научная статья по теме SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF NEW HETEROCYCLIC COMPOUNDS CONTAINING THIENO[3,2-C]COUMARIN AND PYRAZOLO[4,3-C]COUMARIN FRAMEWORKS Химия

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF NEW HETEROCYCLIC COMPOUNDS CONTAINING THIENO[3,2-c]COUMARIN AND PYRAZOLO[4,3-c]COUMARIN FRAMEWORKS

© 2013 Adel M. Kamal El-Dean, Remon M. Zaki#, Ahmed A. Geies, Shaban M. Radwan, Mahmoud S. Tolba

Chemistry Department, Faculty of Science, Assiut University, Assiut, 71516 Egypt Received November 21, 2012; in final form, February 26, 2013

Reaction of 4-chlorocoumarin-3-carbonitrile with ethyl thioglycolate and ethyl glycinate hydrochloride leads to a series of title products. Hydrazinolysis of amino thienocoumarin carboxylate afforded the hydrazi-no derivative which underwent various reactions to build new heterocyclic rings containing thienocoumarin moiety. Chloro acetylation of aminoester compound afforded the chloro acetyl amino which underwent nu-cleophilic substitution reactions various amines. The following treatment with formaldehyde under Mannich conditions afforded the corresponding imidazo derivatives. Reaction of chloroacetylamino with potassium thiocyanate yielded ethylpyrimidothieno coumarin sulfanylacetate which was used as a versatile precursor for synthesis of other heterocycles. On the other hand, reaction of chloro coumarin carbonitrile with hydrazine gave the aminopyrazolocoumaine which reacted with bifunctionally compounds to give the substituted py-rimido derivatives. Diazotization and coupling of aminopyrazole with ethylcyanoacetate yielded ethylami-notriazinopyrazolocoumarine carboxylate. Several of the compounds obtained demonstrated considerable antifungal and antibacterial activity in the in vitro test systems.

Keywords: thienocoumarine, pyrazolocoumarine, pyrimidothienocoumarine, imidazo thienocoumarine, synthesis, anti-microbial activity

DOI: 10.7868/S0132342313040088

INTRODUCTION RESULTS AND DISCUSSION

Coumarins contain the parent nucleus of benzo(-py-rone) and occur in plants of Orchidaceae and Legumi-naceae families [1]. Naturally occurring and synthetic coumarins display important pharmacological properties, such as antitumor [2], anticonvulsant [3], anti-inflammatory [4, 10], anti-HIV [5], anticoagulant [6], antibacterial [7] and antioxidant [8, 9] activities. Among the diverse activities of coumarin the effect against breast cancer seems to draw special attention [11—13]. Cou-marins are also used to prepare other chemicals, in particular rodent poisons, such as warfarin or insecticides such as hymecromone. Their anti-inflammatory properties are usually associated with the capability of modulating the inflammatory cells [14].

The main representatives of the class are the hy-droxyl derivatives, 4- and 7-hydroxy coumarins, also biologically active and very important for the synthesis of other coumarin derivatives. Bearing in mind the above benefits of coumarin derivatives, in this work we aimed to build a heterocyclic ring on coumarin starting from the commercially available 4-hydroxycou-marin and hoping that the new products described below are biologically useful.

# Corresponding author (e-mail: remonch2003@yahoo.com).

Reaction of 4-hydroxycoumarin (I) with HCONMe2: POCl3 mixture in chloroform under Vils-meier—Haack reaction conditions afforded chloro-coumarin carboxaldehyde (II) [15]. Aldehyde (II) was condensed with hydroxyl-amine hydrochloride in re-fluxing ethanol in the presence of fused sodium acetate

to give the corresponding oxime (III). The latter compound was dehydrated using POCl3 to afford 4-chloro-2H-coumarin-3-carbonitrile (IV) (Schemel).

OH Cl

XHO

POCl3

DMF/CHCl3

O

O

oX

(I)

(II)

NH2OH ■ HCl/AcONa EtOH

Cl

Cl

N H

O "O

(IV)

Scheme 1

O O (III)

Chlorocarbonitrile (IV) was reacted with ethyl thioglycolate in ethanolic sodium ethoxide to afford ethyl aminothienocoumarincarboxylate (V). Reaction of amino ester (V) with hydrazine under neat conditions afforded the corresponding carbohy-drazide (VI). On the other hand, chlorocarbonitrile

(V) was reacted with ethyl glycinate hydrochloride in DMF in the presence of K2CO3 to afford glycinate derivative (VII), which cyclized in ethanolic sodium ethoxide solution to ethyl 3-amino-4-oxo-1,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate (VIII) (Scheme 2).

O

(IV)

CO2CH2CH3

■nh2

O "O (V)

HClH2NCH2CO2Et DMF/K2CO3/70°C

NHCH2CO2Et N

O O (VII)

NH2NH2 ■ H2O EtOH

CONHNH2 NH2

OO

(VI)

EtOH/EtONa

CO2CH2CH3

NH2

OO

(VIII)

Scheme 2

Thienochromenecarbohydrazide (VI) was considered as precursor of other heterocyclic compounds. Condensation of carbohydrazide (VI) with acetyl acetone in ethanol afforded pyrazolyl derivative (IX). Condensation of carbohydrazide (VI) with aromatic

aldehyde to gave the corresponding hydrazone (X). which was cyclized using triethyl orthoformate in eth-anol in the presence of catalytic drops of acetic acid to give pyrimidothienochromene (XI). Carbohydrazide (VI) was also reacted with triethyl orthoformate in ethanol in the presence of catalytic drops of acetic acid to give pyrimidothienocoumarine (XII). Also, carbohy-drazide (VI) was converted to the corresponding car-boazide (XIII) using sodium nitrite solution in acetic acid. The product underwent Curtius rearrangement

upon boiling in an inert solvent (dry xylene) to afford imidazothienocoumarine (XIV) (Scheme 3).

Aminothienochromene (V) was reacted with chlo-roacetyl chloride in dioxane at 70°C to afford the corresponding chloroacetyl amino derivative (XV). The latter underwent nucleophilic substitution reaction with aromatic amines to give arylaminoacetyl derivatives (XVIa—f). Treatment of compounds (XVIa,b) with formaldehyde under Mannich conditions afforded 1,3-diaminourea compounds (XVIIa,b). Reaction of chloroacetyl derivative (XV) with potassium thiocy-anate in ethanol lead to pyrimidothienolcou-marinysulfanylacetate (XVIII) in one step [16] (Scheme 4).

O N^Ar

Scheme 3

XVIa, R1 = Ph, R2 = H

O (XVI)

^O

O

O

N

U

N.

OO (XVIIa,b)

XVIb, R1 = C6H4CH3-p, R2 = H

XVIc, R1, R2 = piperidinyl

XVId, R1, R2 = morpholinyl

XVIe, R1, R2 = piperazinyl

XVIf, R1 = C6H4SO2NH2-p, R2 = H

XVIg, R1 = C6H4SO2NH-diazine-p, R2 = H

XVIIa R = H XVIIb R = CH

R

3

Scheme 4

BHOOPrAHOTECKAH XHMH3 tom 39 № 5 2013

8*

O

A

N

NH

OO (XVIII)

OEt

O

Scheme 5

The putative intermediates on the route to pyrimi-dothienocoumarin (XVIII), are showen in scheme 5.

The ethyl thioacetate compound ester (XVIII) was used as versatile precursor for synthesis of other py-rimidothienocoumarine derivatives (XIX—XXI). Hy-drazinolysis of ester (XVIII) with hydrazine under neat conditions afforded the corresponding carbohydrazide derivative (XIX). Reaction of carbohydrazide (XIX) with acetyl acetone in ethanol gave the dimethylpyra-zolyl derivative (XX), while reaction with bezaldehyde in presence of piperidine as a basic catalyst afforded the corresponding Schiffs base (XXI) (Scheme 6).

Reaction of chlorocoumarinecarbonitrile (IV) with hydrazine in ethanol afforded the aminopyrazolocou-marine (XXII) which was used as a starting material for synthesis of other heterocyclic compounds. Thus, condensation of (XXII) with bifunctional compounds namely: acetyl acetone, ethyl cyanoacetate, diethyl malonate, ethyl acetoacetate and ethyl benzoylacetate in acetic acid afforded the corresponding pyrimido derivatives (XXIII)-(XXIV) (Scheme 7).

Reaction of aminopyrazolocoumarine (XXII) with ethyl-2-cyano-3-ethoxyacrylate afforded ethylcyano-dihydropyrazolocoumarinylaminoacrylate (XXVIII). Refluxing ethyl acrylate ester with acetic acid yielded ethylaminopyrimidopyrazolocoumarine carboxylate (XXIX). In this case the pyrazole NH acted as a nu-cleophile and attack carbonitrile group.That step was

followed by tautomerisation, rather than loss of ethanol molecule which would afford oxopyrimidocoumarine carbonitrile (XXX). Diazotization of amino group in compound (XXII) with sodium nitrite solution in conc HCl afforded the diazonium salt (XXXI) which was coupled (in situ) with ethyl cyanoacetate and ethyl acetoacetate in presence of sodiumacetat giving rise to ethylaminotriazinooyrazolocoumarine-carboxylate (XXXII) andethylbutanoate compounds (XXXIII) respectively (Scheme 8).

Chemical structure and homogeneity of all products obtained was confirmed by IR and NMR spectroscopy, mass-spectrometry and elemental microanalysis.

Biological Activities

Some of the synthesized compounds in this work screened in vitro for their antimicrobial activity against some strains of bacteria and fungi by technique described in [17]. 2% concentration of selected compounds in DMSO was used in all cases. The inhibition zone (mm) compared with clortrimazole as a refer-ence.in the case of antifungal tests and with chloramphenicol in case of antibacterial tests.

Some tested compounds showed remarkable antibacterial and anti fungal activities. In case of anti-fungal activity (Table 1) aminothienocoumarinecarboxy-

O

O

OO (XVIII)

J—NH \

O

nn

OH2NMH2 neat

OO

(XIX)

NH

A

N NH2

O

PhCHO/piperidine EtOH

f H

O O (XXI)

O

Scheme 6

O

Cl

(IV)

Ph

N-"

H

O O (XXVII)

OO

(XXIV)

OO

(XXVI)

Scheme 7

ii) CH3COCH2CO2Et/CH3CO2Na/

EtOH / ^Nji) NCCH2CO2Et/CH3CO2Na

/ EtOH

H

N-N

Scheme 8

late (V) is effective only Candida albicans and Scopu-lariopsis, while replacement of the ester group with carbohydrazide group in compound (VI) considerably broadens the spectrum of activity and leads to highly active product. The glycinate derivative (VII) is also quite active. The cyclized compound (VIII) shows low activity, as well as compounds (XV, XVIb, XVId, XVIe, XVIf, XVIg). Somewhat unexpectedly compound (XVIa) shows high activity, comparable to that of (VI) and (VII). Replacement of the thieno ring in compound (V) by pyrazole ring leads to active derivative (XXXII); compound (XXIV) is active only against Candida albicans and Geotrichum candidum.

As for the antibacterial activity, compounds (XVIa, XVIb, XVIe and XXXII) showed no anti-bacterial activity against all bacterial species (Table 2). Almost all of the remaining samples were activ

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