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RELEVANCE OF 1,3-DIPOLAR CYCLOADDITION REACTIONS AND RETROSYNTHETIC ANALYSIS IN THE DESIGNING OF NOVEL ANTIFUNGAL AGENTS

RELEVANCE OF 1,3-DIPOLAR CYCLOADDITION REACTIONS AND RETROSYNTHETIC ANALYSIS IN THE DESIGNING OF NOVEL ANTIFUNGAL AGENTS

Presented By: Joydeep GangulyCourse Name: B.Pharm 4th year( 7th semester)Roll Number: 27701913036Guided 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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Content:Introduction A Review on the 1,3-Dipolar Cycloaddition ReactionsDesigning New Antifungal Agent via 1,3- Dipolar Cycloaddition Reactions A Review on the PyrrolnitrinsRetrosynthetic Analysis For Determining The Synthetic Route of Pyrrolnitrin Discussion, Concluding Remarks and Future Prospects References2

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. 3

Table 1: Drug Class Structure NATAMYCIN Polyenes FLUCONAZOLE Azoles CASPOFUNGIIN Echinocadins

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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)5

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 derivativesPyrazole derivatives1,2,3-triazole derivatives 1,2,4-triazole derivatives6

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. 7

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. 8

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 birds 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). 9

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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Contd:

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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). 12

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. 13

References: Katzung Bertram J and Trevor Anthony J; Basic and Clinical Pharmacology; McGraw Hill Education India Pvt. Ltd., 13th Edition, pp825,2015 Calderone Richard et al; Antifungal Drug Discovery: The Process and Outcomes; Future Microbiol, vol.9 (6), pp-791-805, 2014. 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 Sriram D and Yogeeswari P; Medicinal Chemistry, Pearson Education in South Asia, 2nd Edition, pp- 495-497, 2013. 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. 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.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.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.

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