Synthesis and Insilico Biological Activity of Some Pyrazolines Derived From Inh

8/7/2019 Synthesis and Insilico Biological Activity of Some Pyrazolines Derived From Inh

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SYNTHESIS AND INSILICO BIOLOGICAL ACTIVITY OF SOME

PYRAZOLINES DERIVED FROM INH

INTRODUCTION

The discipline of medicinal chemistry is devoted to the discovery and development

of new agents for treating diseases. Most of this activity is directed to new rational

and synthetic organic compounds.

Inorganic compounds continue to be important in therapy. For example trace

elements in nutritional therapy, antacids and radiopharmaceuticals. But organic

molecules with increasing specific pharmacological activities are clearly dominant.

Hundreds of thousands of new organic chemicals are prepared annually

throughout the world and many of these enter into pharmacological screening to

determine whether they have useful biological activity. This process of random

screening had been considered inefficient, but it has resulted in identification of new

lead compounds whose structures have been optimized to produce clinical agents.


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Chalcones

Chalcones are a group of natural products characterized by the presence of a 1,3-

diphenyl prop-2-ene-1-one skeleton. The radical quenching properties of the

phenolics groups present in many of the naturally occurring chalcones have raised

interest for using chalcones containing plant extracts as drugs or food preservatives.

Chalcones exists as either E or Z- isomers. The E-isomer is in most cases the

thermodynamically most stable form and consequently, the majority of chalcones are

isolated as E-isomer. The general, recrystallization of an E-Z mixture yields E-isomer

as the only stereoisomer. It has been previously reported that the , double bond is

very liable for photoisomerization in solution, giving a mixture of E- and Z- isomers.

The rate of isomerisation and the equilibrium ratio depend on the substitution in the

aromatic rings and the solvent used. Electron donating groups and the chelating

properties of substituents in the 2nd position have a significant influence on degree of

isomerisation. But, it is almost impossible to predict which chalcones are prone to

photoisomerisation and to what extent.

It has been anticipated that the two steroisomers are equipotent but no proof

has been published. If the E- and Z- isomers are equipotent the interpretation of the

biological data should be straight forward, since the degree of isomerisation would be

without effect on the activity of the compounds. On the contrary, if there is a marked

difference between the activity of E- and Z- forms the observed activity is the


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combination of the intrinsic activity as well as photolability of the active isomer. As

isomerisation can be extremely fast (within seconds) the biological evaluation of

compounds can be quite complicated.

Pyrazolines

The chemistry of organic heterocyclic compounds has been an interesting field

of study for a long time. The synthesis of novel pyrazoline derivatives and

investigation of their chemical and biological behavior have gained more importance in

recent decades for biological, medicinal and agricultural reasons. Living organisms

find difficulty in construction on N-N bonds which limits the natural abundance of

compounds having such bonds.

Pyrazolines and their derivatives, a class of compounds containing the N-N

bond exhibit a wide range of biological activities such as antimicrobial, parasiticidal,

bactericidal, anti-inflammatory, antidiabetic, antirheumatic, anticancer, anti-HIV and

antiallergic activites. In addition to this, many pyrazoline derivatives are active

against many mycobacterias.

After the pioneering work of Fischer and Knovenagel in the late 19th century,

the reaction of , -unsaturated aldebydes and ketones with hydrazines and

hydrazine derivatives became one of the most popular methods for the preparation of

2-pyrazolines.

LITERATURE SURVEY

Literature survey reveals that both chalcones and pyrazolines are associated with a

wide range of biological and pharmacological activities. It has been established that

chalcones posses antibacterial, antihelmentic, amoebicidal, antiulcer, antimitotic

effects and immunosupperessive activity including inhibition of lipoxugenase,

cycloxygenase and interleukin biosynthesis. Traditionally chalcone rich plant extracts

were used as food preservatives. In the recent past, chalcone were reported to exhibit

pronounced antimutagenic, anticancer, antitubercular and antimalarial activities.More over chalcones have therapeutic value due to their cholerectic, diuretic,

vasodilatory and pharmacological activities. The fact that chalcones are potent

modifiers of xenobiotic metabolizing activities including microsomal epoxide hydrolase,

cytosolic epoxide hydrolase, arylhydrocarbon hydroxylase and glutathione transferase,

as well as of other pharmacologically important enzymes including DOPA-

decarboxylase, may in part explain their toxic and therapeutic activities. Chalcones


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also possess some synthetic applications, especially in the field of heterocyclics. Upon

reaction with chemical reagents containing one or two heteroatoms, chalcones yields

variety of heterocyclic compounds such as pyrazoles, isoxazoles, pyrimidines,

thiazines etc. Pyrazolines are an interesting group of compounds, many of which

possess wide spread pharmacological properties such as analgesic, antipyretic and

antireheumatic properties. In the recent years, heterocyclic nitrogen derivativesexhibited a general ionophoric potency for divalent cations and are used as novel

thiocyanate seclective membrance sensors.

Due to the interesting activity of variously substituted pyrazolines as biological

agents considerable attention has been focused on this class. The pharamaceutical

importance of these compounds lies in the fact that they can be effectively utilized as

antibacterial, antifungal, antiviral, antiparasitic, antitubercular and insecticidal

agents.

Abd El-galil El-sayed Amr et al reported the synthesis of some new testosterone

derivatives fused with substituted pyrazoline ring as promising 5 - reductaseinhibitiors.

Shahar yar.M., et al reported the synthesis and antimycobacterial activity of novel

pyrazolines.

Davood Azarifar et al reported the synthesis and antimicrobial activity of new 3, 5

dinaphthyl substituted 2- pyrazolines.

Lyidogan .P. et al reported synthesis and anticonvulsant activity of novel pyrazolines.

Nada. M. Abunada et al reported synthesis and biological activity of some new

pyrazolines.


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3. AIMS AND OBJECTIVES OF PRESENT WORK

The antimicrobial agents currently available in the market have side effects vary

in incidence and severity with patients, such as

i. Gastrointestinal disordersii. Anemiaiii. Liver damageiv. Neurological disorderv. Hypersensitivity reactionsvi. Visual disturbancesvii. Dermatological disordersviii. Thrombophlebitisix. Pruritus and Utricariax. Headache, Dizziness and Insomnia

Therefore, numerous attempts have been made to produce new compounds withimproved properties and least possible side effects.

The objective of the present work is

y To develop new, potent and safe antimicrobial compounds.y To attempt a very simple and facile procedures for the synthesis of the title

compounds.

y To purify the intermediates and final compounds by appropriaterecrystallization and chromatographic techniques.

y To characterize all the compounds by physical and analytical data.y To identify the lead and optimize by means of QSAR studies.

The present work is the synthesis and biological evaluation of some five membered

heterocyclic compounds with nitrogen as possible antimicrobial.

In view of the proven potentiality of chalcones and pyrazolines, it has been felt

worthwhile to get them incorporated with antitubercular agent INH by molecular

conjunction method.

In the present investigation, antitubercular agent INH has been incorporated

with another antibacterial pharmacophore such as chalcones by appropriate synthetic

routes with a view to develop them as possible antimicrobial.

4. EXPERIMENTAL PART

Melting points were determined in open capillaries and were uncorrected.

IR spectra were recorded in KBr disc method on SHIMADZU FT-IR

spectrometer.


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NMR spectra were taken on 400MHz BRUKER spectrophotometer using TMS as

internal standard and the solvents used was D2O, CDCI3 deuteriated DMSO and

deuteriated DMF.

Mass spectra were obtained on APEX mass spectrometer using direct insertion

probe method.

Thin layer chromatography was performed on precoated silica gel strips and

spots were visualized by uv radiation using uv radiation chamber.

Special chemicals like aromatic aldehydes, ketones, INH were procured from

OTTO KEMI, SISCO RESEARCH LAB, LOBA CHEMI, S.D.FINE CHEM.

The solvents for chromatography and recrystallization were used after

distillation.

Experimental part has been divided into two parts

4.1 Synthetic methodology

4.2 Evaluation of antimicrobial

4.1 Synthetic methodology:

General planning:

In the present scheme aromatic aldehydes and ketones has been chosen as

starting materials. Chalcones known for nearly a century are extremely versatilecompounds. They carry two electrophilic centres and easily reacts with nuclephile.

Hence, they are widely used in the synthesis of various heterocyclic compounds.


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Different aromatic aldehydes and ketones with specific reactivity and effect on

synthesized compounds have been used. They are as follows

Aromatic aldehydes

Romatic ketones

The formation of intermediates and final products were monitored by TLC on

precoated silica gel plates. The products of each step show significant color under uv

light. All the compounds prepared were purified by recrystallization with suitable

solvents.

Structures of the synthesized compounds have been characterized andconfirmed by IR, NMR and mass spectroscopic techniques, Biological screening for

antitubercular, antifungal activities and antibacterial activities has been done invitro

by paper-disc method.

In the present work, entire scheme has been divided into two steps.


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Step 1

Preparation ofChalcones

A mixture of the given aromatic aldehyde (0.01 M), Ketone (0.01 M) in rectified

spirit (30ml), aqueous potassium hydroxide (15gm in 15ml) was stirred for 3hrs at 15-

200C. Filtered and washed the residue with ice cold water until the washings were

neutral to litmus. Dried and again washed with ice cold rectified spirit (20ml). the

obtained chalcone was used in step-2 without further purification.

Step 2

Preparation of Pyrazolines

To a solution of chalcone (1 millimolar) and INH (500 mg) in rectified spirit

(20ml), pyridine(0.3ml) was added as a catalyst. The mixture was refluxed for 4-6 hrs

and the solvent is evaporated completely. The reaction mixture was poured into

crushed ice. The resulting precipitate was recrystallized from suitable solvent.


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The formation of intermediates and final products were monitored by TLC on

precoated silica gel plates. The products of each step show significant color under uv

light. All the compounds prepared were purified by recrystallization with suitable

solvents.

Structures of

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Synthesis and Insilico Biological Activity of Some Pyrazolines Derived From Inh