DESIGN, SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF CERTAIN NEW DERIVATIVES OF NITROGEN HETEROCYCLES

M. Pharm. Dissertation Protocol

Submitted to the

Rajiv Gandhi University of Health Sciences, Karnataka.

Bangalore.

.

By

Mr. PATEL MAYUR NARENDRABHAI

B. Pharm.

Under the guidance of

Dr. G K KAPSE

M Pharm., Ph.D

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

LUQMANCOLLEGE OF PHARMACY, GULBARGA

2011-12

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

Name of the candidate And
address / Mr. PATEL MAYUR NARENDRA BHAI
s/o PATEL NARENDRA BHAI SAVAILAL
OPP. PRIMARY SCHOOL,
AT & PO –BHADAM PO BOX- 393145
TA. – RAJPIPLA DIST. –NARMADA
GUJARAT
Name of the institution / Luqman college of pharmacy,
BEHIND P&T QUARTERS,
old jewargi road,
gulbarga-585102
Course of study and subject / m.PHARM
(Pharmaceutical Chemistry)
Date of Admission of course / 11/10/2011
TITLE OF THE TOPIC / DESIGN, SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF CERTAIN NEW DERIVATIVES OF NITROGEN HETEROCYCLES
6. / Brief Resume of the intended work:
6.1 Need for the study:
The search for newer drug is an endless effort for which the researchers have always an interesting field open for the discovery of new more efficacious drugs with reduced toxicity profile. The synthesis of heterocyclic compounds has always drawn the attention of medicinal chemists over the years mainly because of their diverse biological properties.
Quinazolin-4-one derivatives are versatile nitrogen heterocyclic compounds which have long been known as a promising class of biologically active compounds possessing wide variety of biological and pharmacological activities like antibacterial1, anthelmintic2, neuroleptic3, antitubercular4,platelet anti-aggregating5,antifungal6,anticancer7,anti-inflammatory8,antiviral9,CNS depressant activity10, antiparkinson11,bronchodilator12 etc.Recently several scientists have elucidated that Quinazolinone system possesses the variable sites like position 2 and 3 which can be suitably modified to yield potent chemotherapeutic and pharmacotherapeutic agents5.
Further it was observed from the literature that certain five member heterocyclic compounds possess interesting biological activity. Among those, Pyrazole and their fused derivatives are known to exhibit diverse biological activities and important applications in pharmacetical industries. Pyrazole derivatives having potent biological acivities such as, antipyretic13, antimicrobial14,antiviral15,16 ,antidepressant17,antilukemic18, anti-inflammatory19, antihistaminic20,antitumor21, anticonvulsant22.
Drug design by either molecular manipulation and/or combination of biologically active moieties into one molecule and syntheses of totally newer moieties have been the methods of approach. Hence, based on the above mentioned facts here in, we propose for the synthesis of some new structural hybrids of nitrogen heterocycles comprising Quinazolinones and Pyrazoles and evaluation for their antimicrobial and antitubercular activities.
This combination suggested, is an attempt to investigate the influence of such hybridization and structure variation on the anticipated biological activities hoping the possibility that the target derivatives might be more efficacious as antimicrobial and antitubercular agents.
6.2 Objective of the study:
  • Substituted 1,3,4 benzoxazinone prepared are reacted with active hydrogen atoms of amino acid by conventional synthetic methods to form Quinazolinone nucleus. The hydrazide of which is then reacted with different aryl aldehydes to give Schiff bases. These are further cyclized to prepare different pyrazoles by the reaction with appropriate cyclising agents.
  • All the reactions are monitored by TLC technique and chemical tests as applicable.
  • The structures of these compounds will be established by means of IR, Proton NMR, Mass spectral analysis and Elemental analysis.
  • The title compounds will be evaluated for antimicrobial activity. Few of the compounds would also beevaluated to determine their antitubercular profile.
6.3 Review of Literature:
Abundant literature is available with the biological active heterocycles Quinazolinones and Pyrazoles, as these are endowed with diverse biological activities. Few important literature have been listed as below:
QUINAZOLIN-4-ONES:
  • Shah R M et al., (2012)23 synthesized novel 2-thioxo-quinazolin-4-one derivatives and their characterization.

  • Haiyang T et al., (2012)24performed Facile Synthesis and Herbicidal Evaluation of4H-3,1-benzoxazin-4-ones and 3H-quinazolin-4-ones with 2-phenoxymethyl substituent.

  • Venkatesh P et al., (2011)25 designed and synthesized quinazolinone, benzothiazole derivatives bearing guanidinopropanoic acid moiety and their Schiff bases as cytotoxic and antimicrobial agents.

  • Abbas S Y et al., (2011)26 synthesized some biologically active 4(3H)-quinazolinones derived from 2,3-pyridine dicarboxylic anhydride. The synthesized compounds were evaluated for their antifungal activity against fungi such as Aspergillus ochraceus wilhelmand Penicillium chrysogenum Thom.

  • Revanasiddappa H D et al., (2010)27 synthesized new Schiff bases containing 4(3H)-quinazolinone ring system and evaluated their biological activity. All the synthesized compounds were tested against fungi such as Aspergillus Niger, Aspergillus flavus and Alternaria solani by disc diffusion method.

  • Reddy P S N et al., (2010)28 evaluated antibacterial, antifungal and antifeedant activity of quinazolinonyl-b-lactams/quinazolinones and bis (quinazolinonyl-b-lactams). The synthesized compounds were tested for antifungal activity against fungi such as Fusarium oxisporium and Macrophomina sorgina.

  • Rajasekaran S et al., (2010)29synthesized of some 2-phenyl-3-substituted quinazolin-4(3H)-ones and evaluated their antituberculor, antibacterial and antioxidant activities. The compounds were evaluated their antituberculor activity against mycobacterium tuberculosis by agar dilution method.

  • Kaur P et al., (2009)30developed new approachof quinazolinone peptides as potent medicinal agents. The synthesized compounds were evaluated their antifungal activity against Microsporam audouinii, Trichophyton mentagrophtes, Candida albicans and Aspergillus Niger.

  • Khairy A M et al., (2009)31prepared novel 4-(3H)-quinazolinone containing biologically active thiazole,pyrazole, 1,3-diathiazole, pyridine, chromene, pyrazolopyrimidine and pyranochromene of expected biological activity. All the synthesized compounds were evaluated for their antifungal activity against Aspergillus ochraceus Wilhelm and Fusarium oxysporium fungi.

  • Al-Deeb A O et al., (2008)32 synthesized of some new 3H-quinazoli-4-one derivatives as potential antitubercular agents. All the compounds were evaluated against Mycobacterium tuberculosis.

  • Dahiya R et al., (2008)33synthesized some peptide derivatives of iodoquinazolinones and nitroimidazoles and evaluated their antimicrobial and anthelmintic activities. They were evaluated their antimicrobial activity such as Bacillus subtilis (NCIM 2063), Staphylococcus aureus (NCIM 2079), Pseudomonas aeruginosa (NCIM 2034) and Klebsiella pneumoniae (NCIM 2011) and fungal strainsMicrosporum audouinii (MUCC 545), Trichophyton mentagrophytes (MUCC 665), Candida albicans (MUCC 29) and Aspergillus Niger (MUCC 177).

  • Desai A R et al ., (2005)34performed Niementowski reaction that is microwave induced and conventionalsynthesis of quinazolinones and 3-methyl-1H-5-pyrazolones and their antimicrobial activity. All compounds were screened for their antifungal against Candida albicansand Candida krusei and antibacterial against B. subtilis, S.aureus as gram positive and E.coli,P. aeruginosa as gram negative bacteria.

PYRAZOLES
  • Adnan A. Bekhit et al.,(2009)35 have synthesized a novel series of structurally related 4-pyrazolyl benzenesulfonamide derivatives. All the newly synthesized compounds were examined for their anti –inflammatory activity using cotton pellet induced granuloma and carrageenan induced rat paw edema bioassays. In addition the inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), ulcerogenic effect and actual toxicity were determined. Furthermore, all the compounds were evaluated for their in vitro antimicrobial activity against Eischerichia coli, Staphylococcus aureus and Candida albicans. The results revealed that compounds exhibited comparable or better anti-inflammatory activity compared to indomethacin and celecoxib with no or minimal ulcerogenic effect and high safety margin. Compounds displayed appreciable antibacterial activity against both bacteria compared with ampicillin.
  • Smitha Nair et al., (2002)36has worked on 2-arylamino-5-mercapto-1,3,4-thiadiazole-(3’-nitrophenyl)-4’-carbohydrazide was cyclized with pentane-2, 4-dione to give substituted pyrazole. The compound was evaluated for anti-bacterial and anti-fungal activities. Some of them were effective against the microbes.
  • Gaikawad M S et al., (2000)37Various N-(1)-[4-methyl-7-oxy-coumarino]-acetyl-5-substitutedphenyl-3-phenyl-4, 5-dihydro pyrazoles have been synthesized. These pyrazoles showed good to moderate anti-microbial activities against Alternaria brassicicola, Aspergillus niger, E.Coli and Lactobacillus.
Materials and Methods:
7.1 Method of collection of data:
Synthetic strategy:
  • Substituted 1,3,4 benzoxazinone prepared are reacted with active hydrogen atoms of amino acid by conventional synthetic methods to form Quinazolinone nucleus. The hydrazide of which is then reacted with different aryl aldehydes to give Schiff bases. These are further cyclized to prepare different pyrazoles by the reaction with appropriate cyclising agents to yield compounds of the type given below.

A. Synthesis of Target Molecules:
The synthesis work will be carried out following the given scheme which includes:
  1. The homogeneity of the compounds in each reaction is monitored by TLC technique and Rfvalues are recorded.
  2. Percentage of yield, melting point for each compound will be determined and recorded.
  3. Physical constant, solubility, elemental analytical data for synthesized title compounds are obtained.
  4. Spectroscopic data of new compounds i.e. I.R., NMR, Mass spectral data will be recorded for structural confirmation of few synthesized compounds.
B. Biological activity:
  • Antimicrobial screening of the compounds would be carried out against gram +ve and gram –ve bacteria and against fungal strains by disc diffusion method to determine zone of inhibition (in mm) and the activity will be compared with that of standard.
  • Antitubercular activity(38) would be carried out by Middle Brook 7H9 agar medium against Mycobacterium tuberculosis H37Rv strain. Middle Brook 7H9 agar medium containing different derivatives, standard drug as well as control is inoculated with Mycobacterium tuberculosis H37Rv strain. The inoculated bottles are incubated at 370C for four weeks. At the end of four weeks they are checked for growth and scaled for inhibition.
7.2-1 Element analysis
  • IR, spectral studies.
  • NMR, specral studies and
  • Mass specral studies.
7.3-1Assessment of toxic effect: ------Not applicable------
7.3-2 Screening of Statistical analysis:------
7.3-3Does the study require any investigations or interventions to be conducted on patients or humans or animals? If so, please describe briefly.------No------
7.3-4 Has ethical clearance been obtained from your institution in case of 7.4?
------Not applicable------
8. List of References:
  1. Singh VKS, Gulati A and Shankar K. Antiparkinsonian agents from quinazolinyl thiazolidinones and azetidinones. Indian Journal of Chemistry. 1987;26:652-656.
  2. Gupta DP, Ahmad S, Kumar A. and Shankar K. Newer quinazolinone derivatives as anthelmintic agents. Indian Journal of Chemistry. 1988; 27(B):1060-1062.
  3. Mukherji DD, Nautiyal SR, Prasad CR and Dhawan BN. CNS-depressant activity of. some newly synthesised 4(3H)-quinazolones. Indian Journal of Medical Research. 1980;71:480-482.
  4. Joshi V, Chaudhari RP. Synthesis, characterization and antibacterial activity of some new 2,3,6-trisubstituted quinazolin-4(3H)-ones. Indian Journal Chemistry.1987; 26(B):602.
  5. Desai AR and Desai K Niementowski reaction: microwave induced and conventional synthesis of quinazolinones and 3-methyl-1H-5-pyrazolones and their antimicrobial activity ARKIVOC. 2005 (xiii) 98-108
  6. Chaurasia MR, Sharma SK. The synthesis of 6,8-disubstituted-2-phenyl-3-(substituted benzothiozol-2-yl)-4-(3H)-quinazolinones and their antifungal activity. Journal Indian Chemistry Soc. 1972; 49:370.
  7. Pandey VK and Lohani HC. The anti-tumour activity of 2-aryl/alkyl-3(2-amino ethyl-1, 3, 4-thiadiazol-5-yl) quinazolin-4(3H) ones. Journal Indian Chemistry Soc. 1979; 56:415.
  8. Ravi S, Devender RA, Malla RV and Sattur PB. The synthesis of new N4-(N-(6,8-dibromo-2-methyl-3-quinazolin-4(3H)-one)acetamido)-N1-substituted sulfanilamides Curr.Science. 1984; 53:1069.
  9. Mishra VS and Sunita D. The synthesis of 2-phenyl-3-benzimidazolyl-alkyl/aryl-6-bromoquinazoline-4(3H)-ones. Journal IndianChem.Society. 1978; 55:172.
  10. Kumar R, Gupta TK and Surendra S. The synthesis of quinazolone azomethines using CNS depressant activity. Indian Journal Pharm. 1970;33:108.
  11. Tiwari SS and Pandey VK, the synthesis of some new benzoxinones and their corresponding quinazolinones. Journal Indian Chem. Society. 1975;52:736.
  12. Raghu RA and Rajesh HB. The synthesis and bronchodilator activity of benzimidazo (1, 2,-c) quinazolines .Indian Journal Chemistry. 1999; 38(B):434.
  13. El-Shimaa M N Abdel-Hafez, Gamal El-Din A A Abuo-Rahma, Mohamed Abdel-Aziz.Design, synthesis and biological investigation of certain pyrazole-3-carboxilic acid derivatives as novel carrier for nitric oxide. Bioorganic and medicinal chemistry 2009;17:3829-3837
  14. Adnan A Bekhit and Tarek Abdel-Aziem. Design, synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory, anti-microbial agents, bioorganic andmedicinal chemistry 2004;12:1935-1945.
  15. Guiping Ouyang, Zhuo Chen, Xue-Jian Cai , Bao-an song, Pinaki S. Bhadury, Song Yang, Lin-Hong Jin, Wei Xue, De-Yu Hu, Song Zeng. Synthesis and antiviral activity of novel pyrazole derivative containing oxime ester group. Bioorganic and medicinal chemistry2008;16:9699-9707
  16. Osama I El-Sabbagh, Mohammed M Baraka, Samy M Ibrahim, Christophe Pannecouque, Graciela Anderi, Robert Snoeck, Jan Balzarini, Abdel A Rashad. Synthesis and antiviral activity of new pyrazole and thiazole derivatives. European Journal of Medicinal Chemistry 2009;44:3746-3753
  17. Mohamed Abdel-Aziz , Gamal El-Din A.Abou-Rahma, Alaa A Hassan. Synthesis of novel pyrazole derivative and evaluation of their anti-depressant ant anti-convulsant activities.European Journal of Medicinal Chemistry 2009;44:3480-3487.
  18. Pier Giovanni Baraldi, Paolo Cozzi, Cristina Geroni, Nicola Mongelli, Romeo Romagnoli and Giampiero Spalluto. Novel benzoyl nitrogen mustard derivatives of pyrazloe analogues of Distamycin A: synthesis and Antileukemic activity. Bioorganic and Medicinal chemistry 1999;7:251-262
  19. Tewari A K, Mishra A. synthesis and anti-inflammatory activity of N4 , N5– Disubstituted -3-methyl-1H-Pyrazolo[3,4-C]pyridazine’s. Bioorganic and medicinal chemistry 2001;9(3):715-718
  20. Yildirim I, Ozdemir N, Akeamur Y, Dincer M, Andac O, 4-Benzoyl-1,5-diphenyl-1H-pyrazole-3-carboxylic acid methanol solvate. Acta crystallogr 2005;61:256-258
  21. Park H J, Lee K, Park S, Ahn B, Lee J C, Cho H Y, Lee K . Identification of antitumor activity of pyrazole oxime ethers. Bioorganic and medicinal chemistry Lett. U 2005;15:3307.
  22. Michno V, Panhoat C Herve du,Tombret F, Gillardin J M, Lepage F and Berthon L. Preparation , structural analysis and anticonvulsant activity of 3- and 5-aminopyrazole N-benzoyl derivatives. European Journal of Medicinal chemistry 1995;30(2):147-155.
  23. Shah RM, Prajapati NK, Patel PS. Synthesis and characterization of novel 2-thioxo-quinazolin-4-one derivatives. International Journal of Science Innovations and Discoveries. 2012;2 (1):90-93.
  24. Zumuretiguli A, Yufeng W, Haiyang T, Xiaoting H, Aidong Z. Facile Synthesis and Herbicidal Evaluation of4H-3,1-benzoxazin-4-ones and 3H-quinazolin-4-ones with 2-phenoxymethyl substituent. Molecules. 2012;17:3181-3201
  25. Venkatesh P, Tiwari VS. Design and synthesis of Quinazolinone,Benzothiazole derivatives bearing guanidinopropanoicacid moiety and their Schiff bases as cytotoxicand antimicrobial agents. Arabian Journal of Chemistry, King Saud University. (2011).
  26. Abbas S Y, Ammar Y A, Mohamed El-sharief A M, El-gaby M S A. Synthesis of some biologically active 4-(3H)-quinazolinones derived from 2,3-pyridine dicarboxylic anhydride. Chemical Sciences Journal. 2011; CSJ-15:1-10.
  27. Revanasiddappa H D, Prasad K S, Shiva K L, Jayalakshmi B. Synthesis and biological activity of new Schiff base containing 4-(3H)-quinazolinone ring system. International Journal of Chem Tech Research. 2010; 2(2):1344-1349.
  28. Reddy P S N, Mittapelli V, Reddy V D. Antibacterial, antifungal and antifeedant activity of quinazolinoyl-β-lactams/quinazolinones and bis (quinazolinoyl-β-lactams). Rasayan J. Chem. 2010; 3:635-640.
  29. Rajasekaran S, Rao G, Sanjay P P N. 2D QSAR studies of some novel quinazolinone derivatives as antitubercular agents. J. Comput. Method. Mol. Design. 2011; 1(3):69-82.
  30. Kaur P, Kaur A, Kaur R, Kaur K. quinazolinone peptides: new approach as potent medicinal agents. Journal of global pharma technology. 2010; 2(4):35-39.
  31. Khairy A M, El B, Aly M M, Mohamed Y A, Basyouni W M, Abbas S Y. Novel 4(3H)-quinazolinone containing biologically active thiazole, pyrazole, 1, 3-dithiazole, pyridine, chromene, pyrazolopyrimidine and pyranochromene of expected biological activity. World Journal of Chemistry. 2009; 4(2):161-170.
  32. Alu-deeb A O, Alafeefy A M. Synthesis of some new 3H-quinazoline-4-one derivatives as potential antitubercular agents. World Applied Sciences Journal. 2008; 5(1):94-99.
  33. Dahiya R, Anil K, Yadav R. Synthesis and biological activity of peptide derivatives of iodoquinazolinnones/nitroimidazoles. M D P I. 2008; 13:958-976.
  34. Desai A R, Desai K. Niementowski reaction: Microwave induced and conventional synthesis of quinazolinones and 3-methyl-1H-5-pyrazolones and their antimicrobial activity. ARKIVOC. 2005; xiii: 98-108.
  35. Adnan A Bekhit , Hayam M A Ashour, Alaa El-din A Bekhit and Salma A Bekhit. Synthesis and Biological evaluation of novel pyrazole derivatives of anti-inflammatory, Anti-microbial agents. Medicinal chemistry 2009;5:103-117
  36. Nair Smitha, Gare S P and Sah Pramilla. Synthesis of some pyrazole,pyrazolones and oxadiazolone bearing 2-arylamino-5-mercapto-1,3,4-thiadiazole nuclei as possible anti-microbial agents. Indian journal of heterocyclic chemistry 2002;12: 09-12.
  37. Gaikawad M S, Mane A S, Chavan R V and shingare M S. Synthesis of newer coumarinoacetyl pyrazole and their anti –microbial activitys. Indian journal of hetrocyclic chemistry 2000;9:315-316.
  38. Elmer W.K., Stephen D A, William M J, Paul C S and Washing C W, Text book of Diagnostic Microbiology, 5th edn (Lippincot and Pubmed), 2002.

9. / SIGNATURE OF CANDIDATE / (Mr. PATEL MAYURNARENDRABHAI)
10. / REMARKS OF THE GUIDE / The work is highly justifiable,
would yield significant data for
researchers and is feasible to
work in this institution.
11. / NAME AND DESIGNATION OF11.1 GUIDE / Dr. G K KAPSE
M Pharm., Ph.D
11.2 SIGNATURE
11.3 CO-GUIDE (IF ANY) / Prof. G. SUDHEENDRA
M Pharm. (Ph.D)
11.4 SIGNATURE
11.5 HEAD OF DEPARTMENT
11.6 SIGNATURE / Prof. G. SUDHEENDRA
M Pharm. (Ph.D)
12. / REMARKS OF THE CHAIRMAN AND PRINCIPALRecommended and Forwarded12.1 SIGNATURE
(Principal)