“STUDIES ON THE SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITIES OFCERTAIN new STRUCTURAL HYBRIDS OF NITROGEN HETEROCYCLES”

M. Pharm. Dissertation Protocol

Submitted to the

Rajiv Gandhi University of Health Sciences, Karnataka.

Bangalore.

.

By

Mr. ANSARI IRFAN ABDUL QUDDUS

B. Pharm.

Under the guidance of

Prof. G. SUDHEENDRA

M Pharm. (Ph.D)

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

LUQMANCOLLEGE OF PHARMACY, GULBARGA

2013-14

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

Name of the candidate And
address /

Mr. ANSARI IRFAN ABDUL QUDDUS

755, FATIMA COMPLEX, DARGAH ROAD, BHIWANDI – 421 302.
DIST: THANE
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 / 10/01/2013
TITLE OF THE TOPIC / “STUDIES ON THE SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITIES OF CERTAIN new STRUCTURAL HYBRIDS 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 antibacterial2, anthelmintic3, neuroleptic4, antitubercular5,platelet anti-aggregating6,antifungal7,anticancer8,anti-inflammatory9,antiviral10,CNS depressant activity11, antiparkinson12,bronchodilator13 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 agents6.
Further it was observed from the literature that certain five membered heterocyclic compounds possess interesting biological activities. Among them the compounds bearing 1,3,4-oxadiazole nucleus have wide applications in medicinal chemistry. These have been reported to have significant antitubercular activity14,15.
During the survey of literature, it is seen that, the drug design by either molecular manipulation and/or combination of biologically active moieties into one molecule and synthesis 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 Oxadiazoles 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 oxadiazoles by the reaction with aromatic acid(s).
  • 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 will also beevaluated to determine their antitubercular profile.
6.3 Review of Literature:
The extensive literature survey revealed that the compounds containing Quinazolinone derivatives are reported to possess the wide range of biological activities. There is few important literatureof Quinazolinone as under.
  • Abbas S Y et al (2011)16 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)17 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 flavusand Alternaria solaniby disc diffusion method.

  • Reddy P S N et al (2010)18 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 oxisporiumand Macrophomina sorgina.

  • Rajasekaran S et al (2010)19synthesized of some 2-phenyl-3-substituted quinazolin-4(3H)-ones and evaluated their antitubercular, antibacterial and antioxidant activities. The compounds were evaluated their antitubercular activity against Mycobacterium tuberculosisby agar dilution method.

  • Kaur P et al (2009)20developed 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)21prepared 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 Wilhelmand Fusarium oxysporiumfungi.

  • Al-Deeb A O et al (2008)22synthesized 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)23synthesized some peptide derivatives of iodoquinazolinones/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)24performed 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 C.albicansandC. kruseiand antibacterial againstB.subtilis, S.aureus as gram positive andE.coli,P.aeruginosa as gram negative bacteria.
  • A. Hussain and M. Ajmal(2009)25 have synthesized novel series of 2-[3-(4-bromophenyl)propan-3-one]-5--(substituted phenyl)-1,3,4-oxadiazoles from 3-(4-bromobenzoyl)propionic acid with the aim to get better anti-inflammatory and analgesic agents with minimum or without side effects. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and antibacterial activities.

  • Ravitas Deshmukh et al (2011)26 have synthesized a series of 2-aryl-7alkyl or aryl-[1,3,4]-oxadiazolo[3,2-a] [1,3,5]triazin-5-one and 2-aryl-7alkyl or aryl–[1,3,4-]oxadiazolo[3,2-a] [1,3,5]triazine-5-thiones. The structures of new compounds havebeen confirmed by spectral and analytical data. The newly synthesized compounds have been evaluated fortheir antibacterial activity.

  • Rakesh Chawla et al (2010)27have been synthesized some new 3-acetyl-5-(3-chloro-1-benzo[b]thiophen-2-yl)-2-substituted phenyl-2,3-dihydro-1,3,4-oxadiazoles and 2-(3-chloro-1-benzo[b]thiophen-2-yl)-5-substituted phenyl-1,3,4-oxadiazoles and evaluated them for antimicrobial activity.

  • Vijay V. Dabholkar and Nitin V. Bhusari(2011)28 have reacted diethyladipate with hydrazine hydrate to give succinohydrazide which on further treatment with carbon disulfide, aromatic aldehydes and cynogen bromide yielded 1,2[di-(2-Mercapto-1,3,4-oxadiazole-5yl)] ethane [R= SH], 1,2[di-(2-Phenyl-1,3,4-oxadiazole-5yl)] ethane [R= substituted phenyl] and 1,2[di-(2-Amino-1,3,4-oxadiazole-5 yl)] ethane [R=NH2] respectively. The structures of thecompounds have been elucidated on the basis of spectral analysis.

  • Rakesh Sainiet al (2009)29synthesised (ethyl 2- (1H Benzo [d] [1, 2, 3] triazole –1- yl] acetate) and (2H – benzo [d] [1, 2, 3] triazole – 1 – yl acetohydrazine) alongwith their derivatives. The entire synthesized compounds were characterized by UV, IR and1H-NMR spectroscopy. The Antimicrobial activity of the synthesized compounds was evaluated on Sreptococcus aureus andE. coli.

  • Aryanasab F, Maleki H. and Saidi M.R.(2011)30carried out a facile and one-pot synthesis of 2-alkylthio-1,3,4-oxadiazoles is reported. This green method relies on thereaction of acid hydrazides with CS2 and an alkyl halide. The reaction is carried out under mild and environmentally friendlyprocedure in water with high to excellent yields. Thirteen different valuable alkylthio-1,3,4-oxadiazoles were synthesized fromCS2 with this method. This is the first report for the synthesis of 1,3,4-oxadiazoles in water.

7. / Materials and Methods:
7.1 Method of collection of data:
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 (31) 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 Synthetic strategy:
All the compounds in the present study would be synthesized by following given scheme. The starting material 1,3,4-benzoxazinone will be synthesized from anthranilic acid by known method. It is then reacted with active hydrogen atoms of amino acid by conventional synthetic methods to form 2,3 disubstituted Quinazolinone nucleus. The hydrazide of which is then reacted with different aryl aldehydes to yield Schiff bases which are further cyclized to prepare different Oxadiazoles by the reaction with aromatic acid(s). The various new compounds will be synthesized by conventional synthetic strategies and their yield, physical constant and analytical profile will be determined. All the reactions will be monitored by TLC technique and chemical tests as applicable.

SCHEME
7.3Biological screening:
1.Antimicrobial activity:-All the compounds will be subjected for screening against 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.
2.Anti-tuberculer activity:- Antitubercular activity 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 370 C for four weeks. At the end of four weeks they are checked for growth and scaled for inhibition.
7.4 Source of data:
  1. From available literature.
  2. From library based books
  3. Web sites
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7.4-1 Assessment of toxic effect: ------Not applicable------
7.4-2 Screening of Statistical analysis:------
7.4-3 Does the study require any investigations or interventions to be conducted on patients or humans or animals? If so, please describe briefly. ------No------
7.4-4 Has ethical clearance been obtained from your institution in case of 7.4?
------Not applicable------
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 conventionalsynthesis of quinazolinones and 3-methyl-1H-5-pyrazolonesand 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. Karia FD, Parsania PH. Synthesis, Biological and Thermal properties of Schiff Bases of Bisphenol-C. Asian J. Chem. 1999;11:991-995.
  14. Gabriel N and Gloria M, Bioorg Med Chem., 15(16), 2007, 5502.
  15. Santilli A A, Kim D H and Gaggory F J, J Ph Sciences, 64, 1975, 1057.
  16. Abbas SY, Ammar YA, Mohamed, El-sharief AM, El-gaby MSA. Synthesis of some biologically active 4-(3H)-quinazolinones derived from 2,3-pyridine dicarboxylic anhydride. Chemical Sciences Journal. 2011; CSJ-15:1-10.
  17. Revanasiddappa HD, Prasad KS, Shiva KL, 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.
  18. Reddy PSN, Mittapelli V, Reddy VD. Antibacterial, antifungal and antifeedant activity of quinazolinoyl-β-lactans/quinazolinones and bis (quinazolinoyl-β-lactams). Rasayan J. Chem. 2010; 3:635-640.
  19. Rajasekaran S, Rao G, Sanjay PPN. 2D QSAR studies of some novel quinazolinone derivatives as antituberculor agents. J. Comput. Method. Mol. Design. 2011; 1(3):69-82.
  20. 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.
  21. Khairy AM, El B, Aly MM, Mohamed YA, Basyouni WM, Abbas SY. 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.
  22. Alu-deeb AO, Alafeefy AM. Synthesis of some new 3H-quinazoline-4-one derivatives as potential antitubercular agents. World Applied Sciences Journal. 2008; 5(1):94-99.
  23. Dahiya R, Anil K, Yadav R. Synthesis and biological activity of peptide derivatives of iodoquinazolinnones/nitroimidazoles. MDPI. 2008; 13:958-976.
  24. Desai AR, 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.
  25. HussainA and AjmalM. Synthesis of novel 1,3,4-oxadiazole derivativesand their biological properties, Acta Pharm. 59 (2009) 223–233.
  26. Ravitas Deshmukh,JhaA.K, Alok Singh Thakur and Dhansay Dewangan. Synthesis and antibacterial activity of some 1, 3, 4-oxadiazole derivatives and their thione analogues, International Journal of Research in Pharmaceutical and Biomedical Sciences. 2011, Vol. 2 (1), 215-219.
  27. Rakesh Chawla, Anshu Arora, Manoj Kumar Parameswaran, Prabodh ChanderSharma, Sukumar Michael and Thengungal Kochupappy Ravi.Synthesis of novel 1,3,4-oxadiazole derivatives as potential antimicrobial agents. Acta Poloniae Pharmaceutica - Drug Research, (2010), Vol. 67, No. 3, 247-253.
  28. Vijay V. Dabholkar and Nitin V. Bhusari, Synthesis of 2-Substituted-1,3,4-Oxadiazole Derivatives, International Journal of Chemical, Environmental and Pharmaceutical Research, (2011)Vol.2, No.1, 1-4.
  29. Rakesh Saini, Awani K Rai, KesariANand Shahar YarM, Synthesis and biological evaluation of 2, 5 di-substituted 1, 3, 4 oxadiazoles, Asian J. Research Chem. 2009 2(1), 34-36.
  1. Aryanasab F, Maleki H. and SaidiM.R., A novel one-pot synthesis of 2-alkylthio-1,3,4-oxadiazoles in water, J. Iran. Chem. Soc., 2011,Vol. 8, No. 2, 525-530.
  2. 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. ANSARI IRFAN ABDUL QUDDUS)
10. / REMARKS OF THE GUIDE / The work is highly justifiable, would yield significant data and is feasible to work in this institution.
11. / NAME AND DESIGNATION OF11.1 GUIDE / Prof. G. SUDHEENDRA
M Pharm. (Ph.D)
11.2 SIGNATURE
11.3 CO-GUIDE (IF ANY) / ------
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)