Kingdom of Saudi Arabia
Majmaah University
Deanship of Scientific Research
Engineering and Applied Sciences Research Center
Application for Research Project Grant
Project No.
Research Title: Synthesis, investigation of nano scale physical structure of some new 4-
hydroxy-2(1H)-quinolinones derivatives and their biological and environmental
effect evaluation
‫حتضري ودراسة خواص النانو الرتكيبية لبعض مشتقات الكينولينون اجلديدة وتطبيقاهتا البيولوجية والبيئية‬
Name of the Principal Researcher: Mohammed Mahmud Mohammed Hassan
Department: Basic Science Unit
College: College of engineering
Mobile: 0508293110
Official E-mail:m.mahmoud@mu.edu.sa
Duration of the research: 10 Months
Total Proposed Budget: 32000SR
Abstract (Summary): (150 – 200 words)
The great importance of 4-hydroxy-2(1H)-quinolinone derivatives oriented our
attention to the synthesis of a series of new heterocyclic derivatives combining 4hydroxy-2(1H)-quinolinone in one molecular frame as new possible medicinal
,industrial and environmental reactive compounds. In our current project the
reactivity of 3-acyl-4-alkylthio-2(1H)-quinolinone towards different nucleophilic and
electrophilic reagents will be investigated.
The structural elucidation of the new synthesized derivatives will be identified and
confirmed using different spectrophotometric techniques such as: Infrared (IR)
,proton magnetic resonance (NMR),mass spectrometry(MS).The reaction
mechanisms will be proposed and discussed on the light of structural and spectral
data obtained. The expected biological and medicinal effects of the synthesized
derivatives will be evaluated. Some selected derivatives will be screened for their
antimicrobial, antituberculosis activities. The phototoxicity as well as the cytotoxic
activities of the title compounds will evaluated against leukemia- and
adenocarcinoma-derived cell lines in comparison to the normal human keratinocytes.
Investigation of nano-scale physical structure of the new synthesized derivatives
will be also useful for determine the volume of empty spaces in the prepared
compounds, as well as their concentration, since it is possible to place, in these
volumes, additional ingredients to accelerate or retard the activity of the drug, or
those removing its side-effects.
Main Researcher Signature: Mohammed Mahmud Mohammed Hassan
1
Date:28/11/1432 H
Research Project Proposal
I.
Names of
Researchers*
Names and Information of the Researchers
Academic Ranking
Department
1-Mohammed
Mahmoud
Mohammed Hassan
Assistant
professor
College of
engineering
(basic science
unit)
2- Ahmed
Mohammed Ismail
Mohammed
Assistant
professor
College of
engineering
(basic science
unit)
General
Specialization
Chemistry
Minor
Specialization
Organic
Chemistry
Physics
Nuclear-Solid
State Physics
3.
4.
*The first name indicates the Principal Researcher (PR) and the Second name is the Co-Researcher
designated by the PM to oblige responsibilities, in case of the withdrawal of the PR.
Very Important Notes:
1.
Only research projects could be submitted for financial support. Therefore completed or
published work will not be accepted. In case that published work has been granted, there will be
a penalty for all the team work, where they do not have the right to apply for research grants for
a period of 2 years as well as all grants will be refunded.
2.
The principal researcher and the co-researchers must hold Ph.D. degree; at least assistant
professor.
3.
The CV of the principal researcher should be provided.
4.
This application must be submitted electronically using the personal web page of the principal
researcher on the Deanship of Scientific Research website. Moreover, all researchers must have
their own web page on the Deanship of Scientific Research website. The researchers’ web pages
must be activated and all the required information should be provided to reflect academic
activities and achievements.
2
II.
Research Problem and Motivation
Our strategy to synthesize the target isolated heterocyclic systems, which contain 4hydroxy-2(1H)-quinolinone moiety in one molecular frame, was obtain an easily
accessible synthetic precursor that on modification can furnish the desired
heterocycles. structural elucidation of the new synthesized derivatives will be
identified and confirmed in addition to their reaction mechanisms . The expected
biological and medicinal effects of the synthesized derivatives will be evaluated.
The modern medicine makes a broad use of achievements of contemporary physics
both for diagnostic and prophylactic purposes. Contemporarily applied medicaments
are, generally, mixtures of a number of components and have a complicated chemical
structure, a not yet thoroughly known physical one. A better recognition of the
physical structure, e.g. the degree of filling up the space by chemical substances,
creates a possibility of investigating them with additional components which possess
required healing properties. In this project, extraordinary attention has been paid to
determine the volume of empty spaces in the synthesized products, as well as their
concentration, since it is possible to place, in these volumes, additional ingredients to
accelerate or retard the activity of the drug, or those removing its side-effects.
Investigations of positrons lifetimes spectra allow determination of radii of the empty
spaces and their concentrations in the investigated porous preparations and liquids.
3
III.
Research Objectives
Objective 1: Synthesis of some new 4-hydroxy-2(1H)-quinolinones derivatives.
Objective 2: structural elucidation of the new synthesized derivatives different
spectrophotometric techniques.
Objective 3: Proposing of the reaction mechanisms of the synthesized products
on the light of structural and spectral data obtained.
Objective 4: Evaluation of The expected biological and medicinal effects of the
synthesized derivatives.
Objective 5: Studying the nano scale physical structure of the promising
synthesized materials for diagnostic and prophylactic purposes.
Objective6: Evolution of the efficiency of the new synthesized products toward
the industrial and environmental concern.
4
IV.
Literature Review
Quinolinones
are the effective moiety in a large number of natural and synthetic
heterocyclic compounds that exhibit significant antibiotic activity with very wide
applications.[1-9] Our current program on chemistry of quinolinone is devoted to the
synthesis of novel five- or six-membered substituted 3- or 4-hetarylquinolinone
derivatives.[10 – 14] A special interest in this program is directed to the production
of derivatives including pyrazoles and isoxazoles, which are known to exhibit
significant antibiotic properties. Thus, pyrazoles showed important antimicrobial
and antifungal activity,[15] cholesterol acyl-transferase inhibitory activity,[16]
antidiabetic activity,[17] antidepressant activity,[18] and antianxiety activity.[19]
Recently pyrazolines have received renewed attention with the registration of
Indoxacarb, which has neuronal target action on insects.[20] On the other hand,
isoxazoles and isoxazolines possess analgesic activity,[19] antiprotozoal activity,[21]
antiinfluenza virus activity,[22] antifungal activity,[23] antibacterial activity,[24]
antidepressant,[25] anti-ischemic effects,[26] and anti-inflammatory activity.[27]
Because of these interesting biological activities of quinolinones, pyrazoles, and
isoxazoles, considerable attention has been directed at the synthesis of some new
derivatives containing these moieties in one molecular frame.
Among the methods employed in the synthesis of 2-pyrazolines and isoxazolines, the
condensation of a,b-unsaturated carbonyl compounds with hydrazines and
hydroxylamine is commonly used.[28] Chromones are usually readily ring-opened
via nucleophilic attack at the 2-position and when treated with a suitable
binucleophile, ring opening can be effected, followed by ring closure leading to new
ring systems (e.g., hydrazine and hydroxylamine give pyrazole and isoxazoles,
respectively.[29 – 31]. In addition to the medicinal importance, multi-substituted
quinolines are valuable synthons used for the preparation of nano- and
mesostructures with enhanced electronic and photonic properties [32-34]
Very recently the technique of measuring positrons lifetimes has been used to
determine empty spaces in liquids [35] and porous materials [36-37]. Applying the
model of annihilation of ortho-Ps in empty spaces [38] on the results of
measurements of positrons lifetimes in medical compounds, we determined the radii
of empty spherical spaces in preparations of different technologies of manufacture.
We noticed as well the existence of correlation between the degree of filling up the
space of the preparation and the time of maximal effectiveness of its performance in
the human organism.
5
V.
Research Methodology
First stage:
Synthesis of some promising 4-hydroxy-2(1H)-quinolinones
derivatives . The reactivity of 3-acyl-4-alkylthio-2(1H)-quinolinone towards
different nucleophilic and electrophilic reagents will be investigated.
SMe
1.CS2 /K2CO3/DMF
2.MeX
3.O-dichlorobenzene/Reflux 4h
Me
Me
H
Electophilic and nucliophili ragents
SMe
Heterocyclo
Heterocycle
Me
H
H
Second stage:
We will build a library from 4-hydroxy-2(1H)-quinolinones
derivatives and all the synthesized compounds will be characterized using
elemental analysis and different spectrophotometric techniques( IR, 1H- NMR,
30
CNMR MS,………….) .
Third stage: Products of the above reactions would be expected to be promising
for biological , medicinal and environmental evaluation.
Forth stage: (Micro-structural physical properties): In order to determine the
positrons lifetimes in the investigated drugs a standard fast slow spectrometer of
250 ps resolution was used. The obtained spectra were analyzed following their
distribution into two and three components by means of LIFE TIME computer
program. In the case of both distributions a component of lifetime of a few
nanoseconds in length was found to occur, testifying to the annihilation of
positrons from the state of bounded ortho-Ps.
6
The promising synthesized materials under investigation will be filled very
tightly two plexiglass vessels being 7 mm deep and 20 mm in diameter. The vessels
were covered with hostaphonic foil of surface density of 0.9 mg/cm2. Between the
vessels there was placed a source of 22Na positrons, also covered with the abovementioned foil. In order to determine the positrons lifetimes in the investigated drugs
a standard fast{slow spectrometer of 250 ps resolution was used. The obtained
spectra were analyzed following their distribution into two and three components by
means of LIFE TIME computer program. In the case of both distributions a
component of lifetime of a few nanoseconds in length was found to occur, testifying to
the annihilation of positrons from the state of bounded ortho-Ps.
Positron Annihilation Lifetime (PAL) Spectroscopy Setup:
 Positron source: 22Na radioisotope
 Scintillation detectors: Two plastic scintillators NE111 with photomultiplier
tubes.
 Amplifiers: Two amplifiers ORTEC 444 gated biased amplifier.
 Constant Fraction Discriminator (CFD): The ORTEC model 583-CFE.
 Timing Amplitude Converter (TAC): The ORTEC model 567-TAC/SCA
 Multichannel Analyzer (MCA): The MCA is an ORTEC Model 919 Spectrum
Master multichannel buffer (MCV).
7
VI.
References
1. Chimichi,S.; Boccalini. M, ; Hassan,M.M.Tetrahedron 62 (2006) 90–96.
2. Abass, M. Heterocycles 2005, 65, 901.
3. Abass, M.; Mostafa, B. B. Bioorg. Med. Chem. 2005, 13, 6133.
4. Tzeng, C.-C.; Chen, Y.-L. Chin. Pharm. J. 2002, 54, 229.
Substituted Quinolinones, Part 12 351
5. Passarotti, C. M.; Valenti, M.; Passarella, D.; Martinelli, M. Boll. Chim. Farm.
1999, 138, 311.
6. Tougou, K.; Nakamura, A.; Watanabe, S.; Okuyama, Y.; Morino, A. Drug. Metab.
Disp. 1998, 26, 355.
7. Michael, J. P. Nat. Prod. Rep. 1997, 14, 11.
8. Sharma, A. K.; Khosla, R.; Kela, A. K.; Mehta, V. L. Indian J. Pharm. 1994
26, 249.
9. A. Lilienkampf, J. Mao, B.Wan, Y.Wang, S.G. Franzblau, A.P. Kozikowski, J.
Med.
Chem. 52 (2009) 2109–2118.
10. Abass, M. Phosphorus, Sulfur Silicon Relat. Elem. 2003, 170, 1413.
11. Abass, M.; Hassan, A. Chem. Papers 2003, 57, 267.
12. Abass, M. Synth. Commun. 2000, 30, 2735.
13. (a) Abass, M.; Othman, E. S. Synth. Commun. 2001, 31, 3361; (b) Abass, M.;
Ismail, M. M. Chem. Papers 2000, 54, 187.
14. (a) Abdel-Megid, M.; Ismail, M. M. Int. J. Chem. 2002, 12, 287; (b) Ismail, M. M.;
Abdel-Megid, M.; Hassan, M. M. Chem. Papers 2004, 58, 117.
15. Chimenti, F.; Bizzari, B.; Manna, F.; Bolasco, A.; Secci, A.; Chimenti, P.;
Granese, A.; Riveanera, D.; Lilli, D.; Scaltrito, M. M.; Branciaglia, M. I.
Bioorg. Med. Chem. Lett. 2005, 15, 603.
16. Jeong, T. S.; Kim, K. S.; An, S.-J.; Cho, K.-H.; Lee, S.; Lee, W. S. Bioorg. Med.
Chem. Lett. 2004, 14, 2715.
17. Ahn, J. H.; Kim, H.-M.; Jung, S.-D.; Yang, S.-D.; Cheon, H. G.; Kim, S. S.
Bioorg.
Med. Chem. Lett. 2004, 14, 4461.
18. Palaska, E.; Aytamir, M.; Uzbay, I. T.; Erol, D. Eur. J. Med. Chem. 2001
36, 539.
19. Li, X. B.; Inouei, T.; Abekawai, T.; Yirui, F.; Koyama, T. Eur. J. Pharm. 2004
50, 145.
18. Silver, K. S.; Soderlund, D. M. Pesticid. Biochem. Physiol. 2005, 81, 136.
20. Silva, N. M.; Tributino, J. L.; Miranda, A. L. P.; Barreirg, E. J.; Fraga, C. A.
Eur.
J. Med. Chem. 2002, 37, 163.
21. Sperandeo, N. R.; Brinon, M. C.; Brun, R. Il Farmaco 2004, 59, 431.
22. Kai, H.; Matsumoto, H.; Hattori, N.; Takase, A.; Fujiwara, T.; Sugimoto, H.
8
Bioorg. Med. Chem. Lett. 2001, 11, 1997.
23. Bassapa, M.; Sadashiva, M. P.; Mantelingu, K.; Swamy, S. N. Bioorg. Med.
Chem.
2003, 11, 4539.
24. Lee, J. S.; Cho, Y. S.; Chang, M. H.; Koh, H. R.; Chung, B. Y.; Pae, A. N. Bioorg.
Med. Chem. Lett. 2003, 13, 4117.
25. Pastor, J.; Alcazar, J.; Alvarez, R. M.; Andres, J. I.; Cid, J. M.; De Lucas, A. I.;
Diaz, A.; Fernandez, J.; Font, L. M.; Itorrino, L.; Lafuento, C.; Martine, S.;
Bakker, M. H. Bioorg. Med. Chem. Lett. 2004, 14, 2917.
26. Matucz, E.; Moricz, K.; Gigler, G.; Simo, A.; Barkoczy, J.; Levay, G.;
Harsing, L. G., Jr.; Szenas, G. Brain Res. 2004, 10, 210.
27. Kumar, M. S.; Swamy, S. N.; Mahendra, M.; Prasad, J. S.; Veswanath, B. S.;
Rangappa, K. S. Bioorg. Med. Chem. Lett. 2004, 14, 3679.
28. Seebacher, W.; Michi, G.; Belaj, F.; Brun, R.; Saf, R.; Weis, R. Tetrahedron
2003,
59, 2811.
29. Sabitha, G. Aldrichimica Acta 1996, 29, 15.
30. Shanker, M. S. S.; Reddy, R. B.; Chandra, G. V. P.; Reddy, Y. D. Asian. J. Chem.
1992, 4, 166.
31. Nazzei, M.; Sottafattori, E.; Dondero, R.; Ryabukhin, S. V.; Plaskon, A. S.;
Volochnyuk, D. M.; Tolmacher, A. A. Synlett 2004, 8, 2287.
32. A.K. Aggarwal, S.A. Jenekhe, Macromolecules 24 (1991) 6806–6808.
33. X. Zhang, A.S. Shetty, S.A. Jenekhe, Macromolecules 32 (1999) 7422–7429.
34 .S.A. Jenekhe, L. Lu, M.M. Alam, Macromolecules 34 (2001) 7315–7324.
35. K. Jerie, A. Baranowski, J. Glinski, K. Orzechowski, J. Przybylski, Acta Phys.
Pol. A 99, 393 (2001).
36. T. Hirade, Acta Phys. Pol. A 107, 615 (2005).
37. M. Mohsen, M.H. Abd-El Salamb, A. Ashry, A. Ismail, H. Ismail, Polym. Deg.
Stab., 87, 3, (2005).
38. M. Eldrup, D. Lightody, J. Sherwod, J. Chem. Phys. 63, 51 (1981).
9
VII.
Detailed Budget
1- Section (1): Researchers Compensations:
Name of Researcher
Duration
1-Mohammed Mahmoud
Mohammed Hassan
2- Ahmed Mohammed Ismail
Mohammed
3 ---------------------------------Total of Section (1)
1
2
Total
10 Monthes
Monthly Compensation
1200 SR Principal Researcher
10 Monthes
1000 SR Co-Researchers
10000 SR
----------------
------------------------------
---------------22000 SR
12000 SR
Important Notes:
1. The maximum monthly compensation for the principal researcher is SR1200 and SR1000 for the
Co-Researcher.
2. The number of Co-Researchers should not be more than one Co-researcher. However, the
council of the Deanship of Scientific Research may exempt some projects from this condition
under special circumstances based on recommendations from research centers and referees.
3. The Co-Researcher could be from outside University, and his participation in the project is
conditionally based on his contribution to the project and that he or she has publications in
ranked ISI journals. However, this requires an approval of both the research center and Deanship
of Scientific Research.
4. The duration of any research project should not exceed 12 months.
5. The duration of the project starts from the date of signing the contract.
2- Section (2): Assistants Compensations:
Assistant Type
Number
Number*Compensation*Duration
Research Assistant
--------------------------------Laboratory Tech.
--------------------------------Statistician
--------------------------------University Student
--------------------------------Total of Section (2) -------------------------------------------------------------------------------
Total
---------------------------------------------------------------------------------
Important Notes:
1- The role of the assistants should be defined and their participation in the project should be for a
limited period of time and should not be more than half of the duration of the project.
2- Assistants’ compensations must be calculated according to the Scientific Research Bylaws;
where master degree holder gets monthly compensation of SR800, bachelor degree holder gets
monthly compensation of SR600 and university students and technicians get monthly
compensation of SR400.
10
3- Section (3): Equipment and Materials:
Equipment and Materials
Number
Cost
Total Cost
---------------- ---------1
2
3
4
5
6
Total of Section (3) ----------------------------------------------------------------------------------------
--------------
Important Notes:
1- You must clearly specify all the required equipment and materials that will be needed to
complete the research project and you have to provide the estimated cost for each of them.
Laptops, statistical software, and stationary should not be included in this section as Majmaah
University provides each factuality member with a laptop and the other things will be provided
by the college or the research centers.
2- In cases, where this section is not filled, this means that your research do not needs any
materials, then materials and equipments will not be provided. Furthermore, if the estimated
costs of the required equipments and materials are not inserted on the specified columns, this
may lead to reject ion of supporting the research project.
4- Section (4): Transportations and other Expenses:
1
Type of Expense
Different Spectroscopic and Biological Analysis Expenses (IR,
1H- NMR, 30CNMR MS,………..)
2
3
Total of Section (4)
Cost
10000 SR
10000 SR
Important Notes:
1- The principal researcher must provide accurate description for the nature of these expenses.
Additionally, he must provide official receipts/vouchers that support each expense and no
compensations will be paid to this section without providing such receipts (bills).
2- The research center and the Deanship of Scientific Research may estimate the expenses based
on justifications provided by the principal researcher.
5- Section (5): Total Budget of the Research Project
Items
Cost
22000 SR
---------------10000 SR
32000 SR
1 Total of Section (1)
2 Total of Section (2)
3 Total of Section (4)
Total Budget of the Research Project
11
Important Notes:
The total budget of the research project do not includes the equipments and non-consumable materials,
where such items will be returned to the research center upon the research completion.
12
RESEARCH TIMETABLE
Items
Starting Date:
/
/ 143
H.
Months
Planned processes of major tasks
Duration
1
1
2
3
4
√
√
√
5
6
√
√
7
8
√
√
9
10
√
Purchase equipments, chemicals and instruments.
2
Design synthesis and structure determination of the new 4-hydroxy2(1H)-quinolinones derivatives.
3
Evaluation of The expected biological and medicinal effects of the
synthesized derivatives.
4
Studying the nano scale physical structure of the promising
synthesized materials for diagnostic and prophylactic purposes.
5
Evolution of the efficiency of the new synthesized products toward
the industrial and environmental concern.
6
Assessment of the project results and preparing data for publication
13
√
√
11
12