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| A Convenient Synthesis of Substituted Dihydropyridine Derivative and its Bioevaluation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paper Id :
17625 Submission Date :
21/04/2023 Acceptance Date :
30/04/2023 Publication Date :
05/05/2023
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| Abstract | Pyridine is a nitrogen containing six membered heterocyclic compounds which is found in many important organic compounds. Pyridine is also used as solvents to dissolve many substances. Nitrogen containing heterocyclic compounds are very common in some existing drugs like Isoniazid, Pyrazinamide etc hence, play important role in the treatment many infectious diseases. 1,4 dihydropyridine is reduced form of pyridine and very actively involved in therapeutic agents. It is a multifunctional compounds and capable of producing different substituted derivatives. 1,4 Dihydropyridine derivative was synthesized by an efficient method of three component reaction between an aldehyde, ammonium acetate and beta di keto compound to give substituted 1,4-dihydropyridine compound and evaluated for antimicrobial activity against bacteria and fungi. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Keywords | Dihydropyridine, Ethylene Glycol, Benzaldehyde, Microorganisms, Antimicrobial. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Introduction |
Pyridine is an aromatic heterocyclic compound used as organic solvents. It has very unpleasant odour and due to presence of nitrogen , it is basic in nature. It is used as a raw material in many chemical industries. It is a widely used as antiseptic, in pharmaceutics for making ant freezing compounds, and as a disinfectant. Further its use in dye and paint industries is very common. Pyridines are also used as ligands in preparation of coordination complexes. Agricultural and food industries are using pyridine derivative as insecticidal agents [1-2]. Reduction at the 1 and 4 position of the Pyridine give more active compound i.e. 1-4 dihydropyridine. These are also known to act as neuroprotectants anti-platelet aggregators. They are also very important in the treatment of Alzheimer,s diseases anti-schemic agents [3-6]. It is interesting to note that an enzyme Nicotinamide Adenine Dinucleotide (NADH) is also related to 1, 4 Dihydro-pyridine nucleus. This co-enzyme play very important role in biological system. Several new derivatives of 1, 4-dihydropyridine have been synthesized and evaluated for their biological activities. [7].
Microbiologists work on antibiotics which are the compounds that either kills bacteria or prevent them from multiplying. Emergence of drug resistance is abig problem in the treatment of infectious diseases like tuberculosis and other lung infections like corona. Therefore scientist community is working in the discovery of new antimicrobial agents. Penicillin, streptomycin, macrolides, azithromycin, fluoroquinolones etc are some examples of common antibiotics. These drugs are also associated with side effects and hence, a hybrid substance that works as a semi synthetic antibiotic, wherein a molecular version produced by the microbe is subsequently modified by the chemist to achieve desired properties of drugs with minimum side effects. Dihydropyridines (DHPs) are reported to have bactericidal activity as it target the biosynthesis of enzymes required for microbial growth. These compounds have both antimicrobial and anticancer activities. Therefore Dihydropyridine derivatives are the new class of compounds found to be active against bacteria and fungi. |
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| Aim of study | Dihydropyridine derivatives are known to have prominant activity against many diseases. In this context, the study of its synthesis, characterization and bioevaluation was done to explore the importance of this class of molecules. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Review of Literature | The 1, 4-dihydropyridine nucleus is very common in existing drugs. One of the most common inhibitory activity is that they are calcium channel blockers. Hence, their ability to relax the vascular smooth muscle, thus decrease the vascular resistance make calcium antagonist potentially useful anti-hypertension drugs. The efficacy of calcium channels blockers is enhanced by the concomitant use of β-adrenergic antagonist, ACEs and methyldopa. Diuretics may be enhanced efficacy of calcium channels blockers [8-9]. Calcium channels blockers have been developed to inhibit the movement of calcium across the membrane of myocardial and smooth muscle, block impulse formation and inhibit the conduction velocity and contraction. As a result,1-4 dihydropyridine derivatives have therapeutics effect in angina, arrhythmias, hyper tension and other cardiovascular disorders. Some of the derivatives of pyridine are also used as an antimycobactrial agents e.g. isoniazid that is used in the treatment of tuberculosis. Several new derivatives of 1, 4-dihydropyridine have been produced and pharmacologically evaluated in order to find drugs with better pharmacological properties [10-11]. Among them, those with a substituted phenyl ring in the C4 position of the 1, 4-dihydropyridine rings have been found to be more active against diseases. Dihydropyridines (DHPs) are the feasible heterocyclic ring compounds with different substitutions at several positions. Some 1,4-DHP compounds are reported as antioxidants, antitubercular and drug resistance modifiers [12]. The presence of lipophilic groups in substituted 1,4-dihydropyridines have been reported to have a very good anti-TB activity which makes them an emerging class of antitubercular agents in the area of drug discovery [13]. Substituted 1,4-dihydropyridines have been reported as potent antitubercular agents against Mycobacterium tuberculosisas well as Mycobacterium smegmatis and also possess antimicrobial activity against Bacillussubtilis, E. coli, and Protius vulgaris bacteria [14-15]. Therefore, 1,4 Dihydropyridine derivatives have been synthesized for their pharmacological importance. These are new class of compounds reported to have very potent antibacterial activity against gram-negative bacteria and high antifungal activity against Candida albicans. Such compounds have been investigated for various other bacteria like Staphylococcus epidermis and found to have binding interaction with its protein. Hence, the scientific community found the 1,4 , Dihydropyridine derivatives a new class of compounds as antibacterial and antifungal agents [16-19].
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| Main Text | The
heterocyclic compound 3,5-diacetyl-2,6-di methyl-4-phenyl-1,4- dihydropyridine
was synthesized by three component reaction of benzaldehyde, ammonium acetate
and Acetyl Acetone (beta-diketo compound) in presence of solvent ethylene
glycol , 4A Molecular Sieve, phase transfer catalyst Tetrabutyl ammonim bromide
(TBAB) in quantitative yield. Procedure involves in the magnetically stirred
slurry of 4Ao molecular sieve (1gm) in ethylene glycol (25ml),
acetyl acetone (9.7ml, 94.170mmol) and ammonium acetate (3.63gm, 47.09mmol) was
added at room temperature, the reaction mixture was heated up to 60oC
and continued for 15 min. and followed by addition of benzaldehyde (5ml,
49.18.mmol) and tetra butyl ammonium bromide (TBAB) as a phase transfer
catalyst (700mg) and stirring continued at 65o– 75oC till
the benzaldehyde was disappeared. After 2.5 hrs the reaction was completed. The
reaction mixture was then poured into the cold water and the precipitate
obtained was filtered and dissolved in suitable solvent (chloroform) and
anhydrous sodium sulphate (Na2SO4) was then added to
absorb the moisture and filtered. The crude product as shown in scheme obtained
as coloured oil after evaporation of solvent under reduced pressure and
weighed.
Compound-A Scheme The compound-A
obtained as colored oil had some impurities which was purified by column
chromatography on silica gel column and TLC method was used to monitor the
reaction as well as column of the compound. The compound was characterized on
the basis of elemental analysis and IR spectroscopy and corresponding data was
given in table 1. Table
1. IR Interpretation of compound-A
Yield
- 7.54 gm Antimicrobial
Assay: The agar well
diffusion method was used. One ml of diluted innoculum (105CFU/ml)
of test organism was mixed on the Muller Hinton agar media (for bacteria) and
Sabraud’s agar (for fungus), shaked and pour in sterilized Petri plates. The
wells of 8mm diameter were punched into the agar medium. To each well 200mg/ml
compound was added and allowed to diffuse, each compound was tested against
each organism in triplicate set. The plate were then incubated aerobically 37oC
for the bacteria stains for 24 hrs and at 27oC for fungi for 72 hrs. The
antimicrobial activities were then tested for each compound and recorded as
diameter of the zone inhibited in mm by our test compound-A. Results obtained
against the above bacteria and fungi are discussed in the Results and
Discussions. Antimicrobial activity against the bacteria: Bacillus cereus,
Staphylococcus aureus, Proteus, E.coli and Antifungal activity
against the fungus: Aspergillus niger, Aspergillus tereus, Penicillium
chrysogenum, Aspergillus japanicus are given in table 2 and table 3. Table
2. The Antibacterial activity of compound-A
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| Result and Discussion | The compound-A
is evaluated for antimicrobial activity. Since pyridine and its
dihydro-pyridine derivatives are well known to show antibacterial activity.
This prompted us to investigate the synthesized compound as possible inhibitor
of pathogenic microorganisms. The compound-A was screened against two gram
positive i.e. Staphylococcus aureus and Proteus mirabilis and
two gram negative bacterial strains i.e. Escherichia coli and Bacillus
cereus. The compound-A was dissolved in DMSO (Dimethyl sulfoxide) and
a concentration of 200 mg/ml was made and added to the petri
plate of each strain. The activity result of compound-A against above mentioned
strains is given above in table 2. The above
activity result shown by synthesized compound-A is very encouraging. Compound-A
was found to have inhibitory activity against gram negative bacteria.
Inhibition zone shown by compound-A, 16 mm, 29mm and 16 mm against Bacillus
cereus, Proteus mirabilis and Escherichia coli respectively.
However no activity is found against Staphylococcus aureus. Further the
synthesised compound-A was also evaluated for antifungal activity. The fungal
strains used as organisms are Aspergillus niger, Aspergillus tereus,
Aspergillus japanicus and Penicillium chrysogenum. The compound was
dissolved in DMSO and 200mg/ml concentration was made and inoculated to the
test organism, after 72 hours a portion of fungal colony was killed by the test
sample and this was appeared as clear zone around the test compound-A. This
zone was measured in mm scale and the result obtained are 15.5mm (Aspergillus
niger), 13mm (Aspergillus tereus), 21mm (Aspergillus japanicus) and
19.3mm (Penicillium chrysogenum) as given below in table 3. Table 3 .The Antifungal activity of compound-A
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| Conclusion | The Dihydropyridine nucleus containing heterocyclic compound-A i.e. (3,5-Diacetyl-2,6-dimethyl-4-phenyl-1,4-Dihydropyridine) was obtained in quantitative yield and it was evaluated for antibacterial and antifungal activity. The maximum inhibition was noticed against the bacterium Proteus mirabilis and better antifungal activity was observed against Aspergillus japanicus. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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