Retrosynthetic Analysis of Pyrrolnitrin......

1. RELEVANCE OF 1,3-DIPOLAR CYCLOADDITION REACTIONS AND RETROSYNTHETIC
ANALYSIS IN THE DESIGNING OF NOVEL ANTIFUNGAL AGENTS
Presented By: Joydeep Ganguly
Course Name: B.Pharm 4th year( 7th semester)
Roll Number: 27701913036
Guided By: Mr. Angshuman Lahiri M. Pharm, F.I.C.S
Assistant Professor At NSHM KNOWLEDGE CAMPUS
KOLKATA GROUP OF INSTITUTION, 124 B.L.SAHA ROAD
KOLKATA-700053
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2. Content:
Introduction
A Review on the 1,3-Dipolar Cycloaddition Reactions
Designing New Antifungal Agent via 1,3- Dipolar Cycloaddition Reactions
A Review on the Pyrrolnitrins
Retrosynthetic Analysis For Determining The Synthetic Route of Pyrrolnitrin
Discussion, Concluding Remarks and Future Prospects
References
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3. Introduction:
 Human fungal infections have increased dramatically in recent years (Katzung Bertram J
and Trevor Anthony J., 2015). Recent data and relevant supportive information indicate
that fungal infection kills in excess of 13 lakhs of people globally. Mortality caused by
these pathogens now equals the same caused by multiple drug resistant (MDR)
Mycobacterium tuberculosis and exceeds malaria (Calderone Richard et al., 2014). Vast
majority of life-threatening fungal infections are affecting people with altered immune
function.
 The increased incidence of invasive fungal infections can be correlated with an
expansion in the number of people living with conditions or treatments that affect immune
function (Roemer Terry and Krysan Damien J., 2014). The therapeutic options for invasive
fungal infections are quite limited and include only three structural classes of drugs:
polyenes, azoles, and echinocandins. Indeed, there are now more classes of antiretroviral
drugs than antifungals (Katzung Bertram J and Trevor Anthony J., 2015; Roemer Terry
and Krysan Damien J., 2014; Sriram D and Yogeeswari P., 2013). Some of the important
antifungal agents are listed in Table 1.
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4. Table 1:
Drug Class Structure
NATAMYCIN Polyenes
FLUCONAZOLE Azoles
CASPOFUNGIIN Echinocadins
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5. A Review on the 1,3-Dipolar Cycloaddition
Reactions:
 Over the past two decades the pericyclic reactions like electrocyclic addition,
cycloaddition and sigmatropic rearrangement has gained prime importance among
the scientists in relevant field.
There are several types of Cycloaddition reactions like (2+2), (4+2), (1+3) etc.
 Copper catalyzed Azide-Alkyne Cycloaddition (CuAAC) :
Ruthenium catalyzed Azide-Alkyne Cycloaddition (RuAAC)
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6. Designing New Antifungal Agent via 1,3-
Dipolar Cycloaddition Reactions
 Recently, nitrogen-linked heterocyclic compounds have received considerable attention
because of their medicinal importance (Chuan Yu Zhang., Xing Hai Liu., Bao-Lei Wang., Su-
Hua Wang and Zheng-Ming Li., 2010).
Pyrrole derivatives
Pyrazole derivatives
1,2,3-triazole derivatives
1,2,4-triazole derivatives
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7. A Review on the Pyrrolnitrins:
 Pyrrolnitrins, contain two carbon-chlorine bonds, is a bio control agent produced by
several strains of Pseudomonas. This halogenated bacterial metabolite with antifungal
activities serves as an important structure of synthetic fungicides. Several Pyrrolnitrin-
producing bacteria are considered to be promising bio pesticides (Bhanja Chittaranjan and
Jena Satyaban.,2016). The antifungal activity of pyrrolnitrin at first was known to be
effective against superficial infections when evaluated against experimental systemic
mycoses.
 Mode of Action of Pyrrolnitrin: Pyrrolnitrin basically inhibit the oxidation of NADH-
linked substrates in monkey kidney cells, and in rat liver mitochondria (RLMw) and the
oxidation of NADH by submitochondrial particles (SMP) of beef heart.
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8. Contd:
The antibiotic inhibit the reduction of 2, 6-dichlorophenolindophenol
and cytochrome c by NADH and by succinate, but it does not affect the
flavins of NADH dehydrogenase and succinate dehydrogenase.
Pyrrolnitrin probably block the electron transfer between the
dehydrogenases and the cytochrome components of the respiratory
chain.
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9. Retrosynthetic Analysis For Determining
The Synthetic Route of Pyrrolnitrin:
 Few synthetic methodologies for ‘Pyrrolnitrin’ although, were well cited in the
literature, some alternative synthetic routs and improvement in its existing processes
are constantly required in pharmaceutical industries for market development. In
continuation with the current interests in the designing of synthesis of natural products
a good number of synthetic schemes for ‘Pyrrolnitrin’ keeping a bird’s eye on the
works published in current journals. Most of these retrosynthetic schemes have been
derived taking in to account the synthesis earlier done for its preparation as found from
different literatures. The actual laboratory execution requires the cross examination of
a considerable number of factors such as reagents, reactions, order of events,
economical viability, environmental benign, saftyness, short time and scalable
synthesis (Bhanja Chittaranjan and Jena Satyaban., 2016).
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10. Contd:
Four different schemes along with the reactions are discussed in my project but I have
explained only one of those here. The schemes are based on two basic principles of
retrosynthesis:
1. Disconnection
2. Functional Group Interconversion
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11. Contd:
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12. Discussion:
 2-Nitro-3-Chloroacetophenone (13) forms the corresponding oxime and then
oximetosylate (12) on treatment withNH2OH followed by TsCl/Na2CO3. Neber
rearrangement of (12) produces the amino ketone (11). Acid catalyzed condensation
of the amino ketone with ethyl acetoacetate (10) forms the biaryl compound (7) with
the appropriately substituted benzene ring via the intermediate (9). Mannich reaction
of (7) with formaldehyde (6) and a 20 amine forms 5-N, Ndimethyl aminomethyl
derivative (5).The methiodide derivative of (5) on subsequent reduction with NaBH4
affords aryl substituted pyrrole 3-carboxylate (4). Hydrolysis of this ethyl ester with
conc. H2SO4 gives corresponding carboxylic acid (3). Chlorination of (3) with
sulfurylchloride and subsequent hydrolysis offers 3-chloro-4-(3'-chloro-2'-
nitrophenyl)-pyrrole-2, 5-dicarboxylic acid (1). Decarbaxyletion of this dicarboxylic
acid produces Pyrrolnitrin (TM). (Scheme-1).
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13. Concluding Remarks and Future
Prospects
 In this dissertation, clearly, there are two segments.
A review is done on some new synthetic antifungal drug designing with the aid of
Cycloaddition reactions, more specifically, 1,3-dipolar cycloadditions in one segment.
In the other segment , a review is done on the retrosynthetic analysis of pyrrolonitrile which
can provide a well-defined and accurately designed synthetic route for the drug.
As a conclusion, it can be said, that in future, more diversified chemical entities can be
designed by applying DC and Retrosynthetic analysis.
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14. References:
1. Katzung Bertram J and Trevor Anthony J; Basic and Clinical Pharmacology; McGraw Hill Education India
Pvt. Ltd., 13th Edition, pp825,2015
2. Calderone Richard et al; Antifungal Drug Discovery: The Process and Outcomes; Future Microbiol, vol.9
(6), pp-791-805, 2014.
3. Roemer Terry and Krysan Damien J; Antifungal Drug Development: Challenges, Unmet Clinical Needs,
and New Approaches; Cold Spring Harbour Perspective Medicines, vol.4(5), 2014
4. Sriram D and Yogeeswari P; Medicinal Chemistry, Pearson Education in South Asia, 2nd Edition, pp- 495-
497, 2013.
5. Hein Jason E and Fokin Valeri V; Copper Catalyzed Azide-Alkyne Cycloaddition (CuAAC) and Beyond:
New Reactivity of Copper (I) Acetylides; Chemical Society Review, vol. 39(4), pp-1302-1315, 2010.
6. Chuan Yu Zhang., Xing Hai Liu., Bao-Lei Wang., Su-Hua Wang and ZhengMing Li ; Synthesis and
Antifungal Activities of New Pyrazole Derivatives via 1,3-Dipolar Cycloaddition Reactions; Chem Biol
Drug Des, vol. 75, pp- 489-493, 2010.
7. Tornoe C.W., Christensen C and Meldal M; Peptidotriazoles on Solid Phase: [1, 2, 3]-Triazoles by
Regiospecific Copper (I)-Catalyzed 1, 3-Dipolar Cycloadditions of Terminal Alkynes to Azides; The Journal
of Organic Chemistry, vol. 67(9), pp- 3057-3064, 2002.
8. Bhanja Chittaranjan and Jena Satyaban ., Strategic Application of Synthon Disconnection Approach in the
Synthesis Planning of Antifungal Natural Product “Pyrrolnitrin”., Journal of Chemical and Pharmaceutical
Research., vol: 8(4)., pp- 1270-1276., 2016. 14

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