research & reviews a journal of drug design & discovery (vol1, issue1)
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Research & Reviews: A Journal of
Drug Design & DiscoveryRRJoDDD
Jan - April 2014
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STM JOURNALS
1. Drug Designing and Research: Ayurvedic Approach Nishant Shukla 1
2. Synthesis and Anti-Bacterial Activity Profile of Cyclized Diazonium Compounds Priti Jain, L. Naga Rajiv, Hemant R. Jadhav 4
3. Targeting Cancer through Angiogenesis Inhibition: Prospective of Azole Based Small MoleculesPratap Chandra Acharya 13
ContentsResearch & Reviews: A Journal of Drug Design & Discovery
RRJoDDD (2014) 1-3 © STM Journals 2014. All Rights Reserved Page 1
Research & Reviews: A Journal of Drug Design & Discovery
Volume 1 Issue 1
www.stmjournals.com
Drug Designing and Research: Ayurvedic Approach
Nishant Shukla*
Morjand Khari, Sriganganagar, Rajasthan
Abstract Ayurveda the ancient Indian medical wisdom has served society through its holistic
approach of healing. Ancient Indian scientists Acharya Charaka, Acharya Sushruta, etc. has done in drug research and clinical research. This approach was not only aims
to treat a person but to bring the original state. Acharya Charaka clarifies that a
physician or researcher ought to look at least four whilst treatment the patient i.e. roga bala (therapeutic effect on disease), deha bala (strength or immunity), chitta bala
(psyche) and agni bala (digestion & metabolism). Herbs used ought to have at least four properties i.e. bahu kalpap, bahu gunam, sampanna and yogya. Preparation of
poly-herbal, herbo-mineral combination ought to be done as per the norms prescribed
by Acharya Charaka. Individualized approach of drug delivery is necessary and research needs to incorporate them. The paper discuss these in details.
Keywords: Ayurveda, Drug designing, poly-herbal, herbo-mineral
*Author for Correspondence E-mail: [email protected]
INTRODUCTION Drug designing is extremely important in
medical research. It is even more important in
Ayurveda system of medicine, where
numerous combination herbal, herbo-minerals,
herb-animal compounds are prepared and
used. Effect of individual drugs were studied
and documented in ancient classics like
Charaka Samhita, Sushruta Samhita, Astang
Hridya, Nighantus, etc. latest work done in this
field is by Acharya Bhavmishra in 18th
century. Many combinations were made by
different scholar in past based on their
observations and experiences, this is practiced
in present era also to search for better
alternate.
Owing to the fact that diseases are always
multifactorial and group of symptoms instead
of using single herb combinations were
prepared and experimented. Today there are
more than ten thousand poly-herbal, herbo-
mineral compound in use for ayurvedic
medical management. The quest is continuing,
and new formulations are prepared,
experimented, used clinically.
Drug designing requires detailed study of
human body and drugs used. Human body is
not physical only; psyche affects body’s
physiology as body & mind are
interdependent. One must attend to holistic
approach while preparing any new poly-herbal
or herbo-mineral combination. Other primary
requisite mentioned in the classics is a drug
must treat disease and at the same time should
not alter other doshas. In order to achieve the
above mentioned goal Acharya Charaka gave
guidelines i.e. physician must examine at least
four aspects very minutely whilst treating
patient i.e. yoga Bala (strength/severity/gravity
/stage of disease), Deha Bala (body strength &
immunity), Chitta Bala (psychological
wellbeing) and Agni Bala (digestion &
metabolism)[1]. This paper will highlight
ayurvedic principles for designing a poly-
herbal medicine.
KNOWLEDGE AND RESEARCH
GAPS Preparation of SOP (standard operative
procedure) for Designing of poly-herbal
formulation is ought to be made from the
guidelines described in ayurvedic classics.
This is hurdle in scientific approach of drug
planning.
Drug Designing & Research Nishant Shukla
__________________________________________________________________________________________
RRJoDDD (2014) 1-3 © STM Journals 2014. All Rights Reserved Page 2
AIMS AND OBJECTIVE A review paper on scientific designing of
poly-herbal ayurvedic medicines was
presented with following aims & objectives
1. Study of ayurvedic principle for drug
research
2. SOP for drug designing
MATERIALS & METHODS Review paper was based on scientific
evidences available in ancient ayurvedic
classics and it’s through study and develops a
SOP from the guidelines.
AYURVEDIC APPROACH TO DRUG
RESEARCH Acharya Charaka and Acharya Bhavmishra
has been described the study of herbs and
Acharya Sharangdhar described guidelines for
drug preparation. This is not completely
followed in the present practice and most of
the drugs are combined with keeping in view
of their chemical constituent. Moreover drugs
used today are prepared from plant extracts
(mostly alcoholic). Ancient scholars used drug
as a whole and extracts used were water
extracts only. Use of whole plant is having
added benefit over its extract; the greatest
example is sarpagandha (Rauvolfia serpentina)
roots when used as whole plant has no adverse
drug reactions like – suicidal tendency,
bradycardia, drowsiness, etc. and controls
blood pressure. But the use of its extracted
alkaloid serpentine (reserpine) produces
adverse drug reaction similar adverse effect is
observed in sarpagandha ghanvati too.
Ayurvedic drug research is based on
pharmaceutical (bahukalpam), pharmacologica
l (bahugunam), pharmacognosical (sampanam)
and therapeutically potent (yogyam) [2]. As
discussed above a physician ought to see deha
bala, chitta bala and agni bala, Acharya
Charaka clarified this in viman 8 whilst
describing karyafala (outcome of treatment).
Acharya Charaka described that a drug is said
to be effective if it heals disease and ought to
improve complexion, physical strength and
immunity, regulate digestion & metabolism,
regular sleep and awakening i.e. it should also
improve general wellbeing of the patient [3]. It
is observed in contemporary science that drug
whilst correcting illness produce adverse drug
reaction or idiosyncrasies; some are even more
dangerous than the primary illness for instance
quinine used for treatment of malaria may
produce ITP, acute renal failure. Amodiaquine
may have agranulocytosis, Amodiaquine may
produce intravascular hemolysis over and
above gastric disturbance, headache,
irregularities, etc. The cited idiosyncrasies are
only the example and most of drug used have
such adverse effects, owing to these adverse
drug reaction FDA has proscribed various
drugs, so research in the medicine ought to be
based on approach of Acharya Charaka.
Importance of prakriti and vikriti [4] in clinical
medicine has been acknowledged in ayurvedic
medicine. Ayurvedic medicines are grouped as
vyadhi-hara, dosha-hara and ubhaya-hara.
1. Vyadhi-hara means a drug has effect on
disease i.e. corrects dosha-dushya
sammurchana (as dosha-dushya
sammurchana is the important event in
disease production) and can be used
irrespective of prakriti of individual,
doshas involved for instance most of
herbo-mineral compounds are of this
nature, vatsanabh (Aconitum ferox) in
jwara, pushkarmula (I. racemosa) in chest
pain, somalata in asthma, etc. A physician
can prescribe this medicine use these
medicines with observing only the age and
gravity of disease for dosage.
2. Dosha-hara means drug that corrects
dosha. It through medical examination –
ten fold examinationiv and analyze morbid
medical condition on doshik paradigm [5–
6]. This is used in ayurvedic practice and
needs perfection in clinical examination
minute observation is prerequisite.
3. Ubhaya-hara means these are such drugs
which not only corrects the dosha
primarily involved in disease but also
corrects dosha-dushya saamurchana, for
example use of dashmula kwath vatic
sotha (pitting edema) is vata shamak and
shothaghana (anti-inflammatory). These
drugs are combinations are appreciated as
has dual action.
This concept of ayurveda is not accepted in
previous years, but concept of individualized
care is now accepted for research purpose also.
A recent research on rheumatoid arthritis
carried out by Ramesh C. Juyal and his team
validated concept of prakriti and its
Research & Reviews: A Journal of Drug Design & Discovery
Volume 1, Issue 1
__________________________________________________________________________________________
RRJoDDD (2014) 1-3 © STM Journals 2014. All Rights Reserved Page 3
importance in clinical efficacy of the drug. The
conclusion drawn by them clarifies this
concept they concluded that “This exploratory
study suggests discrete causal pathways for
RA etiology in prakriti based subgroups,
thereby, validating concepts of prakriti and
personalized medicine in Ayurveda.
Ayurgenomics approach holds promise for
biomarker discovery in complex diseases”[7].
SUMMARY Drug designing and drug research has been
unique approach in ayurveda and not only
objected to treat disease but to bring back
normalcy after treatment, it covers all the three
component of body. This holistic approach
reduces probabilities of adverse drug reaction
or idiosyncrasies. Research in Ayurveda ought
to be based on ayurveda principles to validate
the facts described in ayurvedic treatises.
REFERENCE
1. Achrya Charaka, Charaka Samhita,
Niryana Sagar press third edition.1941:
Ch. Ni. 8/36-37 “ ddhisth na ṣay as
th ṁ ōg ṇ mupala ṣayēt| susū ṣm mapi
ca p jñō dēh gnibalacētas m||36|| y dhy
a asth iśēṣ n hi jñ t jñ t vicakṣaṇaḥ|
tasy ṁ tasy ma asth y ṁ catuḥś ēyaḥ
p apadyatē||37||
2. Achrya Charaka, Charaka Samhita, Niryan
a Sagar press third edition.1941: Ch. Su.
9/7 ”bahut tat ayōgyat amanē a idha al
pan | sampaccēti catuṣ ō'yaṁ d a y ṇ ṁ
guṇa ucyatē||7||
3. Achrya Charaka, Charaka Samhita,
Niryana Sagar press third edition. 1941:
Ch. Vi. 8/89 “ yaṁ dh tus myaṁ, tasya
la ṣaṇaṁ i ōpaśamaḥ| pa ī ṣ t asya-
ugupaśamanaṁ, s a a a ṇayōgaḥ, śa ī ōp
acayaḥ, bala ddhiḥ, abhya ah y bhil ṣa
ḥ, uci h a lē, abhya ah tasya c h asy
a kale samyagja aṇaṁ, nid l bhō yath
laṁ, ai iṇ ṁ ca s apn n mada śanaṁ,
su hēna ca p atibōdhanaṁ, tamūt apu īṣ
a ētas ṁ mu tiḥ, sa ai manōbuddhīn
d iy ṇ ṁ c y pattiriti||89||
4. Achrya Charaka, Charaka Samhita, Niryan
a Sagar press third edition 1941: Ch. Vi.
8/94 “pa ī ṣēta p a titaśca, i titaśca,
s ataśca, saṁhananataśca, p am ṇataśca,
s tmyataśca, satt ataśca, h aśa titaśca, v
y y maśa titaśca, ayastaścēti, balap am
ṇa iśēṣagrahaṇahētōḥ||94||
5. Achrya Charaka, Charaka Samhita,
Niryana Sagar press third edition. 1941:
Ch. Vi. 8/94 “tasyōpalabdhi nid n-
apū a ūpaliṅgōpaśayasamp ptitaḥ||6||
6. Achrya Madhavakar, Madhav Nidan,
Niryana Sagar press third edition. 1939:
Ma. Ni. 1/4 nid naṁ pū a ūp -ṇi
ūp ṇyupaśayastath | samp ptiścēti
ijñ naṁ ōg ṇ ṁ pañcadh sm tam ||4||
7. Juyal RC, Negi S, Wakhode P, Bhat S,
Bhat B, et al. Potential of Ayurgenomics
Approach in Complex Trait Research:
Leads from a Pilot Study on Rheumatoid
Arthritis. PLoS ONE.2012; 7(9): e45752.
doi:10.1371/journal.pone.0045752.
RRJoDDD (2014) 4-12 © STM Journals 2014. All Rights Reserved Page 4
Research & Reviews: A Journal of Drug Design & Discovery
Volume 1, Issue 1
www.stmjournals.com
Synthesis and Anti-Bacterial Activity Profile of Cyclized
Diazonium Compounds
Priti Jain*, L. Naga Rajiv, Hemant R. Jadhav Department of Pharmacy, Birla Institute of Technology and Sciences, Pilani,
Rajasthan, India
Abstract Synthesis of cyclised diazonium compounds and their in vitro activity against various microorganisms is described. Several primary aromatic amines were diazotised and the
resulting diazotised compounds were coupled with active methylene compounds to give
hydrazono derivatives. These were cyclized with hydrazine hydrate, phenyl hydrazine, urea and o-phenylene diamine to give pyrazolin-5-one, substituted pyrazolin-5-ones,
pyrimidin-di-ones and benzodiazepinone derivatives, respectively. Some hydrazine
derivatives were also produced by reduction of diazo compounds with Sn/HCl. The synthesized compounds were assessed for their antimicrobial profile against Escherichia
coli, Staphylococcus aureus, Bacillus cereus and Pseudomonas putida. Chloramphenicol and tetracycline were used as standards for the comparison of activity. Some of the
compounds were found to exhibit promising anti- bacterial activity.
Keywords: diazotization, pyrazolinone, pyrimidinone, benzodiazepine, antimicrobial
*Author for Correspondence E-mail: [email protected]
INTRODUCTION Heterocyclic compounds hold a special place
among pharmaceutically important natural and
synthetic materials. The remarkable ability of
heterocyclic nuclei to serve both as
biomimetics and active pharmacophores has
largely contributed to their unique value as
traditional key elements of numerous drugs.
Five or six membered ring compounds are
ranked high among various classes of organic
compounds in respect to the diverse biological
activities. Pyrazolinone is a five membered
lactam ring compound containing two
nitrogens and ketone in the same molecule.
Lactams are reported to have varying
pharmacological activity. Some pyrazolinones
are nonsteroidal anti-inflammatory agents used
in the treatment of arthritis and other
musculoskeletal and joint disorders. They also
possess activities like antibacterial, antifungal,
anti-inflammatory [1], antidiabetic, analgesic,
antipyretic, antiviral and antineoplastic activity
[2].
Pyrimidine ring structures also have received
significant attention owing to their diverse
range of biological properties. Pyrimidine
nucleus is present in compounds used
clinically such as antibacterial agents,
anticancer agent, antiviral agents, antifungal
agents and antimalarial agents. Several
important sulfonamide drugs are pyrimidine
derivatives namely sulfadiazine, sulfamerazine
and sulfadimidine. The nucleus also is an
integral part of DNA and RNA, hence serves
as an important part of nucleoside antibiotics,
antibacterials and cardiovascular agents [3– 5].
The benzodiazepine nucleus is also a well-
studied traditional pharmacophoric scaffold
that has emerged as a core structural unit of
various sedative-hypnotics, muscle relaxants,
anxiolytics, antistaminic and anticonvulsant
agents. Therefore diversely substituted
benzodiazepine nuclei can serve as synthons
for developing new drugs [6]. Keeping these
facts in mind, we synthesized pyrazolin-5-one,
substituted pyrazolin-5-ones, pyrimidin-di-
ones and benzodiazepinone derivatives for
probable antibacterial activity.
EXPERIMENTAL General:
Melting points were determined on Buchi-530
melting point apparatus and are reported
uncorrected. IR spectra were recorded on a
Synthesis and Anti-Bacterial Activity Profile Jain et al.
RRJoDDD (2014) 4-12 © STM Journals 2014. All Rights Reserved Page 5
Shimadzu-Prestige-21 FTIR and NMR on
Bruker-400 MHz. All analytical samples were
observed by thin layer chromatography, which
was performed on EM Silica gel 60 F254
sheets (0.2 mm) using suitable solvent system.
The spots were detected with a model UV
lamp.
Diazotization of Primary Aromatic Amines
A mixture of aromatic amine (0.01 mole) in
concentrated HCl (5 ml) was cooled to 0 - 5oC
under ice. Cooled sodium nitrite solution (1.5
g in 10 mL of water) was added to it dropwise
over 10 minutes. Addition of the solution was
continued till the reaction mixture gives end
point when tested with starch –iodide paper.
General Procedure for the Preparation of
Hydrazono Derivatives (C)
The diazonium salt formed was then reacted
with ethyl acetoacetate, which serves as a
source of active methylene group (Figure 1).
This proton of methylene group is very active
and can replace anion from other compounds.
Other compounds like ethyl malonate, ethyl
acetone, ethyl cyanoacetate can also be used as
a source of active methylene group.
PROCEDURE To the diazotized compound, the cooled
mixture of active methylene compound formed
from ethyl acetoacetate (0.01 M) and sodium
acetate (0.05 M) in ethanol (50 ml) was added
drop-wise with stirring for about 15 minutes.
The reaction mixture was left for 2 hours at
room temperature. Recrystallization was done
using suitable solvent [7].
Preparation of Pyrazoline-5-one Derivatives
(D1-D8)
To compound ‘C1 to C8’ was added equimolar
Solution of hydrazine hydrate and 20 ml
ethanol. The mixture was then refluxed for
about 4 hours. The completion of reaction was
monitored by TLC using suitable solvent
system. The final product was recrystallised
using ethanol [8, 10].
Preparation of 2-Phenyl Pyrazole-3-one
Derivatives (E1-E8)
30mL of glacial acetic acid was added to ‘C1
to C8’ and stirred. To the resulting solution
was added equimolar quantity of phenyl
hydrazine and anhydrous sodium acetate. It
was then refluxed for about 5 hours. The
reaction mixture was poured in ice cool water
and stored in refrigerator overnight. Filtered
and recrystallized with suitable solvent [8, 10].
Preparation of Substituted 2, 4-Pyrimidine-
dione Derivatives (F1-F8)
To compound ‘C1 to C8’ was added equimolar
solution of urea and 40 ml ethanol. The
mixture was then refluxed for about 3-4 hours.
The completion of reaction was monitored by
TLC using suitable solvent system. On
completion of reaction, the mixture was cooled
under ice and kept for about one hour. The
final product was recrystallised using ethanol
[9, 10].
Preparation of Substituted Benzodiazepine
Derivatives (G1-G8)
To compounds ‘C1 to C8’ was added about 6
ml glacial acetic acid. Half molar of o-
phenylene diamine was taken and dissolved in
minimum quantity of glacial acetic acid. Both
solutions were mixed and refluxed for about 6
hours, cooled and kept overnight. It was then
filtered and recrystallized using acetic acid
[11].
Fig. 1: Reaction of Diazonium Compounds with ethylacetoacetate.
Research & Reviews: A Journal of Drug Design & Discovery
Volume 1, Issue 1
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Preparation of Hydrazine Derivatives (H1-
H8)
To stannous chloride (2.1 gm), 2 ml HCl was
added and cooled. This solution was slowly
added to diazonium salt solution. It was kept
for 2-3 hours, filtered and recrystallized.
Antimicrobial Screening
The synthesized compounds were screened for
their antimicrobial activity against Escherichia
coli, Staphylococcus aureus, Bacillus cerius
and Pseudomonas putida by well plate
method. The nutrient broth was prepared by
dissolving 25 gm of Laurea Bertanni (LB)
broth in 1000 ml of distilled water in a conical
flask. 2% of agar powder was added to the
nutrient broth to prepare agar media. The
solution was autoclaved at 121°C, 15psi for 15
minutes. The broth was then inoculated with
culture as per USP guidelines and incubated
for 15-18 hours at 37°C. 2% of agar powder
was added to the nutrient broth to prepare agar
media. Agar plates were prepared and wells
were made in it for solvent, standard drug and
for different concentrations (200 µg/ ml and
150 µg/ ml) of synthesized compounds. These
were incubated at 37°C and zone of inhibition
in cm was recorded after 12 hours. The
experiments were performed in triplicate and
average of the data is recorded in table 1 and
synthesis of cyclized and reduced diazonium
compounds is shown in Figure 2.
Table 1: Activity Profile of Synthesized Compounds.
Drug code Zone of inhibition in cm
E.coli B. cerius S.aureus P. putida
Standard drug 2.5 3.0 2.5 2.0
E5 0.4 2.1 1 Inactive
C5 1.1 Inactive 0.8 Inactive
G5 Inactive 1.9 Inactive 1.8
H2 3.0 2.8 1.9 2.2
D2 Inactive Inactive Inactive Inactive
F2 Inactive 2 .0 Inactive 1.7
C2 0.3 2.5 Inactive Inactive
G2 2.1 Inactive 1.2 2.2
E2 Inactive Inactive Inactive Inactive
C3 Inactive 1.2 1.9 Inactive
H3 2.5 0.6 Inactive 1.1
C1 Inactive Inactive Inactive Inactive
D1 Inactive 1.5 Inactive Inactive
F1 Inactive 2.5 Inactive 1.8
G1 Inactive Inactive Inactive 1.6
E1 0.2 1.9 0.8 -
Synthesis and Anti-Bacterial Activity Profile Jain et al.
RRJoDDD (2014) 4-12 © STM Journals 2014. All Rights Reserved Page 7
Fig. 2: Reaction Scheme Showing Synthesis of Cyclized and Reduced Diazonium Compounds.
Table 2: Yield and Melting Points (in degrees celcius) of Synthesized Compounds.
S. No 1 2 3 4 5 6 7 8
R H 2-OCH3 3-Cl 4-Cl 4-CH3 3-CH3 4-OCH3 3-OCH3
D %Y 95 96 64 60 15 5 47 5
MP 180 215 200 180 187 - 178 -
E %Y 91 97 17 5 80 43 25 95
MP 120 132 170 5 148 152 121 153
F %Y 92 97 26 67 72.5 5 60 5
MP 142 101 160 162 77 - 65 -
G %Y 90 15 62.5 22.3 57 70 5 82.7
MP 127 123 - 110 98 85 - -
H %Y 75 92 95 51 72 94.8 90 92
MP 120 160 180 - 120 120 178 151
Research & Reviews: A Journal of Drug Design & Discovery
Volume 1, Issue 1
RRJoDDD (2014) 4-12 © STM Journals 2014. All Rights Reserved Page 8
RESULTS AND DISCUSSION All compounds synthesized were characterized
using melting point, infrared, 1H-NMR and
mass spectroscopy.The yield and melting point
of all the compounds is reported in table 2.
D1:5-Methyl-4-(phenyl-hydrazono)-2,4-
dihydro-pyrazole-3-one:
IR data: 3400-3600 cm-1
(N-H stretching),
2900-3100 cm-1
(Aromatic C-H stretching),
1650-1690 cm-1
(C=O stretching), 1600-1700
cm-1
(C=N stretching), 1580-1450 cm-1
(C=C
stretching) NMR: 0.9δ (CH3), 6.2-7.0δ5
(Aromatic protons), 5.6 δ (N-H protons),
m/z:201.31
D2:4-[(2-methoxy-phenyl)-hydrazono]5-
methyl-2,4-dihydro-pyrazole-3-one:
IR data: 3400-3600 cm-1
(N-H stretching),
2900-3100 cm-1
(Aromatic C-H stretching),
2818 (C-H stretching of CH3), 1650-1690 cm-
1 (C=O stretching), 1600-1700 cm
-1 (C=N
stretching), 1580-1450 cm-1
(C=C stretching),
1150 cm-1 (C-O stretching), m/z:232.13
NMR: 0.9δ (CH3), 6.3-6.5 δ (Aromatic
protons), 6 δ (N-H protons), 3.73δ (OCH3)
D3:4-[3-Chloro-phenyl)-hydrazono]5-
methyl-2,4-dihydro-pyrazole-3-one:
IR data: 3380-3400 cm-1
(N-H stretching),
2950-3120 cm-1
(Aromatic C-H stretching),
1650-1690 cm-1
(C=O stretching), 1600-1700
cm-1
(C=N stretching), 1580-1450 cm-1
(C=C
stretching) NMR: 0.9 δ (CH3), 6.3-6.7 δ
(aromatic protons), 6δ (N-H protons), m/z
236.08
D4:4-[4-Chloro-phenyl)-hydrazono]5-
methyl-2,4-dihydro-pyrazole-3-one:
IR data: 3380-3400 cm-1
(N-H stretching),
2950-3120 cm-1
(Aromatic C-H stretching),
1650-1690 cm-1
(C=O stretching), 1600-1700
cm-1
(C=N stretching), 1580-1450 cm-1
(C=C
stretching) NMR: 0.9δ (CH3), 6.4-7.2 δ
(aromatic protons), 6.2 δ (N-H protons), m/z
236.08
D5:4-[4-methyl-phenyl)-hydrazono]5-
methyl-2,4-dihydro-pyrazole-3-one: IR data: 3380-3400 cm
-1 (N-H stretching),
2950-3120 cm-1
(Aromatic C-H stretching),
2750 cm-1
(C-H stretching), 1650-1690 cm-1
(C=O stretching), 1600-1700 cm-1
(C=N
stretching), 1580-1450 cm-1
(C=C stretching)
NMR:0.9 δ (CH3), 2.34 δ (CH3 of phenyl),
6.3-6.8δ (aromatic protons), 6δ (N-H protons),
m/z 216.13
D6:4-[3-Chloro-pheny)l-hydrazono]5-
methyl-2,4-dihydro-pyrazole-3-one:
IR data: 3380-3400 cm-1
(N-H stretching),
2950-3120 cm-1
(Aromatic C-H stretching),
1650-1690 cm-1
(C=O stretching), 1600-1700
cm-1
(C=N stretching), 1580-1450 cm-1
(C=C
stretching) NMR: 0.9δ (CH3), 2.34 δ (CH3 of
phenyl), 6.2-6.8δ (aromatic protons), 6 δ (N-H
protons)
D7:4-[4-methoxy-pheny)l-hydrazono]5-
methyl-2,4-dihydro-pyrazole-3-one:
IR data: : 3400-3600 cm-1
(N-H stretching),
2900-3100 cm-1
(Aromatic C-H stretching),
2818 (C-H stretching of CH3), 1650-1690 cm-
1 (C=O stretching), 1600-1700 cm
-1 (C=N
stretching), 1580-1450 cm-1
(C=C stretching),
1150 cm-1 (C-O stretching) NMR: 0.9δ
(CH3), 3.78 δ (OCH3 of phenyl), 6.2-6.8δ
(aromatic protons), 6δ (N-H protons),
m/z:232.13
D8:4-[3-methoxy-pheny)l-hydrazono]5-
methyl-2,4-dihydro-pyrazole-3-one:
IR data: : 3400-3600 cm-1
(N-H stretching),
2900-3100 cm-1
(Aromatic C-H stretching),
2818 (C-H stretching of CH3), 1650-1690 cm-
1 (C=O stretching), 1600-1700 cm
-1 (C=N
stretching), 1580-1450 cm-1
(C=C stretching),
1150 cm-1 (C-O stretching) NMR: 0.9 δ
(CH3), 3.75δ (OCH3 of phenyl), 6.2-6.8δ
(aromatic protons), 5.6 δ (N-H protons),
m/z:232.13
E1: 5-methyl-2-phenyl-4[phenyl-
hydrazono]- 2,4-dihydro-pyrazole-3-one:
IR data: 3458 cm-1
(N-H stretching), 2900-
3100 cm-1
(Aromatic C-H stretching), 1670-
1690 cm-1
(C=O stretching), 1600-1700 cm-1
(C=N stretching), 1580-1450 cm-1
(C=C
stretching). NMR: 0.9δ (CH3 protons)6.2-6.8,
7.0-7.3 δ (Aromatic protons), 6.8δ (NH)
E2:4[(2-methoxy-phenyl)-hydrazono]- 5-
methyl-2-phenyl-2,4-dihydro-pyrazole-3-
one:
IR data: 3345 cm-1
(N-H stretching), 2900-
3100 cm-1
(Aromatic C-H stretching), 1670-
1690 cm-1
(C=O stretching), 1600-1700 cm-1
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RRJoDDD (2014) 4-12 © STM Journals 2014. All Rights Reserved Page 9
(C=N stretching), 1565-1450 cm-1
(C=C
stretching), 1150 cm-1
(C-O stretching) NMR:
0.9 δ (CH3 protons), 3.73δ (OCH3), 6.2-6.5,
7.0-7.6δ (Aromatic protons), 6.9δ (NH),
m/z=308.13
E3:4-[3-chloro-phenyl)-hydrazono]-5-
methyl-2-phenyl-2,4-dihydro-pyrazole-3-
one:
IR data: 3455 cm-1
(N-H stretching), 2930-
3120 cm-1
(Aromatic C-H stretching), 1670-
1690 cm-1
(C=O stretching), 1600-1700 cm-1
(C=N stretching), 1565-1450 cm-1
(C=C
stretching), NMR: 0.9δ (CH3 protons), 6.2-
6.5, 7.0-7.6δ (Aromatic protons), 7.0δ (NH),
m/z=312.08
E4:4-[(4-chloro-phenyl)-hydrazono]- 5-
methyl-2-phenyl-2,4-dihydro-pyrazole-3-
one:
IR data: 3455 cm-1
(N-H stretching), 2930-
3120 cm-1
(Aromatic C-H stretching), 1670-
1690 cm-1
(C=O stretching), 1600-1700 cm-1
(C=N stretching), 1565-1450 cm-1
(C=C
stretching) NMR: 0.9 δ (CH3 protons), 3.73δ
(OCH3),6.2-6.5, 7.0-7.6 δ (Aromatic protons),
6.8δ (NH), m/z=312.08
E5: 5-methyl-2-phenyl-4[p-tolyl-
hydrazono]-2, 4-dihydro-pyrazole-3-one:
IR data: 3425 cm-1
(N-H stretching), 2930-
3320 cm-1
(Aromatic C-H stretching), 1670-
1690 cm-1
(C=O stretching), 1600-1700 cm-1
(C=N stretching), 1565-1450 cm-1
(C=C
stretching), 2850 cm-
(C-H stretching) NMR:
0.9, 2.35δ (CH3 protons), 6.3-6.81, 7.0-7.64δ
(Aromatic protons), 6.8δ (NH), m/z=292.13
E6:5-methyl-2-phenyl-4[m-tolyl-
hydrazono]-2,4-dihydro-pyrazole-3-one:
IR data: 3425 cm-1
(N-H stretching), 2930-
3320 cm-1
(Aromatic C-H stretching), 1670-
1690 cm-1
(C=O stretching), 1600-1700 cm-1
(C=N stretching), 1565-1450 cm-1
(C=C
stretching), 2850 cm-
(C-H stretching) NMR:
0.9,2.35δ (CH3 protons)6.2-6.8, 7.0-7. δ3
(Aromatic protons), 6.8δ (NH), m/z=292.13
E7:4[(4-methoxy-phenyl)-hydrazono]-5-
methyl-2-phenyl-2,4-dihydro-pyrazole-3-
one:
IR data: 3345 cm-1
(N-H stretching), 2900-
3100 cm-1
(Aromatic C-H stretching), 1670-
1690 cm-1
(C=O stretching), 1600-1700 cm-1
(C=N stretching), 1565-1450 cm-1
(C=C
stretching), 1150 cm-1
(C-O stretching) NMR:
0.9δ (CH3 protons), 3.73 δ (OCH3),6.2-6.5,
7.0-7.6δ (Aromatic protons), 6.8 δ (NH),
m/z=308.13
E8:4[(3-methoxy-phenyl)-hydrazono]-5-
methyl-2-phenyl-2,4-dihydro-pyrazole-3-
one:
IR data: 3345 cm-1
(N-H stretching), 2900-
3100 cm-1
(Aromatic C-H stretching), 1670-
1690 cm-1
(C=O stretching), 1600-1700 cm-1
(C=N stretching), 1565-1450 cm-1
(C=C
stretching), 1150 cm-1
(C-O stretching) NMR:
0.9δ (CH3 protons), 3.73δ (OCH3),6.2-6.5,
7.0-7.6δ (Aromatic protons), 6.84δ (NH),
m/z=308.13
F1:6-methyl-5(phenyl-hydrazono)-5-H-
pyridine-2, 4-dione:
IR data: 3424 cm-1 (N-H stretching), 3052
cm-1 (Aromatic C-H stretching), 2800- 2900
cm-1 (aliphatic C-H stretching), 1688, 1676
cm-1 (C=O stretching), 1592 cm-
1, 1565 cm-
1,
1481 cm-1 (C=N, C=C stretching), 1284 cm-
1
(N-N=C stretching) NMR: 0.9δ (CH3), 7, 10 δ
(NH protons), 6.4-7.01δ (Aromatic protons),
m/z=230.22
F2:5[(2-methoxy-phenyl)-hydrazono]-6-
methyl-5-H-pyridine-2, 4-dione:
IR data: 3424 cm-1 (N-H stretching), 3052
cm-1 (Aromatic C-H stretching), 2800- 2900
cm-1 (aliphatic C-H stretching), 1688, 1676
cm-1 (C=O stretching), 1592 cm-
1, 1565 cm-
1,
1481 cm-1 (C=N, C=C stretching), 1284 cm-
1
(N-N=C stretching), 1243 cm-1
(C-O
stretching) NMR: 0.9 (CH3), 7, 10(NH
protons), 6.3-6.51 (Aromatic protons), 3.5
(methoxy protons), m/z=260.09
F3:5[(3-chloro-phenyl)-hydrazono]-6-
methyl-5-H-pyridine-2, 4-dione:
IR data: 3345 cm-1 (N-H stretching), 3153 cm-
1 (Aromatic C-H stretching), 2800- 2900 cm-
1
(aliphatic C-H stretching), 1688, 1676 cm-1
(C=O stretching), 1592 cm-1, 1565 cm-
1, 1481
cm-1 (C=N, C=C stretching), 1284 cm-
1 (N-
N=C stretching) NMR: 0.9δ (CH3), 7.1, 10.2δ
(NH protons), 6.3-6.6 δ (Aromatic protons),
m/z=264.04
Research & Reviews: A Journal of Drug Design & Discovery
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F4:5[(4-chloro-phenyl)-hydrazono]-6-
methyl-5-H-pyridine-2, 4-dione:
IR data: 3345 cm-1 (N-H stretching), 3153 cm-
1 (Aromatic C-H stretching), 2800- 2900 cm-
1
(aliphatic C-H stretching), 1688, 1676 cm-1
(C=O stretching), 1592 cm-1, 1565 cm-
1, 1481
cm-1 (C=N, C=C stretching), 1284 cm-
1 (N-
N=C stretching) NMR: 0.9δ (CH3), 7, 10 δ
(NH protons), 6.3-6.6δ (Aromatic protons),
m/z=264.04
F5:6-methyl-5-(p-tolyl-hydrazano)-5-H-
pyridine-2, 4-dione:
IR data: 3347 cm-1 (N-H stretching), 3157 cm-
1 (Aromatic C-H stretching), 2800- 2900 cm-
1
(aliphatic C-H stretching), 1688, 1676 cm-1
(C=O stretching), 1592 cm-1, 1565 cm-
1, 1481
cm-1 (C=N, C=C stretching), 1284 cm-
1 (N-
N=C stretching) NMR: 0.9, 2.3δ (CH3), 7, 10
δ (NH protons), 6.3-6.6δ (Aromatic protons),
m/z=244.10
F6:6-methyl-5-(m-tolyl-hydrazano)-5-H-
pyridine-2, 4-dione:
IR data: 3347 cm-1 (N-H stretching), 3157 cm-
1 (Aromatic C-H stretching), 2800- 2900 cm-
1
(aliphatic C-H stretching), 1688, 1676 cm-1
(C=O stretching), 1592 cm-1, 1565 cm-
1, 1481
cm-1 (C=N, C=C stretching), 1284 cm-
1 (N-
N=C stretching) NMR: 0.9, 2.3δ (CH3), 7, 10
δ (NH protons), 6.3-6.6δ (Aromatic protons),
m/z=244.10
F7:5[(4-methoxy-phenyl)-hydrazono]-6-
methyl-5-H-pyridine-2, 4-dione:
IR data: 3424 cm-1 (N-H stretching), 3052
cm-1 (Aromatic C-H stretching), 2800- 2900
cm-1 (aliphatic C-H stretching), 1688, 1676
cm-1 (C=O stretching), 1592 cm-
1, 1565 cm-
1,
1481 cm-1 (C=N, C=C stretching), 1284 cm-
1
(N-N=C stretching), 1243 cm-1
(C-O
stretching) NMR: 0.9δ (CH3), 7, 10 δ (NH
protons), 6.3-6.51δ (Aromatic protons), 3.5δ
(methoxy protons), m/z=260.09
F8:5[(3-methoxy-phenyl)-hydrazono]-6-
methyl-5-H-pyridine-2, 4-dione:
IR data: 3424 cm-1 (N-H stretching), 3052
cm-1 (Aromatic C-H stretching), 2800- 2900
cm-1 (aliphatic C-H stretching), 1688, 1676
cm-1 (C=O stretching), 1592 cm-
1, 1565 cm-
1,
1481 cm-1 (C=N, C=C stretching), 1284 cm-
1
(N-N=C stretching), 1243 cm-1
(C-O
stretching) NMR: 0.9δ (CH3), 7, 10δ (NH
protons), 6.3-6.51δ (Aromatic protons), 3.5δ
(methoxy protons), m/z=260.09
G1:4-methyl-3(-phenyl-hydrazono)-1,3-
dihydro-benzo-1,4-diazepin-2-one:
IR data: 3400-3600 cm-1
(N-H stretching),
2900-3100 cm-1
(Aromatic C-H stretching),
2818 (C-H stretching of CH3), 1650-1690 cm-
1 (C=O stretching), 1600-1700 cm
-1 (C=N
stretching), 1580-1450 cm-1
(C=C stretching)
NMR: 0.9δ (CH3), 3.1δ (CH2), 4, 7δ (NH
protons), 6.4-7.01δ (Aromatic protons),
m/z=264.14
G2:3[(2-methoxy-phenyl)-hydrazono]-4-
methyl-,3-dihydro-benzo-1,4-diazepin-2-
one:
IR data: 3400-3600 cm-1
(N-H stretching),
2900-3100 cm-1
(Aromatic C-H stretching),
2818 (C-H stretching of CH3), 1650-1690 cm-
1 (C=O stretching), 1600-1700 cm
-1 (C=N
stretching), 1580-1450 cm-1
(C=C stretching),
1280 cm-1
(C-O stretching) NMR: 0.9δ (CH3),
3,2 δ (CH2), 3.9δ (methoxy protons), 4, 7δ
(NH protons), 6.4-7.6δ (Aromatic protons),
m/z=308.13
G3:3[(3-chloro-phenyl)-hydrazono]-4-
methyl-,3-dihydro-benzo-1,4-diazepin-2-
one:
IR data: 3424 cm-1 (N-H stretching), 3052
cm-1 (Aromatic C-H stretching), 2800- 2900
cm-1 (aliphatic C-H stretching), 1688, 1676
cm-1 (C=O stretching), 1592 cm-
1, 1565 cm-
1,
1481 cm-1 (C=N, C=C stretching), 1284 cm-
1
(N-N=C stretching) NMR: 0.9δ (CH3), 3,2 δ
(CH2), 3.9 δ (methoxy protons), 4, 7 δ (NH
protons), 6.4-8δ (Aromatic protons),
m/z=312.08
G4:3[(4-chloro-phenyl)-hydrazono]-4-
methyl-,3-dihydro-benzo-1,4-diazepin-2-
one:
IR data: 3424 cm-1 (N-H stretching), 3052
cm-1 (Aromatic C-H stretching), 2800- 2900
cm-1 (aliphatic C-H stretching), 1688, 1676
cm-1 (C=O stretching), 1592 cm-
1, 1565 cm-
1,
1481 cm-1 (C=N, C=C stretching), 1284 cm-
1
(N-N=C stretching) NMR: 0.9δ (CH3), 3,2δ
(CH2), 3.9δ (methoxy protons), 4, 7 δ (NH
Synthesis and Anti-Bacterial Activity Profile Jain et al.
RRJoDDD (2014) 4-12 © STM Journals 2014. All Rights Reserved Page 11
protons), 6.4-8δ (Aromatic protons),
m/z=312.08
G5:4-methyl-3(-p-tolyl-hydrazono)-1,3-
dihydro-benzo-1,4-diazepin-2-one:
IR data: 3345 cm-1 (N-H stretching), 3153 cm-
1 (Aromatic C-H stretching), 2800- 2900 cm-
1
(aliphatic C-H stretching), 1688, 1676 cm-1
(C=O stretching), 1592 cm-1, 1565 cm-
1, 1481
cm-1 (C=N, C=C stretching), 1284 cm-
1 (N-
N=C stretching) NMR: 0.9 , 2.35 δ (CH3),
3.2δ (CH2), 3.9 δ (methoxy protons), 4, 8δ
(NH protons), 6.4-7.6 δ (Aromatic protons),
m/z=292.13
G6:4-methyl-3(-m-tolyl-hydrazono)-1,3-
dihydro-benzo-1,4-diazepin-2-one:
IR data: 3345 cm-1 (N-H stretching), 3153 cm-
1 (Aromatic C-H stretching), 2800- 2900 cm-
1
(aliphatic C-H stretching), 1688, 1676 cm-1
(C=O stretching), 1592 cm-1, 1565 cm-
1, 1481
cm-1 (C=N, C=C stretching), 1284 cm-
1 (N-
N=C stretching) NMR: 0.9 , 2.35δ (CH3), 3.2δ
(CH2), 3.9δ (methoxy protons), 3.8, 7.5 δ
(NH protons), 6.4-7.6δ (Aromatic protons),
m/z=292.13
G7:3[(4-methoxy-phenyl)-hydrazono]-4-
methyl-,3-dihydro-benzo-1,4-diazepin-2-
one: IR data: 3400-3600 cm-1
(N-H
stretching), 2900-3100 cm-1
(Aromatic C-H
stretching), 2818 (C-H stretching of CH3),
1650-1690 cm-1
(C=O stretching), 1600-1700
cm-1
(C=N stretching), 1580-1450 cm-1
(C=C
stretching), 1280 cm-1
(C-O stretching) NMR:
0.9δ (CH3), 3,2δ (CH2), 3.9δ (methoxy
protons), 4, 8δ (NH protons), 6.4-7.6δ
(Aromatic protons), m/z=308.13
G8:3[(3-methoxy-phenyl)-hydrazono]-4-
methyl-,3-dihydro-benzo-1,4-diazepin-2-
one:
IR data: 3400-3600 cm-1
(N-H stretching),
2900-3100 cm-1
(Aromatic C-H stretching),
2818 (C-H stretching of CH3), 1650-1690 cm-
1 (C=O stretching), 1600-1700 cm
-1 (C=N
stretching), 1580-1450 cm-1
(C=C stretching),
1280 cm-1
(C-O stretching) NMR :0.9δ (CH3),
3.2δ (CH2), 3.9δ (methoxy protons), 4, 8 δ
(NH protons), 6.4-7.5δ (Aromatic protons),
m/z=308.13
H1:phenyl hydrazine:
IR data: 3000-3100 cm-1
(aromatic C-H
stretching), 3400-3500cm-1
(N-H stretching),
NMR: 2,4 δ (NH2, NH proton), 6.6-7.18δ
(Aromatic protons), m/z : 108.07
H2:2-methoxy phenyl hydrazine:
IR data: 3000-3100 cm-1
(aromatic C-H
stretching), 3400-3500cm-1
(N-H stretching),
2856 cm-1
(C-H stretching of methoxy), 1150
cm-1
(C-O stretching) NMR: 2,4 δ (NH2, NH
proton), 3.5 δ (methoxy protons), 6.8-7.38δ
(Aromatic protons), m/z : 138.08
H3:3-chloro-phenyl hydrazine:
IR data: 3000-3240 cm-1
(aromatic C-H
stretching), 3380-3500cm-1
(N-H stretching)
NMR: 2.3,4.1 δ (NH2, NH proton), 6.6-7.18δ
(Aromatic protons), m/z : 142.03
H4:4- chloro-phenyl hydrazine:
IR data: 3000-3240 cm-1
(aromatic C-H
stretching), 3380-3500cm-1
(N-H stretching)
NMR: 2.3,4.1 δ (NH2, NH proton), 6.6-7.18δ
(Aromatic protons), m/z : 142.03
H5:4-methyl-phenyl hydrazine:
IR data: 3000-3100 cm-1
(aromatic C-H
stretching), 3400-3500cm-1
(N-H stretching),
2856 cm-1
(C-H stretching of methyl)
NMR: 2.6,4 δ (NH2, NH proton), 2.35 δ
(methyl protons), 6.7-7.58δ (Aromatic
protons), m/z : 122.17
H6:3- methyl-phenyl hydrazine:
IR data: 3000-3100 cm-1
(aromatic C-H
stretching), 3400-3500cm-1
(N-H stretching),
2856 cm-1
(C-H stretching of methyl)
NMR: 2,4 δ (NH2, NH proton), 2.35 δ
(methyl protons), 6.6-7.18δ (Aromatic
protons), m/z : 122.17
H7:4-methoxy phenyl hydrazine:
IR data: 3000-3100 cm-1
(aromatic C-H
stretching), 3400-3500cm-1
(N-H stretching),
2856 cm-1
(C-H stretching of methoxy), 1150
cm-1
(C-O stretching)
NMR: 2,4 δ (NH2, NH proton), 3.5 δ
(methoxy protons), 6.6-7.18δ (Aromatic
protons), m/z : 138.08
H8: 3-methoxy phenyl hydrazine:
IR data: 3000-3100 cm-1
(aromatic C-H
stretching), 3400-3500cm-1
(N-H stretching),
Research & Reviews: A Journal of Drug Design & Discovery
Volume 1, Issue 1
RRJoDDD (2014) 4-12 © STM Journals 2014. All Rights Reserved Page 12
2856 cm-1
(C-H stretching of methoxy), 1150
cm-1
(C-O stretching)
NMR: 2,4 δ (NH2, NH proton), 3.5 δ
(methoxy protons), 6.6-7.18δ (Aromatic
protons), m/z : 138.08
CONCLUSION Various cyclized diazonium compounds were
synthesized possessing different heterocyclic
ring systems in good yield. The well plate
method for antibacterial activity showed
significant reduction in bacterial growth in
terms of zone of inhibition around the well.
Chloramphenicol and tetracycline were used
as standard drugs for the comparison. It was
observed that phenyl group bearing no
substituent, was inactive against E.coli and S.
aureus. Benzodiazepine derivatives and
reduced compounds displayed comparable
activity to standard against all tested strains of
micro-organisms.
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RRJoDDD (2014)© STM Journals 2014. All Rights Reserved
Research & Reviews: A Journal of Drug Design & Discovery
Volume 1, Issue 1
www.stmjournals.com
Targeting Cancer through Angiogenesis Inhibition:
Prospective of Azole Based Small Molecules
Pratap Chandra Acharya* Department of Pharmaceutical Chemistry, SPPSPTM, SVKM'S
NMIMS University, Mumbai, India
Abstract Anticancer drug discovery is a major focus area in the pharmaceutical industry and obtaining targeted drug molecules for the malignant tissue is a major hurdle in this
process. With the advancement in the knowledge of biological targets, cancer specific
molecules such as monoclonal antibodies have been designed and produced in the recent past. However, the cost and effectiveness of these special products are the biggest
challenges for cancer treatment. Small molecules are considered as the best
chemotherapeutic intervention to treat cancer at the present time. This article describes the possibility of azole based small molecules as inhibitor of tumor angiogenesis, which
can be explored for anticancer drug discovery.
Keywords: Angiogenesis, Anticancer Drugs, Monoclonal Antibodies, Azoles, Small
Molecules, HUVEC Assay