and Antimicrobial Activities of Some

FABAD Farm. Bil. Der.

16, 159-166, 1991

BiLiMSEL ARAŞTIRMALAR 159

FABAD J. Pharm Sci.

16, 159-1661991 Syntlıesis

and Antimicrobial Activities of Some

3-Metlıyl-6-

[2-(N ,N-Disn bstitnted

Tlıiocarbonyltlııo)

Propionyl]-2-Benzoxazolones

Cihat ŞAFAK ı•.

Hakkı ERDOGAN .*l Erhan PALASKA (*) Selma SARAÇ (*) Nuran YULUG (**)

Summary: r.even new 3-methyl-6-{2-{N,N-disubstituted thiocarbonylthio)·

propionyl]-2-benzoxazolone derivatives have been prepared by t/ıe reaction of

3-metlıyl-6-(2-bromopropionyl)-2-benzoxazolinone and substituted potassium dithiocarbamate dcrivatives. Tlıeir structures have been confirmed by UV, JR,

1 H-NMR and microanalysis. Antibacterial and antifungal activities of the compounds against Staphylococcus aureus (ATCC 6538), Streptococcusfaecalis (ATCC 10541), Escherichia cali (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853 ), Candida albicans, C. parapsilosis, C. stellatoidea and C. pseudotropicalis were tested by usingfilter paper disc diffusion agar metlıod. it was observed that there was no inhibition zone around the disc containing 100 and 200 Jlg of the compounds.

Key \YOrds: Dithiocarbamate, benzoxazolone, antimicrobial activity, spectra.

Bazı

3-Metil-6-[2-(N,N-Disübstitue tiyokarboniltiyo) Propiyonil]-2-B enzoksazolonlann Sentez

ve Antimikrobiyal Akti:viteleri

Özet: Onbir yeni 3-metil-6-[2-(N,N-disübstitue tiyokarboniltiyo)propiyonil}- 2-benzoksazolon türevi 3-metil-6-(2-bromopropiyonil)-2-benzoksazolinon ve

sübstiıüe potasyum ditiyokarbamat türevlerinin reaksiyonuyla haztrlanrnış, yapıları

UV, IR, lH-NMR ve mikroanaliz ile kanıtlanmıştır. Bileşiklerin Staphylococcus aureus (ATCC 6538), Streptococcus faecalis (ATCC 10541), Esc/ıerichia cali (ATCC 25922), Pseudomanas aeruginosa (ATCC 27853), Candida albicans, C.

parapsilosis, C. stellatoidea ve C. pseudotropicalis'e karşı antibakteriyel ve antifungal aktiviteleri kağıt disk agar difüzyon metodu kullanılarak incelenmiş, 100 ve 200 Jtg bileşik içeren diskler etrafında inhibisyon zonunun oluşmadığı gözlenmiştir.

Analılar kelimeler: Ditiyokarbamat, benzoksazolon, antimikrobiyal aktivite, spektrum.

Başvuru Tarihi Kabul Tarihi

10.12.1990 2.4.1991

(*) Hacettepe University, Faculty of Phannacy, Dcpartment of Phannaccutical Chcmistıy,

Ankara.

(**) Hacettcpe University, Faculty of Medicine, Departmcnt of Microbiology, Ankara.

160

INTRODUCTION

Carbamodithioic acid esters have va- rious pharmacological activitics such as antibactcrial, antifungal, anliviral, hcr- bicidal, tuberculostatic and anticholi- nergic (1-12). On the othcr hand, some compounds bcaring both bcnzoxazolo- nc and N-monosubstitutcd dithiocarba- mate function in thc sarne molccule have alsa antimicrobial activitics (13).

In this papcr, to examinc thc contri- bution of thc second substilucnts on

dithiocarbaınatc nitrogen to antimicro- bial activity, we synthesized some new bcnzoxazolonc dcrivatives having N,N- disubslilutcd dithiocarbamate structure (Tablc J).

EXPERIMENTAL Chemistry

Ali chemicals were supplied from E.Mcrck (Darmstadt, Germany). Mcl- ting points wcrc dctermincd with a Tho- mas Hoover capillary melting point ap- paratus and uncorrected. UV specıra

wcre determincd with a Shimadzu UV- 160 specırophotometer (MeOH). IR spectra wcre recorded ona Perkin Elmer 457 IR spccırophotomctcr (KBr). lH- NMR spccıra were recorded using Bru- kcr AC 80 MHz instrumcnt using TMS as the intcrnal standard (CDC!3). Ali chcmical shifts were reported as 8 (ppm) values. Microanalyses werc performcd by Perkin Elmcr Model 240C at TUBI- TAK-MAE (Gebze-Tıırkcy).

Synthesis of thc compounds In ordcr to synthesize compounds,

ŞAFAK VE ARK.

potassium salts of dithiocarbamic acids and 3-mcthyl-6-(2-bromopropionyl)-2- bcnzoxazolonc were prcparcd as repor- tcd in the litcrature (14-18). Equimolar amounts of 3-methyl-6-(2- bromopropionyl)-2-benzoxazolonc and corresponding potassium dithiocarba- mate dcrivative wcrc rcl1uxed in metba- nol for two h. Thcn the solulion was evaporated to dryness and thc precipita- tc fonned was washed with watcr and crystallizcd from appropriatc solvcnts.

o

ı-ı-c-s-1H-C ~ ⁿ

^~tr;-CH3

o o

R CH3

Compound H

--- ---

1 -~!(Cf-'3l2

11 ^-N(C₂^H₅ ⁾₂

rn -il (C3H7) 2 ^{( c)}

rn

-<J

" -{)

H3C8

"1

_,

8CH3

\JI I _,,

Vl lI -t<=)-cH 3

HJCV

rx

_,,

H

3C

)

-<J

"

"' ^_,

^{\_./ Q}

TABLE 1: Synthesized 3-meıhyl-6-

[2-(N, N-disubstiıuted thiocarbonylthio)- propionyl)-2-benzoxazolone derivatives.

ŞAFAK VE ARK.

Microbiology

Antlbactcrial and antifungal activitics wcrc dctcnnincd by using filler paper disc diffusion agar mcthod (19) pcrformcd in Mucllcr Hinton agar (Oxoid, Basingstoke, Hants., England), Muellcr Hinton broth (Oxoid), Sabouraud dextrose agar (Oxoid) and Sabouraud dextrose broth (Oxoid). The compounds werc tcstcd against Staphylococcus aureus (ATCC 6538), Streptococcus faecalis (ATCC 10541), Escherichia cali (ATCC 25922), Pscudomonas acruginosa (A TCC 27853), Candida albicans, C.

parapsilosis, C. stellatoidca and C.

pscudotropicalis. All cultures withoul identification nun1bcr of source are from the Hacettepe University, Department of Microbiology.

Thc organism to be tcstcd is grown in broth ovcmight and diluted in broth to contain 106 organisms pcr mi. 12.5 ml of agar mcdium in steril pctri dishcs were inoculaled with 0.2 mi of diluted test microorganisms. At the bcginning of our experiment, filtcr papcr discs (5 mm diameter) saturatcd with dimethylsulfaxide (DMSO) and wcre placed on thc agar. it was observcd that DMSO had no effect on the microorganisms studied and 25 discs could absorb 0.2 mi of DMSO. The compounds wcrc dissolved in DMSO to prepare the solutions of 12.5 and 25 mg/ml, rcspectively. Filler paper discs were saturated with 0.2 mi of each solution, so the discs containing 100 and 200 µg of thc compounds were prcpared. The discs wcrc placed on the inoculated agar and incubated far 24 h at

161

37°C far bacıeria and 48 hat 30°C far Candida species. At lhe cnd of incubation period, thc inhibition zones of around the discs wcre examined.

RESULTS AND DISCUSSION

6-[2-(N ,N-Dimcthy lthiocarbony lthio )- propionyl]-3-mcthyl-2-bcnzoxazolonc (1)

Yield 78%, m.p. 123°C (ethanol-

waıer). UY A.nax: 225 (log E: 4.34), 278 (log E:4.30), 301 nm (log E: 4.26, shouldcr). IR: 2910 (CH, aliphatic), 1775 (C=O, lactam), 1665 (C=O, kcto- ne), 1265 (C=S), 885, 760 cm-1 (1,2,4- trisubs. benzene). IH-NMR: ö 1.37 (3H, d, -CH-Cfu), 3.45 (9H,t, N-CH3,

(CH3)ıN-), 5.80 (lH, q, -CH-), 6.95- 8.20 ppm (3H, m, aromatic protons).

Analysis: Calculatcd far C14H16N2 03S2 C: 51.83, H:4.97, N: 8.63; found C:51.48, H:5.ll, N: 8.28.

6-[2-(N ,N-Dicthylthiocarbony lthio )- propionyl]-3-mcthyl-2-benzoxazolone (Il)

Yield 81 %, m.p. 130°C (elhanol- watcr). UY A.nax: 226 (log E: 4.31), 281 (log E:4.29), 301 nm (log e: 4.26, shoulder). IR: 2970 (CH, aliphalic), 1780 (C=O, lactam), 1665 (C=O, kcto- ne), 1270 (C=S), 890, 765 cm-! (1,2,4- trisubs. benzene). IH-NMR: 8 1.24 (6H, t, (CHı-CH2JıN), 1.78 (3H,d, -CH- Cfü), 3.45 (3H, s, N-CH3), 3.71 (2H,

q, CH3-CH2-N), 4.00 (2H,q, CH3-CJ:!2- N), 5.82 (IH, q, -CH-), 6.90-8.10 ppm (3H, m, aromatic protons). Analysis:

Calculatcd for C 16H 20N203Sz C:

54.52, H:5.72, N: 7.95; found C:51.39, H:S.89, N: 7.59.

6-[2-(N ,N-Dipropy lth iocarbony lthio )- propiony l]-3-meıhy 1-2-bcnzoxazo lone (III)

Yield 68 %, m.p. il 0°C (mcthanol- water). UV A,,,,,: 226 (log r: 4.31), 281 (log r:4.29), 301 nm (log r: 4.26, shouldcr). IR: 3020 (CH, aromatic), 2960, 2920 (CH, aliphaıic), 1765 (C=O, lactam), 1670 (C=O, kctone), 1260 (C=S), 885, 760 em-1 (1,2,4- trisubs. benzene). lJ-1-NMR:

o

^0.69

(6H, t, (CH3-CH2-CH2JıN), 1.21 (3H,t, -CH-Cfu, 1.25-1.56 (4H, m, -,

C.!::!2-CH2JıN), 3.35 (3H, s, N-CH3), 3.79 (4H,t, (CH3-CH2-C.!::!z)zN), 5.85 (lH, q, -CH-), 6.85-8.15 (3H, m, aro- matic protons). Analysis: Calculatcd for C1sH24N201S2 C: 56.82, H: 6.36, N: 7.36; found C:56.86, H:6.60, N:

7.31.

6-[2-(N-Pyrrolidinylthiocarbonylthio)- propionyl]-3-mcthyl-2-bcnzoxazolone (iV)

Yicld 79%, m.p. 167°C (mcthanol- water). UV Aınruc: 225 (log r: 4.29), 277 (log r:4.25), 301 nm (Jog e: 4.20, shoulder). IR: 3050 (CH, aromatic), 2960, 2920, 2850 (CH, aliphatic), 1780 (C=O, Jactam), 1650 (C=O, keto-

ne), 1260 (C=S), 885, 765 cm-1 (1,2,4- trisubs. benzene). lH-NMR:

o

^1.24

(3H, d, (-CH-C.!::!3), 1.63 (8H,t, pyrro- lidine), 3.43 (3H, s, N-CH₃),5.88 (lH, q, -CH-), 6.90-8. 10 ppm (3H, m, aro- matic protons). Analysis: Calculated far C16H1sN201S2 C: 54.84, H:S.18, N: 7.99; found C:54.73, H:5.33, N:

7.78.

6-[2-(N-Piperidiııvlthiocarbonylthio)­

propionyl]-3-mcı lıyl-2-benzoxazolone

(V)

Yicld 68 %, "' ;ı 128°C (mcıha­

nol). UV Aınox:

'.'}'

ı lııg E: 4.33), 282 nm (log e:4.35). 1 R: 3060 (CH, aro- matie), 2920 (CIJ, aliphatic), 1765 (C=O, lactaın), 1665 (C=O, kctone), 1250 (C=S), 890, 745 cm-1 (1,2,4- trisubs. benzene). lH-NMR:

o

^1.20-

2.05 (9H, ın, (-CH-Cfü, pipcridine H3- H5), 3.37 (3H, s, N-CH3), 3.50-4.50 (4H, broad s, pipcridine H2,H6), 5.74 (JH, q, -CH-), 6.90-8.10 ppm (3H, m, aromatic protons). Analysis: Calcula- tcd for C17H20N,O;S2 C: 66.02, H:

5.53, N: 7.69; found C:66.12, H:5.81, N: 7.53.

6-[2-(N-(2-Mcthylpipcridinyl) thio- carbonyllhio)propionyl]- 3-mcthyl-

2-bcnzoxazolonc (Vl)

Yield 75%, m.p. J J8°C (methanol- water). UV Amax: 226 (log E: 4.32), 280 nm (log r:4.32). IR: 3060 (CH, aromatic), 2920 (CH, aliphatic), 1770 (C=O, lactaın), 1670 (C=O, kctone),

'

ŞAFAK VE ARK.

1260 (C=S), 890, 750 cm-1 (1,2,4-

ırisubs. benzene). lJ-1-NMR: 8 1.50 (3H, el, -CH-Cfü), 1.96 (6H,t, pipcridinc W- H5), 3.36 (3H, s, N-CH3), 3.52 (3H,t, piperidine-2-Cl-!3), 3.80 (3H,t, pipcricli- ne .H2,H6 ), 5.74 (IH, q, -CH-), 6.80- 8.05 ppm (3H, m, aromatic protons).

Analysis: Calculated for C1sH22N2 03S2 C: 57.12, H:5.86, N: 7.40; found C:56.79, H:5.99, N: 7.18.

6-[2-(N-(3-Methylpiperidinyl)-lhio- carbonyllhio)propionylJ- 3-methyl- 2-benzoxazolonc (Vll)

Yield 83 %, m.p. 104°C (metlıanol­

water). UV Anıwc: 225 (log e: 4.29), 282 nm (Jog e:4.32). IR: 3060 (CH, aroma- tic), 2920 (CH, aliphatic), 1770 (C=O, lactam), 1670 (C=O, ketonc), 1235 (C=S), 885, 765 cm-1 (1 ,2,4-trisubs.

benzene). lH-NMR: 8 1.20-1.50 (6H, m, -CH-Cfü, piperidinc-3-CH3), 1.96 (5H,t, pipericline H3-H5 ), 3.36 (3H, s, N-CH3), 3.80 (4H,t, piperidinc H2, H6), 5.74 (IH, q, -CH-), 6.80-8.05 ppm (3H, m, aromatic protons).

Analysis: Calculated for C1sH22N2 03S2 C: 57.12, H:5.86, N:7.40; found C:56.87, H:5.91, N: 6.99.

6-[2-(N-( 4-Methy lpipcridinyl)-lhio- carbony lthio )propiony !]-3-mcthy 1-2- bcnzoxazolone (VIll)

Yicld 88 %, m.p. 139°C (mcthanol- water). UV Anıax: 225 (Jog e: 4.31), 281

163

mn (log e:4.34). IR: 3050 (CH, aroma- lic), 2910 (CH, aliphatic), 1780 (C=O,

lactanı), 1660 (C=O, ketone), 1260 (C=S), 880, 760 cm-1 (1,2,4-trisubs.

benzene). lH-NMR: 8 J.20-1.50 (6H, m, -CH-Cfu, piperidinc-4-CH3), 1.96 (5H,t, pipcridine H3-H5 ), 3.36 (3H, s, N-CH3), 3.80 (4H,t, piperidine H2,H6), 5.74 (IH, q, -CH-), 6.80-8.05 ppm (3H, m, aromatic protons). Ana- lysis: Calculatcd for C1sH22N2 03S2 C: 57.12, H:5.86, N: 7.40; found C:57.05, H:5.90, N: 7.46.

6-[2-(N-(2,6-DimethyJp;peridinyl)- thiocarbonyl thio )propionyl]-3- mcthyl-2-benzoxazolone (JX)

Yicld 66 %, m.p. 176°C (metha- nol). UV Arrrnx: 226 (log E: 4.33), 281 nm (log E:4.32). IR: 3060 (CH, aroma- tic), 2970, 2930, 2860 (CH, aliphatic), 1790 (C=O, lactam), 1655 (C=O, kcıo­

nc), 1270 (C=S), 900, 890, 770 cm-1 (1,2,4-trisubs. benzene). l H-NMR: 8 1.12-2.00 (15H, m, -CH-Cfu, piperi- dinc H3-H5, piperidine-2-CH3, 6- CH3), 3.44 (3H, s, N-CH3), 4.80 (1 H,q, pipcridine H2), 5.64 (IH, q,pipcridine H6), 5.80 (IH, q, -CH-), 6.90-8.15 ppm (3H, m, aromatic pro- tons). Analysis: Calculaıcd for C19H24N2 03S2 C: 58.14, H: 6.16, N:

7.13; found C: 57.97, H: 6.13, N:

6.76.

6- [2-(N-(Hexamcthylcneimino)- thiocarbonylthio)propionyl]-3-mcthyl- 2-benzoxazolone (X)

Yield 75 %, m.p. 145°C (metha- nol). UV 11,,,,ax: 225 (log e: 4.32), 281 nm (log e:4.30). IR: 3060 (CH, aroma- tic), 2920, 2850 (CH, aliphatic), 1770 (C=O, lactam), 1660 (C=O, ketone), 1265 (C=S), 935, 890, 760 cm-l (1,2,4- trisubs. benzene). lH-NMR: 8 1.05-

1.~2 (7H, m, -CH-C.!::b, hexamethyle- neimine H4.H5), 1.70-1.85 (4H, m, hexamethylencimine H3,H6), 3.37 (3H, s, N-CH3), 3.89-4.15 (4H, m, hexa- methyleneimine H2,H7l, 5.74 (IH, q, -CH-), 6.90-8.10 ppm (3H, m, aroma- tic protons). Analysis: Calculatcd far

CısH22N2 03S2 C: 57.12, H: 5.86, N:

7.40; found C: 56.81, H: 6.07, N:

7.15.

6-(2-(N-(Morpholinyl) thiocarbonyl- thio )propiony l]-3-methyl-2- benzoxazolone (XI)

l_;'l-4

!'~ ^{-t- L.,,~'} - · · · 7

(~,"

G'J-c-s:J:

'

R

VE ARK.

Yield 79 %, m.p. !63°C (metha- nol-watcr). UV Anı": 225 (log e:

4.29), 286 nm (log e:4.36). JR: 3060 (CH, aromatic), 2960, 2900 (CH, alip- hatic), 1770 (C=O, lactam), 1670 (C=O, ketone), 1260 (C=S), 885, 750 cm-1 (1,2,4-trisubs. benzene). lH- NMR: 8 1.56(3H, d, -CH-Cful, 3.46 (3H, s, N-CH3), 3.72 (4H, t, morpholi- ne H2,H6), 3.75-4.56 (4H, broad d, morpholine H3,H5), 5.80 (IH, q, -CH- ), 6.80-8.10 ppm (3H, m, aromatic protons). Analysis: .Calculated far

Cı~ısN2 04S2 C:52.44, H: 4.95, N:

7.64; found C: 52.49, H: 4.77, N:

7.14.

To synthesize compounds, 3- methyl-6-(2-bromopropionyl)-2- benzoxazolone and N,N-disubstituted dithiocarbarnate derivatives, prcpared by thc reaction of aliphatic or hetero- cyclic amines, carbon disulfıde and po- tassium hydroxide, wcre heated in met- hanol (Scheme 1).

ı

G

N-C-S-CH-C~n~ ^{~ ~ ~N-CH}

³

1 o. o

CH3 R

Scheme 1

--

"

ŞAFAK VE ARK,

All spcctral data are in accordance with litcrature (20-23), in UV spectrn, intcnsivc absorption bands arc sccn at about 225 and 280 nm, in IR spccıra,

C=O strctching bands bclonging to

lactaın and kctone were secn al 1 770 and 1670 cm-t respcctivcly, C=S strctching and C-H bcnding vibraLion bands arc at cxpcctcd frcqucncics, in lH-NMR spectra, protons in structurc wcrc obscrvcd at expcctcd chcmical shifıs and integral valucs, Thc ncighbouring protons to nitrogcn atom in amine portion of compound II wcre secn at ¹

various chemical shift valucs. This situation that wcre not seen in other compounds, could be cxplaincd by

magrıctic anisotropy. The protons in N - C H 3 group ha ve bccn sccn approximatcly at 3,35 ppm, -CH- proton at 5,75 ppm, aromatic protons of

-"nzoxazolone ring at 6,80-8,10 ppm,

"· ıtibacterial and antifungal

activıl·cs of the compounds against Staphylococcus aurcus (ATCC 6538),

Sıreptococcus faccalis (ATCC 10541), Escherichia cali (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Candida albicans, C, parapsilosis, C, stellaıoidea and C, pscudoıropicalis were tested by using

fılı:er papcr disc diffusion agar metlıod, it was observed that there \\'.as no inhibition zonc around the <lise containing 100 and 200 µg of the compounds.

165

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