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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

    2

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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.

    3

    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/Nitrogen
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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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    6

    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_medication
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    Mechanism of Action

    8

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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