharmaceuticals and agrochemicals, antimalerial[16, 17], antimicrobial, anti-fungal [18, 19, 20, 21, 22, 23, 24] and antitumor [25, 26] activities.

The structures of the compounds produced were assigned on the basis of elemental analysis, IR, ¹H NMR, ¹³C NMR, and Mass spectra data. These discoveries prompted the authors to synthesize 5,6-dimethoxyl and 6-methoxyl quinazolinone derivatives via the interaction of the benzoxazine derivatives with nitrogen nucleophiles, with the aim of obtaining more precise information about the course of the reaction and evaluate them for their Antibacterial activity..

The speedy appearance of antibiotic resistant strains today and misuse of antibiotics and more resistant to most antibacterial and analgesic drugs, synthetic Medicinal Chemists are in a search to develop and synthesize novel antibacterial and analgesic drugs with more potent antibacterial and anagesic activities. This motivates us to develop and synthesize these novel antibacterial and analgesic quinazolinone by–products with more potent antibacterial and analgesic activities. These current challenges make us to synthesize these novel antibacterial and analgesic quinazolinone derivatives with a high antibacterial and analgesic potential.

Customary Hypothetical Strategy

The whole chemical and solvent that were used for the investigation were bought from sigma-Aldrich chemical company in Germany. Melting points were inaugurated using the Kefler hot stage appliance and were not alter. The Buck scientific IR M500 instrument was used for the recording of the IR spectra. The ¹H and ¹³ C N M R spectra were recorded in D M S O at 400 MHz with HAZ VOLATILE V2.M. As usually known, chemical shifts are reported in ppm relative to tetramethylsilane. Gas chromatography Mass (GC/MS) spectra were obtained on a Finingem MAT 44S mass spectrometer operating at electron impact energy of 70eV. Elemental analysis data were fully related to the calculated values. Analytical Thin Layer Chromatography (TLC) was used to monitor the reactions.

2.1. Synthesis of 5, 6-dimethoxyl-2-methyl-4H-benzo [D] [1, 3]-oxazin-4-one (1)

This involved the condensation of Methyl-2-amino-4, 5-dimethoxyl-benzoate 2.11g (0.01mol) and 1.02g (0.01mol) acetic anhydride in 30ml ethanol medium were reacted. The reaction was heated under reflux with stirring using a magnetic stirrer until the reaction mixture showed no trace of starting material when the TLC was developed (2 hours).

At the end of the reaction, work up was done. Ethanol was removed in vacuum and the crude mixture was poured into 50ml of ice water on a cold water bath. The mixture was stirred for 30 minutes filtered and extracted into ethyl acetate and allowed to evaporate at room temperature to give solid products which were recrystallized from hexane or dichloromethane-hexane mixture. Yield was 2.01g (95%), mp: 148-150^oC.

2.2. Synthesis of 3-amino-5, 6-dimethoxy-methyl quinazolin-4 (3H)-one. (2)

The condensation of equimolar amounts of 2-methyl-5, 6-dimethoxyl-4H-benzo [D] [1, 3] –oxazine-4-one (1.06g, 0.005mol) and hydrazine hydrate (0.93g, 0.01mol) were added to 30ml boiling ethanol with stirring using a magnetic stirrer until the reaction mixture showed no trace of starting material when the TLC was developed (3 hours).

At the end of the reaction, the reaction mixture was concentrated in vacuum under reduced pressure using rotary evaporator. The white precipitate formed was then filtered, washed three times with 20ml of distilled water [20ml x 3]. The white crystals were dried and recrystallized from dimethylformamide (DMF) to give pure 3-amino-2-methylquinazolin-4 (3H) –one. Yield was 1.00g (94%) mp: 97-99^oC.

2.3. Estimations of microbicidal activeness

Agar well diffusion method was utilized for the microbicidal activeness. [33] Six species: Staphylococcus aureus(ATCC10145),Bacillus species (NCTC 8236), Escherichia coli(ATCC 25923),Klebsiella pneumonia (NCTC 10418),Serratiamarcescens(ATCC 14756)and Candida albicans (ATCC24433) stock cultures were used. The test organisms were obtained from the Pharmaceutical Microbiology Department of the University of Benin, Benin City, Nigeria. The test organisms were cultured overnight in nutrient broth, diluted to the turbidity of 0.5 McFarland standard. Broth culture (0.2 mL) were seeded on nutrient agar (for bacterial organisms)orSabouraud dextrose agar (for the fungus) andallowed to dry. The various concentrations of the compounds (20–640 mg/mL) were introduced. The culture plates were incubated at 37^oC for 24h (for bacterial organisms) or at room temperature (28^oC) for 48 h (for the fungus). The results were taken by considering the zones of inhibition by the test compounds. Ciprofloxacin (20 mg/mL) was used as positive control while the vehicle (10% DMSO) was used as negative control. Activity and inactivity were observed in accordance with standard and accepted method. [34]

2.4. Lowest prohibition congregation

The micro dilution susceptibility test was used for the resolution of microbicidal and antifungal activeness. The nutrient broth was prepared and added in microiter plates except first well in which inoculum was not added and considered as negative control. A stock solution of test compounds was prepared in DMSO (200 µg/ml) followed by twofold dilution at concentrations of (100, 50, 25….3.125 µg/ml). The 75 µl inoculums were added to the other all wells containing test compounds ranging from 100, 50, 25….3.125 µg/ml. The microtitre plates were then incubated at 37°C for 48 h, and minimal inhibitory concentration was measured in the growth in the form of turbidity. The ciprofloxacin was used as reference drugs for the antibacterial study while ketonaxol was used for antifungal study [35].

2.5. Statistical analysis

All Data were expressed as the means ± SEM ( standard error of mean ), of triplicate determination. Student’s t-test was applied to determine the significance of the difference between the control group and the test compounds.

3.0 Microbicidal activeness of control drugs and tested compounds against tested standard organism

Control drugs

Ciprofloxicin (CPX) for bacteria

Ketonaxol (PEF) for fungus

Compound 1 (1)

Compound 2 (2)

3.1. Characterization of 5,6 -dimethoxyl-2-methyl-4H–benzo[d] [1,3]–oxazine–4–one (1).

¹H NMR (400MHz, DMSO) δ 7.16 (s, 1H), 6.40 (s, 1H), 3.78 (s, 6H), 3.68 (s, 3H), ¹³(NMR (400MHz, DMSO) δ 168.28, 155.80, 149.23, 140.28, 113.37, 100.56, 100.05, 56.94, 56.94, 56.13, 51.93, 16.95: IR (KBr, cm^-1) 3381, 3203, 3135, (NHz), 3018 (CH aromatic), 2951, 2s871, 2718 (CH aliphatic), 1662 (C=0). Anal.Cal 1159 (C0) for C₁₁H₁₁N0₄; C 62.20; H 5.18. Found: C 62.10, H 4.98.

3.2. Characterization of 3-amino-5,6-dimethoxyl 2-methyl quinazoline-4-(3H)-One (2).

¹H NMR (400 MHz, DMSO) δ 7.41 (s, 1H), 7.10 (s, 1H), 5.80 (s, 2H), 3.90 (s, 6H), 2.58 (s, 3H), ¹³C NMR (400MHz, DMSO) δ 160.28, 155.29, 154.57, 149.07, 143.77, 113.65, 108.24, 105.64, 56.80, 56.63, 22.58, IR (KBr, cm^-1) 3301 (NH₂), 1622 (C=0), Anal. Cal. for C₁₁H₁₃N₃0₃; C 56.11, H 5.53; Found, C 56.40, H 5.41.

Table 1: Characterization and physical data of synthesized compounds

Compound No	Solvent	Formula M. wt	Analysis% Calc/Found C H

1	Ethanol	C₁₁H₁₁N0₄ (221.209)	62.20 62.10	5.18 4.98
2	Ethanol	C₁₁H₁₃N₃0₃ (235.239)	56.11 56.40	5.53 5.41

Table 4: Lowest prohibition congregation (MIC) in mg/mL of tested compounds against tested standard microorganisms.

Test Organism

Compund

Escherichia Coli

Biscillus Species

Staphylococcus Avreces

Klebsiela Pneumonia

Serratia Narcenses

Candida Albicans

6:00

7:00

8:00

6:00

7:00

12:00

6:00

7:00

8:00

6:00

7:00

12:00

Discussion

The introduction of 2-amino substituent is a successful strategy to improve the chemical stability of benzoxazinone. Due to the pharmacological activities of 4(3H)-quinazolinone derivative, 5,6-dimethoxyl derivatives of quinazoline-4-one was synthesized via the interaction of the benzoxazinone derivative with nitrogen nucleophile with the aim of obtaining more pricise information about the course of the reaction and some interesting pharmaceutical compounds. The reaction of 4, 5-dimethoxyl derivatives of methylanthranilate and acetic anhydride yielded the cyclic compound 2-methyl-6,7 dimethoxyl-4H–benzo[d] [1,3]–oxazine–4–one. The reaction of this compound with hydrazine hydrate yielded the novel 5, 6-dimethoxyl quinazoline-4-one.

Structural elucidations of compounds synthesized were characterized by correct elemental analysis and careful inspections of spectral data. Looking at the ¹H NMR spectra of the compounds synthesized, compound 1 displayed a singlet signal at: δ 3.78 attributed to methoxy group and singlet at δ 3.68 which was due to methyl group. Other singlets appeared at δ7.16 and 6.40 attributed to aromatic protons. Also, ¹H NMR spectrum of compound 2 showed a characteristic signal at δ 2.56 (singlet) corresponding to methyl group and duplet at: δ 3.90 for methoxy group. Two singlets appeared at δ7.41 and 7.10 attributed to aromatic protons. Another signal appeared at 5.80 which was attributed to the protons of the amino group. For the IR spectra, compound 1 was characterized by absence of υ NH₂and presence of υ C-O stretch in 1101cm^-1 region of the compound. Compound 2 was characterized by absence of υ C-0 and presence of υNH₂ in 3301cm^-1and 3300 region of the compounds.

The ¹³C NMR spectrum of compound 1, revealed signals at δ16.95, 51.93 and 56.13 attributed to methyl and the two methoxy groups respectively, while the aromatic carbon atoms appeared between δ values 100.05-168.28 with the carbonyl carbon atom appearing as the highest δ value of 168.28. Similarly, compound 2 showed signals at δ22.58, 56.63 and 56.80 attributed to methyl and the two methoxy groups respectively, while the aromatic carbon atoms appeared between δ values 105.64-160.28, with the carbonyl carbon atom appearing as the highest δ value of 160.28.

The ¹³C nuclear magnetic resonance revealed low δ values for the aliphatic carbons. This is because the alkyl group is electron donating and hence produces a shielding effect which makes the carbon atom to resonate at low δ values. The aromatic and the carbonyl carbon atoms appeared at high δ values. This is because the aromatic ring is electron withdrawing and the aromatic carbons are highly deshielded and resonate at high frequency. The electronegative effect of the oxygen atom on the carbonyl group makes the carbonyl carbon to appear at higher δ value.

The compounds were investigated for their antimicrobial activity. The compounds synthesized exhibited promising antimicrobial activity against Staphylococcus aureus, Bacillus species, Escherichia coli, Klebsiella pneumonia, Serratiamarcescens and Candida albicans (ATCC24433) In addition, compound 1 showed activity against Escherichia coli while compound 2 was active against Klebsiellapneumonia(Figure 1). Table 3 Showed the MIC of both compounds against the susceptible organisms. Compound 2 had a slightly lower MIC (7 and 12 mg/mL) than compound 1 (6 and 8 mg/kg) against Staphylococcus aureus and Serratiamarcescens, respectively (table 3). This indicated that compound 2 is slightly more active against Staphylococcus aureus and Serratiamarcescenscompared to compound 1.

Activity and inactivity were observed in accordance with standard and accepted method. [34]

The present study has showed that the quinazolinone derivatives 1,2,3 and 4 have antibacterial and analgesic activity. Compounds 1 and 2 showed activity against: Staphylococcus aureus andSerratiamarcescens. Compound 1 has a higher activity against Staphylococcus aureuscompared to compound 2. In the overall compound 2 has activity againstStaphylococcus aureus, Bacillus species, Escherichia coli, and Serratia marcescens while compound 1 has activity against Staphylococcus aureus, Klebsiella pneumonia, and Serratiamarcescens. Compound 2 has a higher antibacterial activity compared to Compound 1 and the control drugs, Ciprofloxicin (CPX) and Ketonaxol (PEF).Compound 2 and 4 showed a higher analgesic activity compared to compound 1, indomethacin and acetylsalicyclic acid, which is a standard analgesic drug.

Acknowledgements: The authors appreciate the assistance of Dr. Marvis E, in England for running the spectra and the Department of Pharmaceutical Microbiology, Faculty of Pharmacy, University of Benin for providing the test organisms.

Author contributions: Dr. OsarumwenseOsarodionPeterdid the work. Proffessor Edema Mary Oliremay and ProffessorUsifoh Cyril Odianose carefully supervised the work. Dr. MarvisErhunse, help in the spectral analysis of the samples.

Conflicts of interest: The authors declare no conflict of interest.

Declaration: The authors hereby declare that the work presented in this article is original and that any liability for claims relating to the content of this article will be borne by them.

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Tables 2 and 3 are available in the Supplementary Files section.

Schemes 1 and 2 are available in the Supplementary Files section.

No competing interests reported.

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Systematization, symbolization and microbicidal activeness of 3-amino 5,6-dimethoxyl-2-methyl derivatives Via 4H–benzo[d] [1,3]–oxazine–4–one and quinazolin-4-(3H)-one

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Abstract

Figures

1. Introduction

2. Materials and Methods

2.1. Synthesis of 5, 6-dimethoxyl-2-methyl-4H-benzo [D] [1, 3]-oxazin-4-one (1)

2.2. Synthesis of 3-amino-5, 6-dimethoxy-methyl quinazolin-4 (3H)-one. (2)

2.3. Estimations of microbicidal activeness

2.4. Lowest prohibition congregation

2.5. Statistical analysis

3. Results and Discussion

4. Conclusions

Declarations

References

Tables

Schemes

Additional Declarations

Supplementary Files

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