Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents

G. Grover, S.G. Kini

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144 Citations (Scopus)

Abstract

In continuation of our work on synthesis of biheterocycles carrying the biodynamic heterocyclic systems at position 3, a series of new nalidixic acid derivatives having quinazolones moiety were synthesised to achieve enhanced biological activity and wide spectrum of activity. Nalidixic Acid was first converted into its acid chloride using thionyl chloride as an acylating agent at laboratory temperature. Later it was converted to methyl ester. Nalidixoyl chloride formed vigorously reacts with methanol to give a methyl ester of nalidixic acid. The ester on addition of hydrazine hydrate furnished nalidixic acid hydrazide. Appropriate anthranilic acid was refluxed with acetic anhydride to form Benzoxazine/Acetanthranil. 5-iodo-derivative of anthranilic acid was prepared and also utilised to obtain 6-iodo-Benzoxazine/Acetanthranil. Also, 6-nitro-Benzoxazine/Acetanthranil was obtained by nitration of acetanthranil using conc. H2SO4 and fuming HNO3. Equimolar proportions of the appropriate synthesised acetanthranils and nalidixic acid hydrazide in the presence of ethanol were refluxed to synthesise quinazolones. Elemental analysis and IR spectra confirmed nalidixic acid hydrazide formation. The structures of the compounds obtained have been established on the basis of Spectral (IR, 1H NMR and mass) data. The current study also involves in vitro antimicrobial screening (using Agar dilution and Punch well diffusion method) of synthesised quinazolone derivatives bearing nalidixic acid moiety on randomly collected microbial strains. The derivatives Ga (NAH), Gb (QN) and Gd (NiQNA) showed marked inhibitory activity against enteric pathogen like Aeromonas hydrophila, a causative agent of diarrhoea in both children as well as adults. Among the respiratory pathogens included in study, derivative Gd (NiQNA) was found to be active against Streptococcus pyogenes. No significant inhibitory activity was seen by any of synthesised derivatives against Coagulase negative Staphylococcus. Derivative Ga (NAH) was found to show very high activity against the Candida colonies and derivative Gd (NiQNA) was also found to exhibit inhibitory activity against Candida albicans; a normal flora of the human body which plays an important role in causing opportunistic infections in immunocompromised hosts. Proteus vulgaris, a gram-negative bacteria included in our study was found to be inhibited by derivative Gb (QN). © 2005 Elsevier SAS. All rights reserved.
Original languageEnglish
Pages (from-to)256-262
Number of pages7
JournalEuropean Journal of Medicinal Chemistry
Volume41
Issue number2
DOIs
Publication statusPublished - 2006

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Nalidixic Acid
Antifungal Agents
Anti-Bacterial Agents
Derivatives
Benzoxazines
Esters
hydrazine
Candida
Chlorides
Pathogens
Proteus vulgaris
Aeromonas hydrophila
Bearings (structural)
Streptococcus pyogenes
Coagulase
Opportunistic Infections
Immunocompromised Host
Nitration
Gram-Negative Bacteria
Candida albicans

Cite this

@article{a9e4f2e4b0b94df8a2469599f01d6377,
title = "Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents",
abstract = "In continuation of our work on synthesis of biheterocycles carrying the biodynamic heterocyclic systems at position 3, a series of new nalidixic acid derivatives having quinazolones moiety were synthesised to achieve enhanced biological activity and wide spectrum of activity. Nalidixic Acid was first converted into its acid chloride using thionyl chloride as an acylating agent at laboratory temperature. Later it was converted to methyl ester. Nalidixoyl chloride formed vigorously reacts with methanol to give a methyl ester of nalidixic acid. The ester on addition of hydrazine hydrate furnished nalidixic acid hydrazide. Appropriate anthranilic acid was refluxed with acetic anhydride to form Benzoxazine/Acetanthranil. 5-iodo-derivative of anthranilic acid was prepared and also utilised to obtain 6-iodo-Benzoxazine/Acetanthranil. Also, 6-nitro-Benzoxazine/Acetanthranil was obtained by nitration of acetanthranil using conc. H2SO4 and fuming HNO3. Equimolar proportions of the appropriate synthesised acetanthranils and nalidixic acid hydrazide in the presence of ethanol were refluxed to synthesise quinazolones. Elemental analysis and IR spectra confirmed nalidixic acid hydrazide formation. The structures of the compounds obtained have been established on the basis of Spectral (IR, 1H NMR and mass) data. The current study also involves in vitro antimicrobial screening (using Agar dilution and Punch well diffusion method) of synthesised quinazolone derivatives bearing nalidixic acid moiety on randomly collected microbial strains. The derivatives Ga (NAH), Gb (QN) and Gd (NiQNA) showed marked inhibitory activity against enteric pathogen like Aeromonas hydrophila, a causative agent of diarrhoea in both children as well as adults. Among the respiratory pathogens included in study, derivative Gd (NiQNA) was found to be active against Streptococcus pyogenes. No significant inhibitory activity was seen by any of synthesised derivatives against Coagulase negative Staphylococcus. Derivative Ga (NAH) was found to show very high activity against the Candida colonies and derivative Gd (NiQNA) was also found to exhibit inhibitory activity against Candida albicans; a normal flora of the human body which plays an important role in causing opportunistic infections in immunocompromised hosts. Proteus vulgaris, a gram-negative bacteria included in our study was found to be inhibited by derivative Gb (QN). {\circledC} 2005 Elsevier SAS. All rights reserved.",
author = "G. Grover and S.G. Kini",
note = "Cited By :108 Export Date: 10 November 2017 CODEN: EJMCA Correspondence Address: Kini, S.G.; Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal 576119, Karnataka, India; email: suvarna.gk@manipal.edu Chemicals/CAS: acetic anhydride, 108-24-7; agar, 9002-18-0; alcohol, 64-17-5; anthranilic acid, 118-92-3; chloride, 16887-00-6; hydrazine, 10217-52-4, 13775-80-9, 18500-32-8, 302-01-2, 7803-57-8; methanol, 67-56-1; nalidixic acid, 389-08-2; nitric acid, 7697-37-2; sulfuric acid, 7664-93-9; thionyl chloride, 7719-09-7; Ampicillin, 69-53-4; Anti-Bacterial Agents; Antifungal Agents; Nalidixic Acid, 389-08-2; Quinazolines Manufacturers: cfl pharma, India References: Albrecht, R., Development of antibacterial agents of the nalidixic acid type (1977) Prog. Drug Res., 21, pp. 9-104; (1747) American Medical Association-Drug Evaluations-Fifth Edition; (1120) Text Book of Pharmacology, Sixth Edition; Shirodkar, P.Y., Vartak Meghna, M., Synthesis, biological evaluation and QSAR evaluation of Mannic bases of 6-nitro-quinazolones (2000) Indian J. Heterocyclic Chem., 9, pp. 239-240; Pandey, V.K., Misra, D., Shukla, A., Synthesis and antiviral activity if 2-aryl-5-[3′-2′-methyl-6: 8 substituted-quinazolyl)-phenyl], pyrazoles (1994) Indian Drugs, 31 (11), pp. 532-536; Desai, N.C., Shah, B.R., Bhatt, J.J., Patel, H.H., Undavia, N.K., Trivedi, P.B., Narayanan, V., Synthesis of 2,3-disubstituted-3,1-quinazolin-4 (4H)-ones as potential anticancer and anti-HIV agents (1995) Indian J. Chem., 34, pp. 201-208; Werbel, L.M., Elslager, E.F., Newton, L.S., (1987) J. Heterocyclic Chem., p. 24; Patel, N.B., Lilakar, J.D., Synthesis of new substituted-4-(3H)-quinazolinones and their antibacterial activity (2001) Indian J. Heterocyclic Chem., 11, pp. 85-86; Ashok, R., (2000) Antimicrobials in Laboratory Medicine, pp. 62-70. , B. I. Churchill Livingstone; Gaurav, G., Kini, S.G., Synthesis and Evaluation of certain new 1,3,4-oxadiazole derivatives of Nalidixic acid moiety as potential Antifungal and Antibacterial agents (2003) Indian J. Heterocyclic Chem., 12 (3), pp. 289-290; Parmar Surendra, S., Arora, R.C., Some 2,3,6,8-tetrasubstituted quinazolone hydrazides as monoamine oxidase inhibitors (1967) European J. Org. Chem., 10, pp. 1182-1183; Desai, K.R., Naik, N.M., Reactive disperse dyes: Synthesis of sulphonylazido group reactive disperse dyes and their application on nylon and polyester fibres (1989) J. Indian Chem. Soc., 66, pp. 495-496; Abdel-Hamide, S.G., Synthesis of some new quinazoline derivatives (2000) Indian J. Hetrocyclic Chem., 10, pp. 59-64; Waheed, A., Khan, S.A., Synthesis of certain substituted 1,2 Pyrazolines from nalidixic acid as Antibacterial and Analgesic agents (2001) Indian J. Hetrocyclic Chem., 11, pp. 59-62",
year = "2006",
doi = "10.1016/j.ejmech.2005.09.002",
language = "English",
volume = "41",
pages = "256--262",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",
number = "2",

}

TY - JOUR

T1 - Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents

AU - Grover, G.

AU - Kini, S.G.

N1 - Cited By :108 Export Date: 10 November 2017 CODEN: EJMCA Correspondence Address: Kini, S.G.; Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal 576119, Karnataka, India; email: suvarna.gk@manipal.edu Chemicals/CAS: acetic anhydride, 108-24-7; agar, 9002-18-0; alcohol, 64-17-5; anthranilic acid, 118-92-3; chloride, 16887-00-6; hydrazine, 10217-52-4, 13775-80-9, 18500-32-8, 302-01-2, 7803-57-8; methanol, 67-56-1; nalidixic acid, 389-08-2; nitric acid, 7697-37-2; sulfuric acid, 7664-93-9; thionyl chloride, 7719-09-7; Ampicillin, 69-53-4; Anti-Bacterial Agents; Antifungal Agents; Nalidixic Acid, 389-08-2; Quinazolines Manufacturers: cfl pharma, India References: Albrecht, R., Development of antibacterial agents of the nalidixic acid type (1977) Prog. Drug Res., 21, pp. 9-104; (1747) American Medical Association-Drug Evaluations-Fifth Edition; (1120) Text Book of Pharmacology, Sixth Edition; Shirodkar, P.Y., Vartak Meghna, M., Synthesis, biological evaluation and QSAR evaluation of Mannic bases of 6-nitro-quinazolones (2000) Indian J. Heterocyclic Chem., 9, pp. 239-240; Pandey, V.K., Misra, D., Shukla, A., Synthesis and antiviral activity if 2-aryl-5-[3′-2′-methyl-6: 8 substituted-quinazolyl)-phenyl], pyrazoles (1994) Indian Drugs, 31 (11), pp. 532-536; Desai, N.C., Shah, B.R., Bhatt, J.J., Patel, H.H., Undavia, N.K., Trivedi, P.B., Narayanan, V., Synthesis of 2,3-disubstituted-3,1-quinazolin-4 (4H)-ones as potential anticancer and anti-HIV agents (1995) Indian J. Chem., 34, pp. 201-208; Werbel, L.M., Elslager, E.F., Newton, L.S., (1987) J. Heterocyclic Chem., p. 24; Patel, N.B., Lilakar, J.D., Synthesis of new substituted-4-(3H)-quinazolinones and their antibacterial activity (2001) Indian J. Heterocyclic Chem., 11, pp. 85-86; Ashok, R., (2000) Antimicrobials in Laboratory Medicine, pp. 62-70. , B. I. Churchill Livingstone; Gaurav, G., Kini, S.G., Synthesis and Evaluation of certain new 1,3,4-oxadiazole derivatives of Nalidixic acid moiety as potential Antifungal and Antibacterial agents (2003) Indian J. Heterocyclic Chem., 12 (3), pp. 289-290; Parmar Surendra, S., Arora, R.C., Some 2,3,6,8-tetrasubstituted quinazolone hydrazides as monoamine oxidase inhibitors (1967) European J. Org. Chem., 10, pp. 1182-1183; Desai, K.R., Naik, N.M., Reactive disperse dyes: Synthesis of sulphonylazido group reactive disperse dyes and their application on nylon and polyester fibres (1989) J. Indian Chem. Soc., 66, pp. 495-496; Abdel-Hamide, S.G., Synthesis of some new quinazoline derivatives (2000) Indian J. Hetrocyclic Chem., 10, pp. 59-64; Waheed, A., Khan, S.A., Synthesis of certain substituted 1,2 Pyrazolines from nalidixic acid as Antibacterial and Analgesic agents (2001) Indian J. Hetrocyclic Chem., 11, pp. 59-62

PY - 2006

Y1 - 2006

N2 - In continuation of our work on synthesis of biheterocycles carrying the biodynamic heterocyclic systems at position 3, a series of new nalidixic acid derivatives having quinazolones moiety were synthesised to achieve enhanced biological activity and wide spectrum of activity. Nalidixic Acid was first converted into its acid chloride using thionyl chloride as an acylating agent at laboratory temperature. Later it was converted to methyl ester. Nalidixoyl chloride formed vigorously reacts with methanol to give a methyl ester of nalidixic acid. The ester on addition of hydrazine hydrate furnished nalidixic acid hydrazide. Appropriate anthranilic acid was refluxed with acetic anhydride to form Benzoxazine/Acetanthranil. 5-iodo-derivative of anthranilic acid was prepared and also utilised to obtain 6-iodo-Benzoxazine/Acetanthranil. Also, 6-nitro-Benzoxazine/Acetanthranil was obtained by nitration of acetanthranil using conc. H2SO4 and fuming HNO3. Equimolar proportions of the appropriate synthesised acetanthranils and nalidixic acid hydrazide in the presence of ethanol were refluxed to synthesise quinazolones. Elemental analysis and IR spectra confirmed nalidixic acid hydrazide formation. The structures of the compounds obtained have been established on the basis of Spectral (IR, 1H NMR and mass) data. The current study also involves in vitro antimicrobial screening (using Agar dilution and Punch well diffusion method) of synthesised quinazolone derivatives bearing nalidixic acid moiety on randomly collected microbial strains. The derivatives Ga (NAH), Gb (QN) and Gd (NiQNA) showed marked inhibitory activity against enteric pathogen like Aeromonas hydrophila, a causative agent of diarrhoea in both children as well as adults. Among the respiratory pathogens included in study, derivative Gd (NiQNA) was found to be active against Streptococcus pyogenes. No significant inhibitory activity was seen by any of synthesised derivatives against Coagulase negative Staphylococcus. Derivative Ga (NAH) was found to show very high activity against the Candida colonies and derivative Gd (NiQNA) was also found to exhibit inhibitory activity against Candida albicans; a normal flora of the human body which plays an important role in causing opportunistic infections in immunocompromised hosts. Proteus vulgaris, a gram-negative bacteria included in our study was found to be inhibited by derivative Gb (QN). © 2005 Elsevier SAS. All rights reserved.

AB - In continuation of our work on synthesis of biheterocycles carrying the biodynamic heterocyclic systems at position 3, a series of new nalidixic acid derivatives having quinazolones moiety were synthesised to achieve enhanced biological activity and wide spectrum of activity. Nalidixic Acid was first converted into its acid chloride using thionyl chloride as an acylating agent at laboratory temperature. Later it was converted to methyl ester. Nalidixoyl chloride formed vigorously reacts with methanol to give a methyl ester of nalidixic acid. The ester on addition of hydrazine hydrate furnished nalidixic acid hydrazide. Appropriate anthranilic acid was refluxed with acetic anhydride to form Benzoxazine/Acetanthranil. 5-iodo-derivative of anthranilic acid was prepared and also utilised to obtain 6-iodo-Benzoxazine/Acetanthranil. Also, 6-nitro-Benzoxazine/Acetanthranil was obtained by nitration of acetanthranil using conc. H2SO4 and fuming HNO3. Equimolar proportions of the appropriate synthesised acetanthranils and nalidixic acid hydrazide in the presence of ethanol were refluxed to synthesise quinazolones. Elemental analysis and IR spectra confirmed nalidixic acid hydrazide formation. The structures of the compounds obtained have been established on the basis of Spectral (IR, 1H NMR and mass) data. The current study also involves in vitro antimicrobial screening (using Agar dilution and Punch well diffusion method) of synthesised quinazolone derivatives bearing nalidixic acid moiety on randomly collected microbial strains. The derivatives Ga (NAH), Gb (QN) and Gd (NiQNA) showed marked inhibitory activity against enteric pathogen like Aeromonas hydrophila, a causative agent of diarrhoea in both children as well as adults. Among the respiratory pathogens included in study, derivative Gd (NiQNA) was found to be active against Streptococcus pyogenes. No significant inhibitory activity was seen by any of synthesised derivatives against Coagulase negative Staphylococcus. Derivative Ga (NAH) was found to show very high activity against the Candida colonies and derivative Gd (NiQNA) was also found to exhibit inhibitory activity against Candida albicans; a normal flora of the human body which plays an important role in causing opportunistic infections in immunocompromised hosts. Proteus vulgaris, a gram-negative bacteria included in our study was found to be inhibited by derivative Gb (QN). © 2005 Elsevier SAS. All rights reserved.

U2 - 10.1016/j.ejmech.2005.09.002

DO - 10.1016/j.ejmech.2005.09.002

M3 - Article

VL - 41

SP - 256

EP - 262

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

IS - 2

ER -