SYNTHESIS, CHARACTERISATION AND ANTI-MICROBIAL ACTIVITY OF SUBSTITUTED FLUOROQUINOLONE ANALOGUES

PROTOCOL FOR

M.PHARM DISSERTATION

SUBMITTED TO

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

BY

TATHAPUDI SANDEEP ISRAEL, B. Pharm.,

Department of Pharmaceutical Chemistry

2008-2009

UNDER THE GUIDENCE OF

DR. SENTHIL KUMAR. G.P.,M.Pharm., Ph.D.,

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

BHARATHICOLLEGE OF PHARMACY

BHARATHI NAGARA, MANDYA (DIST)

KARNATAKA-571422.

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name of the Candidate and Address (In Block Letters) / PRESENT ADDRESS:
TATHAPUDI SANDEEP ISRAEL,
I M. Pharm.,
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY,
C/O BHARATHICOLLEGE OF PHARMACY,
BHARATHI NAGARA,
MANDYA (DIST),KARNATAKA-571422.
2. / Name of the Institution / BHARATHICOLLEGE OF PHARMACY,
BHARATHI NAGARA, MANDYA. 571422
3. / Course of Study and Subject / MASTER OF PHARMACY IN PHARMACEUTICAL CHEMISTRY.
4. / Date of Admission of Course / 30-06-2008
5. / Title of Topic / “SYNTHESIS, CHARACTERISATION AND ANTI-MICROBIAL ACTIVITY OF SUBSTITUED FLUOROQUINOLONE ANALOGUES.”
6. / Brief Resume of the Intended Work
6.1 Need for the study
6.2 Review of the literature
6.3 Objectives of the study / ENCLOSURE-I
7 /

Materials and Methods

7.1 Source of data

7.2 Method of collection of data

7.3 Does study require any investigations or interventions to conducted on patients or other human or animal? If so, please describe briefly.

7.4 Has ethical clearance been obtained from your institution in case of 7.3

/ ENCLOSURE-II
8 / List of References / ENCLOSURE-III
9.
10.
11.
12. /
Signature of the candidate:
(T.Sandeep Israel)

Remarks of the guide: This work can be carried out in our laboratory

Name And Designation of:
11.1 Guide Dr. Senthil Kumar.G.P., M.Pharm., Ph.D.,
Professor and Head
Department of Pharmaceutical Chemistry,
BharathiCollege of Pharmacy,
Bharathinagara, Mandya (Dist),
Karnataka-571422
11.2 Signature

11.3 Co-Guide
----
11.4 Signature

11.5 Head of the department Dr. Senthil kumar.G.P., M.Pharm., Ph.D.,
Professor and Head
Department of pharmaceutical Chemistry,
Bharathi college of pharmacy,
Bharathinagara, Mandya (Dist),
Karnataka-571422.
11.6 Signature

12.1 Remarks of the Chairman and Principal:
FORWARDED FOR APPROVAL Prof. Dr. Tamizh Mani. T
Principal
BharathiCollege of pharmacy,
Bharathinagara, Mandya (Dist),
Karnataka-571422.
12.2 Signature

ENCLOSURE-I

6. BRIEF RESUME OF THE INTENDED WORK

6.1 NEED FOR STUDY:

The earliest antibacterial agents to be used as chemotherapeutic drugs in the 1920s were synthetic agents the sulfonamides. Their introductions lead to a sharp decline in the morbidity and mortality of infectious diseases.

The rapid development of wide spread resistance to the sulfonamides soon after their introduction and the increasing use of the broad spectrum penicillin’s in the treatment of infectious diseases.

The Fluoroquinolones are the only synthetic antibacterial agents to rival β-lactams for impact in clinical usage in the antibacterial field.

The quinolones are a family of synthetic broad-spectrum antibiotics. The parent of the group is nalidixic acid. The majority of quinolones in clinical use belong to the subset of fluoroquinolones, which have a fluoro group attached the central ring system, typically at the 6-position.

The need for the study is to develop the newer fluoroquinolones with broad spectrum anti-microbial activity because, the growth of resistance to many antibacterial agents become a major problem includes β-lactams and macrolide resistant Streptococcus pneumoniae and S.aureus.

Over the past 10 years, fluoroquinolone research of microbiological properties has thus been aimed at:

Improved activity against pneumococci, including strains resistant to β-lactams and non β-lactam drugs, such as macrolides.

Improved activity against staphylococci, particularly MRSR.Improved activity generally against gram–positive cocci.

Improved activity against anaerobes

Activity against ciprofloxacin and ofloxacin-resistant strains,including Staphylococci and Enterobacteriaceae.

Good activity against Gram–negatives, including Pseudomonasand othernon-fermentative species and lower rate of emergence of resistance.

6.2 LITERATURE REVIEW:

Mazzieri et al.,1Studied the antibacterial activity and SAR for a new class of fluoroquinolones; Benezenesulfonamide fluoroquinolones (BSFQs).

Pandeya et al.,2 evaluated the antibacterial, antifungal and anti-HIV activities of norfloxacin Mannich bases.

Ramesh kumar et al.,3 synthesized 6-fluoro-1,4-dihydro-4-oxo-quinolones-3-carboxylic acid derivatives and are evaluated for antimicrobial activity. All compounds exhibited sigificant antibacterial activity.

Daniel chu et al.,4synthesized novel aryl fluoroquinolone and studied the SAR.

Baskaran et al.,5synthesized a quinolone carboxylic acid derivatives by microwave assisted amination.

Patel et al.,6 synthesized sulfonamides and 4-(p-nitrobenzoyl) piperazine incorporated fluoroquinolones and are evaluated for anti-microbial activity.

Alovero et al.,7did the comparative study of benzene sulphonamide fluoroquinolones, structurally related to ciprofloxacin against selected species of cocci, and proved that BSFQS showed potent activity than ciprofloxacin against fluoroquinolone resistant gram positive cocci.

Toshio Uno et al.,8reported the synthesis and invitro antibacterial activity of optically active 7-(3-hydoxypyrrolidin -1-yl) quinolones.

Om Reddy et al.,9 reported the synthesis of novel antibacterial quinolones.

Carl Ziegler et al.,10 reported the synthesis and invitro biological activity of 7-(5-Aminomethyl -2-isoxazolidinyl quinolone-3-carboxylic acids.

Yoshikazu Asahina et al.,11 reported the synthesis of novel 1-(2-fluorovinyl)-7-substituted-4-quinolone-3-carboxylic acid derivatives, conformationally restricted analogues of fleroxacin.

stulin et al.,12 reportetd the anti-microbial activity ofcertain 2-(1-naphthyl)-thiophene derivatives.

Dzhuraev et al.,13 reported the anti-microbial activity of novel thiophene derivatives.

Bratenkoet al.,14 reported the anti-microbial activity of furan containing pyrazolines.

Bratenko et al.,15 reported the anti-microbial activity of furan containing isoxazoles , triazoles and 1,4-diketones.

RELATED LINKS:

6.3 OBJECTIVE OF STUDY:

The main objective of the study is to develop newer substituted fluoroquinolone analogues.

The synthesized fluoroquinolones will be characterized by using IR, H-NMRandMASS spectroscopic techniques.

To evaluate the anti-microbial activity of synthesized fluoroquinolones against gram negative, gram positive bacteria and fungi.

ENCLOSURE-II

7. METHODOLOGY

7.1 SOURCE OF THE DATA:

The literature survey on the area on present investigation will be done by referring chemical abstracts of all the national and international journals pertaining to synthetic, medicinal and pharmaceutical chemistry.

The information about biological activities will be collected by referring European journals of Medicinal chemistry, Current Medicinal chemistry, Bio-organic Medicinal chemistry, Indian Journal of Chemistry, Indian journal of heterocyclic chemistry, Tetrahedron letter, Anti-microbial agent and Chemotherapy, Indian journal of pharmaceutical sciences etc.

For this purpose the library facilities are available at Bharathi college, Indian Institute of science Bangalore, IIT Chennai & IICT Hyderabad will be made use of. The day-to-day development will be updated by literature survey through E-publishing & current periodicals in BharathiCollege E-library & elsewhere.

All the basic facilities required for synthetic pharmaceutical chemistry are available in our college laboratories. For purification of the products TLC, column chromatography, HPLC & other facilities are also available in our laboratory.

7.2 METHOD OF COLLECTION OF DATA:

The chemical structure of the synthesized compounds shall be established on the basis of physical, chemical and analytical data. Melting point of new compounds shall be determinedby open capillary tube. They are expressed in degree Celsius.

The synthesizedcompounds will be characterized by UV, IR, H-NMR, C13MASS spectral data. This will be collected by sending the sample to other advanced research centres like IISC Banglore, IICT Hyderabad & IIT Chennai.

All the molecules will be screened for anti-microbial activities against different gram positive, gram negative bacteria and fungi in our college laboratory.

7.3Does the study require any investigation or interventions to be Conducted on patients or other humans or animals?

NO

7.4 Has ethical clearance been obtained from your institution in case of 7.3?

NOT APPLICABLE.

ENCLOSURE-III

8. REFERENCES:

  1. Marcelo J.N., Fabianadel L.A., Ruben H.M., Mazzieri M.R.,“A new class of Fluoroquinolones; Benzenesulfonamide Fluoroquinolones (BSFQS), antibacterial activity and SAR studies”. Eur. J. Med Chem, 1999, 34, 209 – 214.
  2. Pandeya S.N., Dhamrajan Sriram., Gopal Nath., Erik De clercq.,”Synthesis, antibacterial, antifungal and anti – HIV activities of norfloxacin Mannich bases”. Chemotherapy, 2001, 47(4), 266-269.
  3. Natesh Rameshkumar., Mohan Ashokkumar., SubramanianE.H., Ilavarasan., SridharS.K.,“Synthesis of 6- Fluoro -1,4-dihydro -4-oxo-Quinoline -3-Carboxylic acid derivatives as potential antimicrobial agents”. Eur.J.Med. Chem, 2003, 38, 1001 – 1004.
  4. ChuD.T.W., FernandesP.B., ClaiborneA.K., PihuleacE., NordeenC.W., MaleczkaR.E., and PernetA.G.,“Synthesis and structure–Activity Relationships of Novel Arylfluoroquinolone Antibacterial agents”. J. Med. Chem, 1985, 28(11), 1558 -64.
  5. Ganapati ReddyP., BaskaranS.,“Microwave assisted amination of quinolone carboxylic acids; an expeditious synthesis of Fluoroquinolone antibacterials”. Tetrahedron Letters, 2001, 42, 6775 – 6777.
  6. PatelN.B., & BhagatP.R.,“Synthesis and anti microbial activity of sulfonamides and 4-(p-Nitrobenzoyl) piperazine incorporated fluoroquinolones”. Indian journal of Heterocyclic Chem, 2006,16,205-206.
  7. AloveroF., BarnesA., Nieto M., MazieriM.R., ManzoR.H.,“Comparative study of new benzene sulphonamide Fluoroquinolones structurally related to ciprofloxacin against selected ciprofloxacin susceptible and resistant gram–positive cocci”. Journal of Antimicrobial Chemotherapy, 2001, 48,709-712.
  8. UnoT., Iuch.K., KawahataY., TsukamotoG.,“Synthesis of Antimicrobial AgentsII. Synthesis and Antibacterial Activities of optically Active 7- (3 – Hydro Pyrrolidin-1-y1)quinolones”. J. Heterocyclic Chem, 1987, 24, 1025 – 1028.
  9. SharmaM.R., Vasanth KumarN., PrasadA.S.R., EswaraiahS., PrabhakarC., Om ReddyG., Sitaram KumarM., SadhukhanA.K., VenkateswarluA., Anji ReddyK., “Synthesis and biological activity of novel antibacterial quinolones”. Indian J. Chem, 2001, 40B, 331 – 335.
  10. Carl ZieglerB., Curran W.V., NydiaKuck., HarrisS.M., & Yang-I Lin., “Synthesis and Antibacterial Activity of some –7– Substituted 1-Ethyl-6-Fluoro-1,4-dihydro-4-oxoquinoline-3-CarboxylicAcids. Ethers, Secondary Amines and sulfides as C-7 substituents”J. Heterocyclic Chem, 1989, 26, 1141 – 1144.
  11. AsahinaY., IwaseK., IinumaF., HosakaM., and IshizakiT., “Synthesis Antibacterial Activity of 1-(2-Fluorovinyl)–7 – Substituted–4- Quinolone -3- Carboxylic Acid derivatives, Conformationally Restricted Analogues of Fleroxacin”. J. Med Chem, 2005, 48, 3194 – 3202.
  12. Bratenko M.K., DeinekaS.E., ProdanchukN.G., and ShevchukM.I., “synthesis anti-microbial activity of furan containing Isoxazoles, Triazoles and 1,4-Diketones”.Translated from khimiko – farmatsevticheskii journal, 1991, 25 (9),642.
  13. StulinN.V., Lipkin A.E., KulkinovaD.A., Rudzim E.A., “synthesis and anti-microbial activity of certain 2-(1-Naphthyl)-Thiophene Derivatives”.Translated from khimiko farmatsevticheskii journal ,1975, 9(11), 702.
  14. Dzhuraev A.D., Karimkulov K.M., Makshumov A.G., AmanovN., “Anti-microbial activity of Novel Thiophene Derivatives”. Translated from khimiko farmatsevticheskii, 1992, 26 ( 11-12), 882.
  15. BratenkoM.K., Deineka S.E.,“synthesis and Anti-microbial activity of furan-containing Pyrazolines”. Translated from khimikofarmatsevticheskii, 1990,22, 702.