научная статья по теме SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF NOVEL BENZO[F]COUMARIN COMPOUNDS Химия

EHOOPrÄHH^ECRAaXHMH3, 2012, moM 38, № 6, c. 721-728

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF NOVEL BENZO[F]COUMARIN COMPOUNDS

© 2012 Remon M. Zaki#, Yasser A. Elossaily, and Adel M. Kamal El-Dean

Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt Received November 17, 2011; in final form, January 18, 2012

The acetyl benzo[f]coumarin condensed with phenyl hydrazine to afford the corresponding phenyl hydrazone which cyclized into the pyrazolyl benzocoumarin under Vilsmeier reaction conditions. The pyrazolyla-ldehyde was used as starting material for synthesis of other heterocyclic compounds containing pyrazolylben-zocoumarin moiety. The ethyl benzo[f]coumarin carboxylate were subjected to react with other reagents to synthesize thiazolidinyl and oxadiazolyl derivatives attached to benzocoumarin system. Some of novel synthesized compounds showed highly antibacterial and antifungal activities.

Keywords: acetylbenzo[f]coumarin, pyrazolylbenzocoumarin, bromoacetylbenzo[f] chromenone, synthesis, antimicrobial activity.

INTRODUCTION

Natural and synthetic coumarins have been found to exhibit a variety of pharmacological activities like anti-HIV [1], anticoagulant [2], antibacterial [3], antioxidant [4], and anti inflammatory [5]. Among the diverse biological activities of coumarin the most intriguing bioactivity is the effect against breast cancer [6—10]. Figure shows the chemical structures of some potent anti-breast cancer molecules that contain a coumarin in their molecular makeup and in this regard it is worth mentioning that 667 COUMATE is in phase1 clinical trials for the treatment of hormone dependent breast cancer in postmenopausal women [11]. In continuation of our work on naphtholaldehyde which was used as versatile starting materials for synthesis of many heterocyclic compounds containing naphtha[2,1-^]furan moiety with anti-microbial activity. Here in we synthesized a series of novel benzo-coumarin compounds with high biological activity [12, 13].

RESULTS AND DISCUSSION

Coumarins are widely available from the natural sources [14—16] and exhibit various biological activities such as anticancer [17], inhibition of platelet aggregation [18, 19], inhibition of steroid 5a-reductase [20] and anti-HIV activity [21]. Acetylbenzo[f]cou-marin (I) which synthesized from commercially available starting material and according to the literature procedure was used as a precursor starting material for synthesis other heterocyclic compounds containing chromene moiety. Compound (I) condensed with

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

phenyl hydrazine in refluxing ethanol in the presence of catalytic drops of acetic acid to afford corresponding phenyl hydrazone (II). When compound (II) subjected to react with Vilsmeier's reagent was cyclized into pyrazolylbenzocoumarin (III). Formation of car-boxaldehyde (III) was identified using spectral analyses. IR spectrum showed two bands at 1720, 1680 cm-1 for (2C=O). 1H-NMR (CDCl3) showed two signals at 8.6, 10.1 for CH-pyrazole, and CHO. Mass spectrum of aldehydes (III) showed a peak at m/z = 366 corresponding to molecular ion peak and base peak. When pyrazolylaldehyde derivative (III) was condensed with thiosemicarbazide in acetic acid afforded the corresponding thiosemicarbazone (IV), IR of compound (IV) showed bands at 3450, 3390, 3350 cm-1 (NH, NH2). Thiosemicarbazone (IV) was cyclized with a-halogenated compounds, namely, ethyl chloroace-tate, chloroacetone or «-bromoacetophenone in ethanol in the presence of sodium acetate to afford thiaz-olylpyrazolylbenzocoumarins (V) and (VI). Compound (I) undergoes cycloaddition reaction on arylidene malononitrile in ethanol in the presence of catalytic amount of piperidine to afford 2-amino-6-(2-oxo-benzof]chromen-3-yl)-4-phenyl-4H-pyran-3-carbonitrile (VII) (Scheme 1). The formation of compound (VII) was supported using elemental and spectral analyses. IR of compound (VIIa) showed absorption bands at 1720 cm-1 for one carbonyl group in addition to bands at 3480, 3380 cm-1 for NH2 group and at 2220 cm-1 for CN group. 1H-NMR spectrum showed signals at 6: 4.6 (1 H, s, H4 pyran, 5.7 (1 H, s, H5 pyran), 7-8.7 (m, 12 H, Ar-H) , 8.8 (1 H s, CH-coumarin).

Neo Tanshinlactone

,O

Et

1st Generation Neo Tanshinlactone analogue

HO ^ O O

SP500263

Figure.

O ii

-S-

H2N ii O'

O

O O

667 COUMATE

DNH-2

h2n

CN

Ar Ar-CH=C(CN)2

(VII)

O O

(Vila), Ar = Ph (VlIb), Ar = C6H4OCH3p

Ph

H

"O N' (IV) S

h2nnhcsnh2

.NH AcOH

NNHPh

Ph

O O

CHO

(III)

ClCH2CO2Et EtOH/AcONa

H

O "O N ^f V^O (VI) S

Ph

N-N

O "O N ^f V^R (V)

(Va), R = Ph (Vb), R = Me

Scheme 1.

When aldehyde (III) allowed to react with hydroxyl tained. The produced pyrazolaldehyde oxime (VIII) amine hydrochloride in ethanol in the presence of so- was dehydrated into corresponding pyrazole carboni-dium acetate, the corresponding oxime (VIII) was ob- trile derivative (IX) by heating with acetic anhydride.

Compound (III) reacts with cyanothioacetamide in etha-nol in the presence of piperidine to give 2-amino-6-mer-capto-4-[3-(2-oxo-benzo [f] chromen- 2-yl)-1-phe-nyl-1H-pyrazol-4-yl]-pyridine-3,5-dicarbonitrile (X). Struc-

ture of compound (X) was elucidated from elemental and spectral analyses. IR ofcompound (X) showed appearance ofnew absorption bands at 3410, 3310 cm-1 (NH2), and at 2220 cm-1 (2 CN) group (Scheme 2).

N-N

Ph

N-OH

Ph

O O

(X)

Scheme 2.

Bromination of acetylbenzo[f]coumarin (I) using NBS in CHCl3 afforded bromoacetyl derivative (XI), which react with mercaptopyridine carbonitrile in ethanol in the presence of sodium acetate to afford compound (XII). The latter compound underwent cy-

clization in ethanol in the presence of potassium carbonate to give compound (XIII). Compound (XIII) can be synthesized directely from (XI) by refluxing with mercaptopyridine carbonitrile in ethanol in the presence of potassium carbonate (Scheme 3).

CH2Br

NCW

(XIII)

O (XII)

Scheme 3.

On the other hand ethyl 2-oxo-benzo[f]coumarin-3-carboxylate (XIV) was reacted with hydrazine hydrate in ethanol to afford 2-oxo-benzo[f]coumarin-3-carbohydrazide (XV). The latter compound was reacted with carbon disulfide in the mixture of dioxan/am-

monium hydroxide to produce the corresponding ammonium dithiocarbamate (XVI). Dithiocarbamate salt (XVI) was cyclized using sodium chloroacetate solution followed by treatment with dilute HCl to give thi-azolidinone derivative (XVII).

Treatment of carbohydrazide (XV) in acetic acid with sodium nitrite solution at 0—5°C affording the coumarin carboazide derivative (XVIII). Carboazide (XVIII) underwent Curtius rearrangement when refluxed in different alcohol to give carbamate esters of coumarin (XIV).

On the other hand carbohydrazide (XV) was reacted with carbon disulfide in pyridine on steam

bath to give 3-(5-mercapto[1,3,4]oxadiazol-2-yl)-benzo[f]chro-men-2-one (XX) in good yield. Compound (XX) in turn was reacted with phenacyl bromide in ethanol in the presence of sodium acetate to afford 3-(5-benzoylmethylmercapto[1,3,4]oxa-diazol-2-yl)-benzo[f] chromen-2-one (XXI) (Scheme 4).

1-ClCH2CO2Na/H2O H S2-HCl

O "O (XVII)

H

n^ ^snh4

N-'"Y

S

O O

NH2NH2 ■ H2O/EtOH

(XIV)

H

Y R

, , O O O

(XIX)

(XIXa), R = Et (XIXb), R = -CH(CH3)2

CS2

Dioxan/NH4OH

O

NH

O O (XVIII)

Scheme 4.

2

CS2/pyridine

N-N

SH

O O

(XX)

PhCOCH2Br/AcONa EtOH

N~N

I 3— SCH2COPh O

O O (XXI)

Biological activities:

Some of the synthesized compounds in this work were chosen and screened in vitro for their antimicrobial activity against some strains of bacteria and fungi.

The antifungal, antibacterial activities of tested compounds were evaluated by the reported method [22] using 2% concentration of selected compounds in DMSO as a solvent. The inhibition zone (mm) compared with Clotrimazole as a reference. In the case of antibacterial the concentration of tested compound is also 2% and the inhibition zone in mm were compared with chloramphenicol as a reference.

Some tested compounds showed remarkable antibacterial and antifungal activities. In case of anti-fungal activity (Table 1) we find that pyrazolylcarboxal-dehyde (III), which has no effect against all fungi species use except Fusarium oxysporum, when the carboxaldehyde group replaced with thiosemicarba-zone group in compound (IV), show activity against all tested species. When thiosemicarbazone group cy-clized into thiazole ring in compound (V&), (Vb), (VI) we noticed that the activity was increased, when pyra-zole ring in compound (III) replaced with pyran ring

in compound (VIIa), (VIIb) the activity diminished to zero against most of fungi species tested. While the maximum inhibition for all species growth was exhibited by pyrazolyloxime (VIII) which shows highly anti-fungal activity against Geotrichum candidum and Candida albicans, whereas the aldehydic group in compound (III) was converted into oxime. Also compound (IX) shows moderate activity towards all of the tested species. Replacing the pyrazole ring in compounds (VIII), (IX) by oxadiazole ring in compounds (XX), (XXI) showed no anti-fungal activity against most of tested fungi species as in case of pyran compounds (VIIa), (VIIb).

On the other hand, we noticed that all tested compounds showed remarkable activity against all bacterial species except in case of phenylthiazole compound (V&) which showed low activity against Serratia marce-scens and Bacillus cereus (Table 2). For example, the pyrazolylcarboxyaldehyde showed moderate activity against all the tested bacteria species except against Escherichia coli which showed high activity. The thiosemicarbazone (IV) and methyl thiazole (Vb) showed activity against all tested species. The thiazolone compound (VI) exhibited remarkable activity especially

Table 1. Antifungal activity (Inhibition Zone mm)

Compd. Geotrichum Candida Aspergillus Scopulairopsis Trichophyton Fusarium

candidum albicans flavus brevicaulis rubrum oxysporum

(III)

Для дальнейшего прочтения статьи необходимо приобрести полный текст. Статьи высылаются в формате PDF на указанную при оплате почту. Время доставки составляет менее 10 минут. Стоимость одной статьи — 150 рублей.