DESIGN, SYNTHESIS, CHARACTERIZATION OF SOME NEW PYRAZOLINE DERIVATIVES AND EVALUATION FOR THEIR ANTIMICROBIAL PROFILES

M. Pharm. Dissertation Protocol

Submitted to the

RajivGandhiUniversity of Health Sciences, Karnataka.

Bangalore.

.

By

Mr. SHOUVIK DEBNATH

B. Pharm.

Under the guidance of

Prof. G. SUDHEENDRA

M Pharm. (Ph.D)

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

LUQMANCOLLEGE OF PHARMACY, GULBARGA

2014

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

Name of the candidate And
address / Mr. SHOUVIK DEBNATH
Luqmancollege of pharmacy,
BEHIND P&T QUARTERS,
old jewargi road,
gulbarga-585102
Name of the institution / Luqmancollege 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 / 13-06-2013
TITLE OF THE TOPIC / DESIGN, SYNTHESIS, CHARACTERIZATION OF SOME NEW PYRAZOLINE DERIVATIVES AND EVALUATION FOR THEIR ANTIMICROBIAL PROFILES
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 study of heterocyclic systems has attracted theattention of organic chemists in the past decadesbecause of their natural occurrence and large numbersof their derivatives are essential to human life in variousforms.
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, Pyrazolines 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, antibacterial, antifungal,antiviral, diuretic, analgesic and anti-inflammatory agents 13-18.Also, Pyrazolines have many industrialapplications19-23.
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 Pyrazolines 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 hydrazides of dicarboxylic acids by conventional synthetic methods to form Quinazolinone nucleus. These are then reacted with chalcones to give pyrazoline derivatives.
  • 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 Pyrazolines, 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)24 synthesized novel 2-thioxo-quinazolin-4-one derivatives and their characterization.

  • Haiyang T et al., (2012)25performed 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)26designed and synthesized quinazolinone, benzothiazole derivatives bearing guanidinopropanoic acid moiety and their Schiff bases as cytotoxic and antimicrobial agents.

  • Abbas S Y et al., (2011)27 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)28 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)29 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)30synthesized 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)31developed 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)32prepared 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)33synthesized 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)34synthesized 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)35performed 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.

PYRAZOLINES
  • S.A.Rahaman, Y.Rajendra Prasad, K.Bhuvaneshwar, Phanikumar (2010)36The condensation of chalcones of 41-piperazineacetophenone with phenyl hydrazine hydrochloride gives pyrazoline derivatives(RP1-8). The structures of the synthesizedRP1-8 were assigned on the basis of elemental analysis, IR and 1H NMR spectroscopy data. These compounds were alsoscreened for their anti-histaminic activity. The recorded % of histamine inhibition showed significant anti-histaminicactivity, when compared with standard antihistamine drug mepiramine.
  • Biresh K Sarkar, Ritesh Patel, Upendra Bhadoriya (2011)37have synthesizeddifferent Pyrazoline derivatives by cyclization of substituted chalconederivatives in presence of hydrazine hydrate (P1-P6). All the synthesized compoundswere characterized by spectral analysis (IR, MS and NMR). These compounds werescreened for their antibacterial activity against Gram-positive bacteria and Gramnegative bacteria. Antifungal activity was also performed using agar cup plate method.The minimum inhibitory concentrations (MICs) of the compounds were also determined.

.
  • Baluja S and Chanda S (2012)38 have synthesized ten pyrazoline derivatives and their antibacterial activity was studied against four Gram positive Bacillus cereus ATCC11778, Staphylococcus aureus ATCC29737, Staphylococcus epidermidids NCIM2493 and Micrococcus luteus ATCC10240, and three Gram negative bacteria viz. Proteus mirabilis NCIM2241, Escherichia coli ATCC25922 and Klebsiella aerogenes NICM2098 bacteria. The antibacterial activity was done using Agar well diffusion method. The pyrozoline derivatives showed different activity against different bacteri-al strains depending on their structural formula. Gram positive bacteria were more susceptible than Gram negative bacteria. E. coli was the most resistant bacteria and B. cereus was the most susceptible bacteria. The pyrazoline derivatives which had nitro group at para position showed best antibacterial activity.

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(39) 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. DesaiAR 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. Sudheendra, Sreenivas Rao P, Udupi R.H. Synthesis and biological evaluation of certain new pyrazolinederivatives. Oriental Journal of Chemistry 2007; 23(1):359-363.
  14. Khali H Z and Yanni S A. Journal of Indian Chemical Society. 1981; 58; 168.
  15. Fahmy A M, Hassan K M, Khalaf A A and Ahmed R A. Indian Journal of Chemistry. 1987; 26 (B); 884.
  16. Havaldar F H and Fernandes P S. Journal of Indian Chemical Society. 1988; 65; 691.
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  18. Udupi R H, Kushnoor A S and Bhat A R. Ind. J. Heterocyclic Chem. 1988; 8; 63.
  19. Azarifar D and Shaebanzadeh M 2002 Molecules 7 885
  20. Solankee A, Lad S, Solankee S and Patel G IndianJ. Chem. 2009, 48B1442.
  21. Padmavathi V, Reddy V K, Padmaja A and ReddyBhaskar D.Syn. Commun.2002, 32(8)1227.
  22. Modzelewska A, Pettit C, Achanta G, Davidson E N,Huang P and Khan R S. Bioorg. Med. Chem.2006; 14, 3491.
  23. Bhat R A, Athar F and Azam A 2009 Eur. J. Med. Chem.2009;44;426.
  24. 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.
  25. Zumuretiguli A, Yufeng W, Haiyang T, Xiaoting H, Aidong Z. Facile Synthesis and Herbicidal Evaluation of 4H-3,1-benzoxazin-4-ones and 3H-quinazolin-4-ones with 2-phenoxymethyl substituent. Molecules. 2012;17:3181-3201
  26. Venkatesh P, Tiwari VS. Design and synthesis of Quinazolinone, Benzothiazole derivatives bearing guanidinopropanoic acid moiety and their Schiff bases as cytotoxic and antimicrobial agents. Arabian Journal of Chemistry, KingSaudUniversity. (2011).
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
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  35. 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.
  36. Rahaman S A, Rajendra Prasad Y, Bhuvaneshwar K, Phanikumar. Synthesis and antihistaminic activity of novel pyrazoline derivatives, International Journal of ChemTech Research, 2010, Vol 2 (1), 16-20.
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9. / SIGNATURE OF CANDIDATE / (Mr. SHOUVIK DEBNATH)
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 / 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)