Indian Journal of Chemi stry VoL 388, March 1999, pp. 343-347

Studies on arylfuran derivatives: Part IX-Synthesis and characterization of some fluorine containing arylfurylvinylquinazolinones as possible antibacterial agentst

B S hi varama Holla " , M K Shivarianda·, Shalini She!lol , P M Akberal{ & G A Naganagowdad

"Department of Chemistry, Mangalore University, Mangal agangotri 574 199. Indi a

bDepartment of Microbiology, Kasturba Medical College, Man galore 575 00 I , India

' Pl ama Laboratories Ltd., 120 Al B, Industrial Area, Baikampady, New Mangalore 575 0 II , India

dDcpartment of Oral Biology, School of Dental Medicine, University at Buffalo , New York 14214-3092, USA

Received 3 August 1998; accepted (revised) 1 February 1999

In v1ew of the biological activities of fluorinated derivati ves, a senes of fluorine containing arylfury lvinyl-quinazolinones 5 have been synthesized . The title compounds have been synthesized by treating 2-methyl-3-(3-chloro-4-fluoro)phenyl-quinazolin-4-one 3 with arylfurfurals 4 in the presence of a base such as piperidine. The required quinazolinone 3, in tum, is obtained by the condensation of 2-methyl-3,I-benzoxazin-4-one 2 with 3-chloro-4-fluoroaniline in the presence of phosphorus oxychloride. The structural elucidations of 5 were carried out on the basis of elemental analysis , IR, NMR and mass spectral data. In the mass spectra of 5, the loss of aryl radical and CO from the molecular ions is observed as a characteristic feature. All the newly synthesized compounds have been screened for their in vitro antibacterial activities against E coli , S aureus , Ps. aeruginosa and B. subtilis. Their minimal inhibitory concentrations (MIC values) are determined. The screening data indicate that the compounds Sa, 5d, 5e and 3 are promising antibacterial agents.

Quinazol in-4-ones and related fused heterocycles are of interest as potential bioactive molecules. They are known to exhib it pharmacological activities such as CNS depressane , neuroleptic 2

, hypoglycemic3,

nonsteroidal 4 and tuberculostatic5. Important

derivati ves of quinazolinones, namely, mecloqualone and methaqualone are being used as hypnotic , sedative and anticonvulsive drugs6

. It was also found

tPresented at the UGC-DRS National Symposium on "Newer Vistas in Synthet ic . Protocols and Structural Elucidation in Chemi stry" held at Madurai KamaraJ University, Madurai during April 22-24 , 1998.

that the incorporation of a side chain at position-2 markedly enhanced the antiinflammatory activity in quinazolinones7

. Besides, many fl uorinated quinazolone derivatives were found to possess significant hypnotic , analgesic , anticonvulsant and antiinflammatory activities8

. Arylfuran-2-carboxal­dehyde derivatives display wide spectrum of biological activities9

•12 such as antibacterial ,

antidepressant, antiinflammatory, spasmolytic, muscle relaxant and antiasthmatic properties. Moreover, incorporation of fluorine can alter the course of the reaction as well as biological activities I3

-15

.

Prompted by the varied biological activities of quinazolinone derivatives and in continuation of'our work on quinazolinone derivatives I 6

•17

, it was contemplated to synthesize a novel series of fluorine containing quinazolin-4-ones carryIng aryl fury I substituents and to screen them for biological activities.

Results and Discussion Anthranilic acid 1, on treating with acetic

anhydride yielded 2-methyl-3,I-benzoxazin-4-one I 8•19

2 in good yield. 3-Chloro-4-fluoroaniline was then condensed with benzoxazinone 2 in the presence of phosphorus oxychloride to afford 2-methyl-3 -(3-chloro-4-fluoro)phenyl-quinazolin-4-one 3 in rather good yield. The latter was condensed with arylfurfurals 4 or aromatic carboxaldehydes in the presence of a base such as piperidine to obtain 2-[(5-aryl-2-furyl) vinyIl2-styryl]-3- (3-chloro-4-fluoro) -phenyl-quinazolin-4-ones 5 in fairly good yields (Scheme I). The characterization data of these compounds 5 are given in Table I. However, our attempt to carry out the same reaction employing

344 INDIAN J CHEM, SEC B, MARCH 1999

c("' ~I + Acz 0 ~

COzH (1) j •

(J' j Arf -CHO or ArCHO, Pi peridine , f1

(4 )

~-O~ lJl .. ~ -N CH=CH-Ar (Arf)

(5)

Art = JCJ-Ar o

Scheme I

ac idic conditions did not meet with success. The required arylfurfurals were synthesized through Meerwin reaction20. The structural elucidations of all the compounds were carried out QI1 the basis of elemental analys is and spectral data (Table I) . The spectral data of all these compounds support the ass igned structures .

The 500 MHz PMR spectrum of the compound 5f showed a doublet at 0 6.09-6.12 integrating for one proton with a coupling constant of 15 .5 Hz characteristic of vinyl proton. The furan protons signal s resonated as two sharp doublets at 0 7.05 (J=3.S Hz) and 7.21 (J=3.S Hz). A complex multiplet

was observed centered at 07.28-7.57 which is due to o-nitrophenyl protons. A doublet was seen in the range 87 .. 72-7.75 (J=15 .0 Hz) which accounts for the other vinylic proton. One of the aromatic protons signals of chlorofluorophenyl group appeared as a singlet at 8 7.73, while the other two aromatic protons were observed as two doublets of doublets in the range 8 7.64-7 .66 (J=9 .5 Hz, 4.0 Hz) and in the range 8 7.68-7.70 (J=8 .0 Hz, 6.5 Hz) respectively due to cou~ing with the neighbouring fluorine atom. The quinazolinone ring protons appeaJed as two doublets of doublets in the range 8 7.79-7.82 (J=9.5 Hz, 1.5 Hz) and in the range 8 8.12-8.14 (J=8 .0 Hz, 1.5 Hz) respectively due to ortho coupling of protons. The other two quinazolinone ring protons appeared as a complex multiplet in the range 8 7.8 1-7.89 which is explained due to interaction with neighbouring protons. The NMR spectral data of compounds 5b and 5g are given in Table I .

The mass spectra of compounds 5a, 5b, 5c, 5d, 5e and 5g were fully consistent with the assigned structures. In most cases, intense molecular ion peaks were observed. Thus, the compound 5c showed an intense molecular IOn peak at mlz 476/478 corresponding to the molecular formula C26H lsChFN20 2. The M+2 and M+4 peaks were also observed along with the molecular ion peak due to the presence of isotopes of chlorine atoms present in the compound. The loss of p-chlorophenyl radical and CO from the molecular ion resulted in an ion at m1z 337, .while the loss of p-chlorophenyl radical resulted in a peak at m1z 365. The major fragment ions and their relative abundances observed in the mass spectra of these compounds are given in Table I and the important fragmentation processes occurring in these series of compounds are depicted in Scheme II.

Antibacterial activity All the newly synthesized compounds 5a-f and 5g

were screened for their in vitro antibacterial activities against B. subtilis. S. aureus. P. aeruginosa and E. coli according to the disc-diffusion method11

.

Dimethylformamide was used as a solvent for the above test compounds. Furacin was employed as a standard drug for comparison and solvent control was kept. The minimal inhibitory concentrations (MIC values) of the above compounds were determined by serial dilution method. The results of screening studies are given in Table II.

The screening results indicate that compounds 5a, 5d, 5e and even 3 exhibit a greater degree of

1

HOLLA et ai.: STIJDIES ON ARYLFURAN DERIVATIVES: PART IX

(A) Scheme II

-0 &.CO

R

345

Tab le J--{::haracterization data of 2-[( 5-aryl-2-furyl )vinyl]-3-(3-chloro-4-fluoro )phenylquinazol in-4-ones 5a-f, 2-styryl-3 -(3-chloro-4-fluoro )phenyl-qu inazol in-4-one 5g and 3-(3-chloro-4-fluoro )phenyl-2-( 5-nitro-2-furyl)vinyl-quinazolin-4-one 5h

Compd Arf/Ar m.p. Yield Mol. formula N Found

' 0C) (%) (Caled) (%)

Sa p-Nitro 168-170 97 C 26H 1SC IFN}04 8.66 (8.62) Sb p-Bromo 200-202 96 C26H I jBrCIFN20 2 5.31 (5.38) Sc p-Chloro 208-210 97 C26H IsCl2FN 20 2 5.80 (5 .88) Sd m-Nitro 165-167 78 C26 H IsC IFN}04 8.57 (8 .62) Se a -C hloro 155- 157 62 C26H IsC I2FN 202 5.79 (5 .88) Sf a -Nitro 223-224 61 C26H IsC IFN}04 8.68 (8 .62) Sg p-Ch lorophenyl 176-178 50 C2.1H I3CI2FN20 6.74 (6.83) Sh a -nitro-2-fu ryl 196 81 C 20H II ClFN}04 10.13 (10.21)

Recrystall izat ion sol vent : DMF+EtOH

IH NMR (90 MHz, DMSO-do): Sa : 8 6 .1 (d , IH , J= 15.2 Hz, o lefinic proton), 7.05 (d , IH, J=3.6 Hz, furan 4H), 7.2 (d, IH , J=3 .6 Hz, furan 3H), 7. 3-8 .0 (m. ')H, olefinic, ary l and qu inazolinone ring protons), 8.2 (d, I H, qui nazolinone, J=8.5 Hz);

I fj NMR (500 MH z, DMSO-do): Sb: 8 6.23-6.24 (d, I H, J= 15 .5 Hz, o lefini c proton), 7 .03-7.04 (d , I H, J=3.5 Hz, furan 4H), 7.16-7. 17 (d , 1 H, J=4.0 Hz, furan II ), 753-7.55 (d , l H, J= 8.5 Hz, p -bromophenyl), 7.62-7 .64 (d, 2H, J=8.5 Hz, p -bromopheny l), 7.75 (s, I H, chl orofluo rophen yll , 7.72-7.73 (d, IH, J=5.5 Hz, chlorofluorophenyl), 7 .76-7.77 (d , IH , J=6.0 Hz, cbloro tluorophenyl ), 7.94-7.96 (dd, 21-1 , J=9.0 Hz, 2.0 II I., qUlOaLo linone), 7.86-7 .88 (d , IH , J=8 .5 Hz, quinazolinone), 8. 12-8. 14 (dd , 1 H, J=9.0 Hz, 1.0 Hz) IH NMR (500 MH z, DM SO-db ) : Sf: 0 (, 09 -6 . 12 (d , IH,J= 15 .5 Hz, olefinic proton), 7.05 (d, IH, J=' .5 Hz, furan 3H), 7.2 1 (d , IH, J=3.5 Hz, furan 4H), 7.28-7 .57 (m, 4H , o-nltrophen y ll, 7.64-7.66 (dd, IH, J=9 .5 Hz, 4 .0 Hz chlorotl uorophenyl), 7.68-7 .70 (dd, IH , J=8.0 Hz, 6.5 Hz, chlorofluorophenv n , 7.7,\ (5, : H, chlo rofluoropheny l), 7. 72-7.75 (d, IH, J= 15 .0 Hz, olefinic), 7.79-7 .82 (dd, IH , J=9.5 Hz, 1.5 Hz,

quinazolinone ), 8. 12-8 . 14 (dd, I H, J=8.0 Hz, 1.5 Hz, quinazolinone); IH NMR (500 MHz, DMSO-d6): 5g: 8 7.51-7 .52 (d , 1 H, J=15 .0 Hz, o lcfirtic) , 7 6 1-7.63 (d , 11-1 , J= 9 Hz. p -ch loropheny l), 7.65-7.67 (d, 1 H, J=8.5 Hz, p-chloropheny l), 7.54 (s, 1 H, chlorofluorophenyl), 7 .55-7.57 (Ill , 2H , hlo rofl uorophcny l), 7.83-7.84 (d, I H, J=8.5 Hz, quinazolinone), 7.83-7.86 (d, I H, J= 15 .0 Hz, olefinic) , 7.863-7 .89 (111 , 3H , qUlOazo linonc), 809-8. 11 (d, I H, J=9 Hz, quinazolinone) Mass: mil.; Sb: 5201522/524 (M +/M+2fM+4, 81.2%, 25 .4%, 8.9%), ., 64 (A, 10.2% ),338 (B, 64 .3% ), 183 (C, 5.8%); 5c: 476/478 (M+/M+2, 77.2%, 54. 1% ), 365 (A , 4 .8%), 337 (B, 9 1.4%),139 (C, 100%); Sd : 487 /489 (M+/M+2, 7 4%, 5. 6%), 150 (C , 53.0%); Se, 476/478 (M+!M+2, 33.2%, 24.6%), 365 (A, 7.5% ), 377 (B, 45 .2%), 139 (C, 56 .0%); Sf: 487/489 (M '/M+2, 17 5%,7.3%), 336 (B , 5 .2%); Sg: 410/412 (M +I M+2, 100%,77.3%)

346 INDIAN J CHEM, SEC B, MARCH 1999

Table II---Antibacterial activity data of compounds Sa-g and 3

Compd Minimum inhibitory concentration (Ilg/ml) E. coli _S aureus P. aeruginosa B. subtilis

Sa 6 6 6 6

Sb 12.5 12.5 12.5 12.5

Sc 12.5 12.5 12.5 12.5

Sd 6 6 6 6

Se 12.5 6 6 12.5

Sf 12.5 12.5 12.5 12.5

Sg 12.5 12.5 12.5 12.5

3 12.5 6 6 6

Furacin 6 12.5 12.5 12.5

(Standard)

antibacterial actlVloes against S. aureus, P. aeruginosa and B. subtilis compared to Furacin . However, the antibacterial actiyjty of compound Sg was comparable to that of Furacin especially against S. au., P.aer. and B. subti. It was concluded that compounds Sa, Sd, Se and 3 were found to be promising antibacterial agents.

Experimental Section Melting points are uncorrected. The IR spectra

were recorded on a Perkin-Elmer 529 Infrared Spectrophotometer in KBr pellets. PMR spectra of a few selected compounds were recorded in DMSO-d6

on a Perkin-Elmer R-32 (90 MHz) or on a 500 MHz NMR spectrometer using TMS as internal standard. Mass spectra were recorded on a Jeol JMS-D 300 Mass spectrometer operating at 70 eV.

2-Methyl-3- (3-chloro-4-fluoro) phenyl-quina­zolin-4-one 3. 3-Chloro-4-fluoroaniline (10 mmole) and 2-methyl-3,1-benzoxazin-4-one (2; 10 mmole) were suspended in dry toluene (50 mL) and phosphorus oxychloride (10 mmole) was added to this mixture with constant stirring. The solution was then refluxed on a water bath for 3 hr. The solution was cooled and excess of toluene was removed. The residue was digested with about 100 mL water containing 10 mL conc. HCI for 2 hr. The solution was cooled and neutralized with sodium bicarbonate solution . The resultant solid was filtered, washed with water, dried and recrystallized from ethanol, yield 54%, m.p. l80-82°e. Anal. Ca1cd for C, 62.39; H, 3.46; N, 9.7 . Found: C, 62.09; H, 3.42; N, 9.72%. IR: 1692 cm" (C=O); Mass: m/z 288/290 (M+, 27.3%, 4.7%), 273(M-CH3, 9-.9%), 41(CH3CN, 21.9%). 'H NMR (90 MHz, CDCI3); 8 2.5 (s, 3H, CH3), 7.6-7.8 (m, 3H, quinazolinone), 7.2-7.5(m, 3H, chlorofluorophenyl), 8.1-8.3 (d, I H, quinazolinone).

2- I(S-Aryl-2-furyl)vinyl] -3-(3-chloro-4-fluoro)­phenylqumnazolin-4-ones Sa-f: General procedure. Arylfurfural(4, 0.0 I mole) was dissolved in dioxane (25 mL) and then, a solution of 2-methyl-3-(3-chloro-4-fluoro)phenyl-quinazolin-4-one (3, 0.01 mole) in dioxane and piperidine (10 mL) were added to this solution. The solution was then heated under reflux for 6 hr. Excess of solvent was distilled off. The separated solid was filtered, washed with ethanol , dried and recrystallized from a mixture of DMF and ethanol. Their physical data are given in Table I. IR (KBr):Sb, J 682(C=O); Sc, I 679(C=O) Sd, I 720(C=O); Se, 1690(C=O); Sf, I 689(C=O); Sh, 1700(C=O) .

Acknowledgement The authors wish to thank Head, RSIC, CDRJ,

Lucknow for providing mass spectral and microanalysis data, Head, RSIC, nT, Madras for providing IR spectra of compounds, Prof. Michael 1. Levine for providing 500 MHz PMR spectra of compounds reported herein and Prof. Ananthakrishna, Head, Department of Microbiology, KMC, Mangalore for providing necessary facilities of the College for antibacterial screening. Further, the grant received from US Public Health Service Grant DE 08240 is gratefully acknowledged. One of the authors (MKS) is grateful to CSIR, New Delhi for granting Senior Research Fellowship.

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