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7/31/2019 JANA RM PPT
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1
byJanardan Sannapaneni
Reg. No 11PHD0074
Research Supervisor:
Dr. Akella SivaramakrishnaOrganic Chemistry DivisionSchool of Advanced Sciences
Synthesis and Biological
Activities of Azole Derivatives
Research Methodology Seminar
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Contents Background
Significance of Azole compounds
Mechanism of Action Reported synthetic routes
Proposed research work
Results and Discussion
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Back ground
An azole is a class of five-membered nitrogenheterocyclicring compounds containing at least one other non-carbonatom of either nitrogen, sulfur, or oxygen.
The parent compounds are aromatic and have two doublebonds
One, and only one, lone pair of electrons from each
heteroatom in the ring is part of the aromatic bonding in anazole.
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http://en.wikipedia.org/wiki/Nitrogenhttp://en.wikipedia.org/wiki/Heterocyclichttp://en.wikipedia.org/wiki/Cyclic_compoundhttp://en.wikipedia.org/wiki/Nitrogenhttp://en.wikipedia.org/wiki/Sulfurhttp://en.wikipedia.org/wiki/Oxygenhttp://en.wikipedia.org/wiki/Aromatichttp://en.wikipedia.org/wiki/Double_bondhttp://en.wikipedia.org/wiki/Double_bondhttp://en.wikipedia.org/wiki/Heteroatomhttp://en.wikipedia.org/wiki/Heteroatomhttp://en.wikipedia.org/wiki/Double_bondhttp://en.wikipedia.org/wiki/Double_bondhttp://en.wikipedia.org/wiki/Aromatichttp://en.wikipedia.org/wiki/Oxygenhttp://en.wikipedia.org/wiki/Sulfurhttp://en.wikipedia.org/wiki/Nitrogenhttp://en.wikipedia.org/wiki/Cyclic_compoundhttp://en.wikipedia.org/wiki/Heterocyclichttp://en.wikipedia.org/wiki/Nitrogen7/31/2019 JANA RM PPT
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Basic Azole rings
4
S
N
Thiazole N
H
N
imidazoleO
N
isoxazole
NH
N
pyrazole
O
N
oxazole
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Azoles
5-(Pyridine-4-yl)-1, 3, 4
-oxadiazole-2-(3H)-thione
5
N
NN
H
O
S
1-aryl-4-(4, 5-dihydro-1H-imidazolo-2-yl)-1H-pyrazoles
N
N
N
NH
Anti amoebic
Anti lesmanial activity
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N
N
N NH
NN
N
F
F
OH
R1
Fluconazole analogue
Anti fungal activity
Y. Yan, S. Yu, X. Chai, H. Hu, and Q. Wu, Arch Pharm Res., Vol
34, No 10, (2011) 1649-1656
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Significance These compounds showing good activities like Antibacterial and
Antifungal, Antiamoebic and anti Lesmanial activities.
Many azoles are used as antifungal drugs, inhibiting the fungalenzyme 14-demethylase which produces ergosterol (an importantcomponent of the fungal plasma membrane).
Antifungals
Clotrimazole
Posaconazole Ravuconazole
Econazole
Ketoconazole
Voriconazole 7
Triazole-based
Fluconazole
Itraconazole
http://en.wikipedia.org/wiki/Antifungal_medicationhttp://en.wikipedia.org/wiki/14%CE%B1-demethylasehttp://en.wikipedia.org/wiki/14%CE%B1-demethylasehttp://en.wikipedia.org/wiki/14%CE%B1-demethylasehttp://en.wikipedia.org/wiki/Ergosterolhttp://en.wikipedia.org/wiki/Ergosterolhttp://en.wikipedia.org/wiki/14%CE%B1-demethylasehttp://en.wikipedia.org/wiki/14%CE%B1-demethylasehttp://en.wikipedia.org/wiki/14%CE%B1-demethylasehttp://en.wikipedia.org/wiki/14%CE%B1-demethylasehttp://en.wikipedia.org/wiki/Antifungal_medication7/31/2019 JANA RM PPT
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Mechanism of Action
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Reported Synthesis
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N
NH
O
NH2
CS2, KOH/H+
, Reflux 10h
N
N N
H
O
S
N
NH
O
NH
S
NHC6H5NCS, C2H5OH, reflux 1h
N
N N
NSH N
NN
SNH
2N NaOH, reflux 2h H2SO4, rt 1h,
1
4
2 3
S. M. Siddiqui, A. Salahuddin, A. Azam., European journal ofMedicinal Chemistry., 49 (2012) 411-416
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Procedure
5-(Pyridine-4-yl)-1, 3, 4-oxadiazole-2-(3H)-thione (1) wassynthesized by the cyclization of isonicotinic acid hydrazideusing carbon disulfide in presence of KOH.
(2), (3) was synthesized through an intermediate compoundnamedN-Phenyl-2-(pyridine-4-ylcarbonyl)hydrazinecarbothiamide (4) which was obtained by the reaction ofisoniazid with phenylisothiocyanate.
The compound (2) was obtained by the cyclization ofcompound 3 in the presence of 2N NaOH and the compound(3) was obtained by the acid catalysed intramoleculardehydrative cyclization of compound(4)
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NH
NH2 . HCl
R
NN
NH2
CN
R
NN
CN
R
NN
N
NH
R
i ii iii
i.Sodiumacetate,ethanal,0.5h reflux
ii.t-butylnitrile THF 2h, reflux
iii.Ethylenediamine, CS212-14h,1100C
5 6 7 8
M. S. D. Santos, M. L. V. Oliveira, A. M. R. Bernardino, R. M. D. Leo,V. F. Amaral, F.T. D. Carvalho, L. L. Leon, M. M. Canto- cavalheiro.,
Bioorganic and Medicinal Chemistry Letters 21 (2001) 7451-7454.
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The synthesis of 1-aryl-4-(4, 5-dihydro-1H-imidazolo-2-yl)-1H-pyrazoles (8) was synthesized by the treatment ofarylhydrazine hydrochlorides (5) reacted withethoxymethylene malononitrile and sodium acetate in ethanol
Reflux the reaction mixture to form 5-amino-1-aryl-1H-pyrazole-4-carbonitriles (6) and the compounds wereconverted to the 1- aryl-1H-pyrazole-4-cabonitriles (7) by theaprotic deamination using t-butyl nitrile and tetrahydrofuran
After refluxing the target molecule can b obtained by thereaction of 1-aryl-1H-pyrazole-4-cabonitriles with carbondisulfide and 1, 2 di amino ethane
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Procedure
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Proposed Synthesis
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O O
+ 2 NH2 NH2
N N
NH2 NH2
NH NH
NH2 NH2
N N
N NNC
NH2 NH2
CN
N N
N N
NH2 NH2
N
NHNH
N
N N
N N
NC CN
i
ii
iii
H2/Metal
Benzil
i.Sodiumacetate,ethanal,0.5h reflux
ii.t-butylnitrile THF 2h, reflux
iii.Ethylenediamine, CS212-14h,1100C
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Results and Discussion
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S.No Time factor(h) Inhibitory action of
the drug (mg)
1 1 0.49
1 0.48
1 0.476
2 2 0.512 0.514
2 0.512
3 3 0.478
3 0.48
3 0.487
The calculated F (34.85532) value is much Smaller than critical F (5.143253)
value so the null hypothesis was rejected. The P value is 0.000497718 so the
test is significant. By observing above calculations the null hypothesis was
rejected i. e there is a huge change in the inhibition action of the drug at
regular intervals of time
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Conclusion
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Thank You All