Abdel-Halim, A M

Abdel-Rahman, R M

EI-Edfawy, S

Gabr, Y

Ibrahim, S S

NOPR

Indian Journal of ChemistryVol. 37B, January 1998, pp. 62 - 67Synthesis and biological activities of some new fully fused quinazolinederivativesS S Ibrahim, A M Abdel-Halim, Y Gabr, S EI-Edfawy & R M Abde1-Rahman*Department of Chemistry, Faculty of Education, Ain-Shams University, Roxy, Cairo, EgyptReceived 13 March 1997; accepted (revised) 26 August 1997Some fully fused quinazoline derivatives have been synthesized via condensation of 3-formylpyrazolo[5,1-b]quinazolin-9(lH)one 2 with bifunctional reagents followed by ring closure reactions.The structures of the products have been established by their elemental analyses and spectral data (UV, IR,IH NMR, mass and X-ray). The antibacterial activity of some products have been also described.Compounds 7, 12b and 13 show a relatively better activity against some tested bacteria in comparison withgentamycin.4-Quinazolinone derivatives play a vital role inmany biological processes and as synthetic drugs'".Furthermore, many fused quinazolinones are foundto exhibited remarkable pharmacological agents'".In search for new antimicrobial agents, it wasthought worthwhile to incorporate some additionalheterocyclic moieties in the quinazoline nucleus andstudy their biological activity via the interactionbetween formylpyrazoloquinazolinone 2 with nitro-gen and oxygen compounds. The starting compound3-formylpyrazolo[5, l-b ]quina-zolin-9(1H)one 28was obtained from formylation of 3-amino-2-methylquinazolin-4-one 1 by treatment with DMF-POCl3 [Vilsmeier-Haak reagent].Condensation of 2 with hydroxylaminehydrochloride, hydrazine hydrate, semicarbazidehydrochloride, thiosemicarbazide, 4-aminophenoland 4-aminom::etophenone refluxing in ethanol,produced 3a-f (Scheme I). Structure of 3 wasestablished from elemental analyses and spectraldata (Table I). IR spectrum of 3e showed bands dueto NH-OH, C=O and exo, endo CH=N functionalgroups. Its UV spectrum revealed the presence ofabsorption band at ",",ax 305, 349 and 485 nm in thevisible region. These bands reported the 1t* electrontransition and the charge transfer band respectively.The greater reactivity of the hydrogen atom of theNH of quinazolinone 2 is presumably due to itsfavourable location between two carbonyl functionsin position 9 and CHO group in the position 3 ofpyrazoloquinazolinone. Thus, cyclization of 3a byrefluxing in abs. ethanol-fused sodium acetate"yielded quinazolino[l ,2-b:2,3-b ]dipyrazolo-l O-one4, while attempts to the cyclization of 3b using gl.acetic acid-fused sodium acetate afforded 6-methyl-I ,2,4-triazino[5,6:4,5]pyrazolo[5, I :2,3']quinazololin-12- one 5.The structures 4 and 5 were preferred on thefollowing' grounds: i) absence of NH or OHabsorption bands in the IR spectra, ii) the presenceof only one c=o absorption band at 1677 cm-I .On the other. hand addition of HCN tothiosemicarbazone 3d in the presence of gl. aceticacid-ethanol" afforded 4H-3( o-cyano-c-thiosemi-carbazido )methylpyrazolo[5, l-b ]quinazolin-9-one 6,which on boiling with cone, HCl furnished" 6-[(4H)pyrazolo[5, 1-b]quinazolin-9-one-3-yl]-I, 6-di-hydro-3-mercapto-1 ,2,4-triazin-5( 4H)one 7, whilebasic cyclization of 7 by refluxing with aq. KOItproduced 3H-5-mercapto-1,2,4-triazino[5',6' : 2,3]-[4,5-c :1,5-a]pyrazolo-quinazolin-12-one 8 (SchemeI).Structure of compounds 6-8 was confirmed fromtheir elemental analyses and spectral data (Table I).Their IR spectra showed characteristic bands at2700 (SH) and 1200-1100 cm' (C-S) withdisappearance of band at 2300-2200 cm-! (CN) in 7and 8 while IR spectra of 6 and 8 revealed only oneabsorption band at 1693 cm-! due to cyclic C=O ofquinazolinone and a broad band at 3300-3100 cm'was observed in case of 7 and 8 due to cyclicmRAHIM et al. : SYNTIfESIS & BIOLOGICAL ACTIVITIES OF QUINAZOLINE DERIVATIVES 63diNCHH+o~H-N~N~H ••.(H"2N-~41-H "'CN•• S H H(6) L I q )H(Io 0~N=-IN ~N:lN~N~ KOH ~~N--H )~IJ-'HOII It I?» '/17 I H __ H N NNY \-jHSH So@(),J~H CHaNA.R I I J )• A, OHe , NHCOHHze , C,H,-OH9b. HHZd. HHCSHM!" C,Hc.CDCIf)-pb@CJ,.)I_T14) N-CH151@X)~H (HOI 2 )11o@(,yhydrazo structure. In addition, structure assigned to8 was verified from IH NMR spectrum whichshowed signals at 5 2.8 (s, IH, of pyrole moiety),7.5-8.5 (m, 5H, benzo protons of quinazoline andCH ofpyrazole moiety), 10.1 (s, IH, SH), 10.4 and11.0ppm (each singlet for NH of 1,2,4-triazine).Conversion of 6 to 8 was. established via acidichydrolysis of cyano group to carboxylic groupfollowed by cyclization and then elimination of amolecule of water by refluxing with aq. KOH.Condensation of 1 with 2 gave the Schiff base 9which on refluxing with sodium methoxide affordedthe adduct 10. Reaction of arylidine 9 withmercaptoacetic acid in dry dioxane-fused sodiumsulphate yielded the thiazolidin-4-one 11 (SchemeI).Structures of 10 and 11 were deduced fromelemental analyses and IR spectral data. Compound10 revealed absorption bands in the IR spectrumH(Ho II~_N~N~M~IlI.b.a , C~HI. ·OH1Ib. C.H•.NO,l'.pIlb.11 01Scheme Iregion due to c=o and C-O-R, while that of 11exhibited absorption bands at 3120 (NH ofquinazoline), 2880 (aliphatic CH), 1740, 1700, 1680(3 C=O of quinazoline and thiazolidine-d-onej'".On the other hand, condensation of 3-formylpyrazolo[5,I-b]quinazolin-9-(IH) one 2 withacetophenone derivatives in gl. acetic acid, affordedthe chalcones 12 a,b. Cycloaddition reaction of 12a,b by boiling with ethanol in the presence of a fewdrops of piperidine'< gave heterotricyclic moiety 13.The chemical transformation of 12 to 13 is outlinedin Chart 1.Structures of 12 a,b were deduced from theirelemental analyses and spectral data. Their IRspectra showed absorption bands at 3190 (NH ofquinazoline), 3067 (aromatic CH), 2926 (aliphaticCH), 1690 (C=O), 1601 (C=C), 1573 cm-I (C=N);'H NMR spectrum of 12b revealed the presence ofsignals at 6.8-7.1 (m, 2H, -CH-CH-), 7.4-8.5 (m,64 INDIAN J CHEM, SEC. B, JANUARY 19988H, pyrazolo & aromatic protons) and 8.8 (s, tH,NH). UV spectrum of 12b in DMF displayed Amax at526 nm with fluorescence in UV light, as possiblefluorescent brighteners for synthetic fibres andplastics.Proton Transf~rChart 1Refluxing compound 12b in ethanol with a fewdrops of piperidine afforded compound 13. Itsstructure was established on the basis of elementalanalyses and spectral data. IR spectrum of it showedabsorption bands at 1694, 1660 (2 C=O), 2900, 1490(str. and def. CH2) and 1530, 1320 em" (asy. andsy. N02) with absence of a band due to OH or NHgroups. Finally the structure of 13 was confitmedfrom mass spectra which showed a molecular ionpeak at rnIz 360 (1.23%), a base peak at rnIz 150(100%) attributed to p-nitrobenzoyl ion and underfurther fragmentation arrived to benzyene radical atrnIz 76 (28.6%). All fragmentation paths leading tovarious daughter ions deduced the postulatedstructure (Chart II). In addition, compound 13 didnot give phenolic test with FeCl3 solution.a.,~Unsaturated ketones 12 a,b reacted withhydroxylamine hydrochloride in the presence ofpyridine via Michael addition reaction to giveisoxazole derivatives 14 a,b. Structures of theseproducts were elucidated by spectroscopic analyses.Thus, IR spectra of 14a and 14b showed absorptions3600.23 ,,')•.J-erOCo""'Lo@'~-t--~HaCf©¢Xd -e-19812-25'1.) 2 1501100'1.1·.0, +OCI ·:·~flH .I 1711100°"1"'1.-il:s.4 0 .-co .~)J --4H117 ( J.61·/,)13 41Chart 2IBRAillM et al. : SYNTHESIS & BIOLOGICAL ACTIVITIES OF QUINAZOLINE DERIVATIVES 65Table I---Physical and spectral data of the compounds 3-14IR(cm-l)OH NH SH CO C=N C-S C-O-R3500 3090 1670 16003200 1675 16103300 3100 1680 16203200 2700 1670 1590 1190Compd. Solvent M.P. Yield Mol. formula"eC) % (M. wt.)3a EtOH 155 80 CIIHsN.02(228)3b EtOH 295 75 CIIH9NsO(227)3c EtOH 300 100 CI2HION602(270)3d EtOH 280 76 C12HION6OS(286)3e EtOH 280 90 C17H\3N402(305)3f EtOH 238 88 CI~ISN.02(331)4 EtOH 270 75 CIIH6N.O(210)S EtOH 295 70 CI3H~sO(251)6 Oil. 290 84 C\3HIIN,oSDMF (313)7. Oil 300 95 C\3HION602SDMF (314)8 Oil.OMFOMF 300300910 300OMF11 143OMF12. 265OMF12b 225OMF13 Oil.OMFOMF 30027514.14b 270OMF66907570501008060753193 308031001649 16081675 16101700 15801677 15901670 15803100 1680 1590 12003550 3300 2650 1680 1590 11903300309031203400 319031803150310016931670170016801700168017001680161015801600157016001590120011751050C\3HsN60S(296)CzJiI.N602(370)Cz.H.sN603(402)CzzH.6N603S 3300(444)C.~\3N303(331)C.~.2N.O.(360)C.~.2N.O.(360)C •.}I ••N.03(346)C.~\3NsO.(375)*All the compounds gave satisfactory ofC, H, and N analyses. Sulfer element has been determined by X-ray analyses:3d: EOund 10.62; Calcd 11.18%; 6: Found 9.61; Calcd 10.22%; 7: Found 9.78; Calcd 10.19%; 8: Found 9.99; Calcd10.81%; 11: Found 6.80; Calcd 7.20%.W (DMF, A....x nm): 3e: 305,349,485; 12b: 526; 14b: 339,526.·H NMR'(OMSO) 0:8: 2.8 (IH ofpyro1es), 3.1 (H ofpyrazo1e), 7.5-8.5 (l4H benzo ofquinazoline), \0.1 (IH, SH),10.4 and I \.0 (each IH, NH of 1,2,4-triazine); 12b: \.5 (3H, CH3), 3.5 (lH, pyrazole), 7.5-7.7 (2H, CH=CH), 7.8-8.1(4H, aromatic), 8.2-8.7 (4H, benzol and 8.9 (lH, NH).15801610159011851690 157316941660168015901580 10501675 1590 1060which are correlated to the NH. CH2, C=O and C-O-N stretching frequencies of these compounds. Theelectronic spectra of these led further support to theproposed structure where they lack the absorptionbands due to extended conjugation.Antimicrobial activities. Compounds 3-13 havebeen tested for their antimicrobial evaluation againstS. aures, S. marcescens, B. subtilis, C, albine, E. coliand M lutea by the disc method" using DMF assolvent and gentamycin was used as standard atthree different concentration (100, 500, and 1000ug/ml) and growth inhibition was calculated.The results showed that compounds 8 and 13were active against E. coli, while compounds 6, 766 INDIAN J CHEM, SEe. 8, JANUARY 1998Table II---Antimicrobial activities of the compounds 3-13Compd* S. aures S. marcescencs B. subtilis C. albine E. coli M. lutea3a3b3c 10 II 9 9 8 83d 12 14 10 8 10 73e 14 15 12 II 12 II3f456 14 15 17 12 10 127 16 13 15 II II 128 24 23 2091011 1512b 16 14 14 11 8 613 17 16 15 12 21 1014Gentamycin 23 23 24 23 23 20*Diameter of inhibition zonesand 8 were active against S. aures, S. lutes and B.subtilis. All other compounds, exhibited varyingdegree (20-30%) of the antimicrobial activity.Compound 8 which was substituted with thioxo-1,2,4-triazine moiety to the pyrazoloquinazolinoneshowed maximum activity (38%). When phenyl ringwas substituted with nitro group (at position-4),compound 13 showed maximum activity (34%),while both compounds 6 and 7 containingthiosemicarbazide and/or 3-mercapto-5-hydroxy-1,2,4-triazine moiety exhibited greater degree ofinhibition when compared with other testedcompounds (Table II). In conclusion, thecompounds which contain the mercapto-l,2,4-triazine moiety, enhanced the inhibition percentageof the tested organisms.Experimental SectionMelting points are uncorrected. IR spectra (KBr)were recorded on a Perkin-Elmer 293 FTspectrophotometer ('-malt in cm"), UV spectra (inDMF) on a LASTACQU. MRD (300-400) testspectrophotomer ('-malt in nrn), IH NMR spectra on aEM NMR spectrometer 200 MHz PMR usingDMSO and/or acetone as a solvent and TMS asinternal reference (chemical shifts in 8, ppm) andmass spectra on GCMS qp 1000 ex Schemimadzuinstrument (70 eV). X-ray. measurement wererecorded in X-ray phosphorescences. Elementalanalysis were performed on a Perkin-Elmer CHN240A analyzer in unite, Cairo University (ARE).Synthesis of condensation derivatives 3 a-f:General method. A suspension of 2 (10 m. molt inethanol (50 mL) and the appropriate aminocompounds namely hydroxylamine hydrochloride(in H20), hydrazine hydrate, semicarbazide (inH20), thiosemicarbazide (in hot water, drops ofacetic acid), p-aminophenol and p-amino-acetophenone (each 10 m. mol) was refluxed for lh,cooled and poured onto ice. The solid thus obtainedwas crystallized from the suitable solvent to give3 a-f (Table I).Synthesis of quinazolino[1,2-b : 3,2-b]dipyra-zoio-IO-one 4. A suspention of3a (10 mrnol) in abs.ethanol (50 mL) and fused sodium acetate (5g) washeated under reflux for 4h, cooled and poured ontoice. The resultant solid was crystallized to give 4(Table I).Cyclization of 3b into heterotricyclic com-pound 5. A solution of 3b (l0 mrnol) in gl aceticacid (100 mL) and fused sodium acetate (5 g) wasrefluxed for 2 h, cooled and poured onto ice. Thesolid obtained was filtered off and recrystallized togive 5 (Table I).Synthesis of 4H-3-(a-cyano-a-thiosemicarba-zido)methyl-pyrazolo[5,1-b)quinazolin-9-one 6.To 3d (5 mmol) in ethyl alcohol (50 mL) and glacetic acid (50 ml.), aq solution of sodium cyanideIBRAHIM et al. : SYNTHESIS & BIOLOGICAL ACTIVITIES OF QUlNAZOLINE DERlVATIVES 67(5 mmol in H20 5 mL) was added. The reactionmixture was refluxed for 6 h, cooled and pouredonto ice. The solid obtained was filtered off andrecrystallized to give 6 (Table I).Acidic hydrolysis of 6:Synthesis of 6-(4H-pyrazolo(5, I-bJquinazolin-9-one-3-yl)-I, 6-dihy-dro-3-mercapto-1,2,4-triazin-5(4H)one 7. To 6 (5mmol),HCl (20%, 20 mL) was added and thereaction mixture was refluxed for 10 h. The solidproduct was filtered off and recrystallized to give 7(Table I).Basic cyclization of 7:Synthesis of 3H-S-mercapto-l, 2, 4-triazino(5,6 : 2,3)[4, 5- c : 1, 5-aJpyra-zoloquinazolin-12-one 8. To 7 (5 mmol), aqKOH (5%, 20 mL) was added and the reactionmixture was refluxed for 10 h. The solid obtainedwas recrystallized to give 8 (Table I).Preparation of Schif's base 9. A mixture of 2(10 mmol) and compound 1 (10 mmol) in gl aceticacid (50 mL) was heated under reflux for 2 h, cooledand poured onto ice. The resulting solid wascrystallized to give 9 (Table I).Addition of sodium methoxide to 9: Formationof 10. A suspention of 9 (0.5 g) in sodiummethoxide (0.5 g Na in 50 mL abs ethanol) wasrefluxed for 12 h, cooled and poured onto ice-HCI.the solid obtained was recrystallized to give theadduct 10 (Table I).Cycloaddition of 9 with thioglycolic acid:Formation of thiazolidinone 11. A mixture of 9(10 m.mol) and mercaptoacetic acid (50 m. mol) indioxan (100 mL) was refluxed for 8 h. The excesssolvent was removed and the resulting solid masswas crystallized to give 11 (Table I).Preparation of chalcones 12a and 12b. Equi-molar mixture of 2 (10 mmol), the appropriateacetophenones namely, 4-hydroxyacetophenone, p-nitroacetophenone (10 mmol each) and acetic acid(3.3 mL), piperidine (0.5 mL) in benzene (100 mL)was refluxed for 24 h. The solid obtained wasfiltered off and recrystallized from the propersolvent to give 12a,b (TableI).Synthesis of heterotricyclic system 13. Amixture of 12b (0.5 g), ethanol (50 mL), andpiperidine (0.5 mL) was refluxed for 10 h. The solidobtained was filtered off and recrystallized to give13 (Table I).Synthesis of isoxazole derivatives 14a,b. Amixture of 12a,b (10 mmol) and hydroxylaminehydrochloride (10 mmol in H20 5 mL), in pyridine(50 mL) was refluxed for 6 h, cooled, -and pouredonto ice-HCl. The solid obtained was filtered offand recrystallized to give 14 (Table I).ReferencesI EI-Kerdawy M M, YousifM Y, EI-Emam A A, Moustafa MA & EI-Sherbeny M A, Egypt J Pharm Sci, 35,1994, I.2 Chemobrovin N J, Kozhevnikov Yu V, Morozova G E &Chemobrovin T A, Khim Farm Zh, 26, 1992, 48; ChernAbstr, 117,1992, 171361g.3 Ramana D V, Indian J Heterocycl Chern, 3, 1994, 215.4 Srivastava B & Shulka J S, Indian J Chern, 30B, 1991,332.5 Mishra P, Paneerselvam P & Jain S, J Indian Chern Sac, 72,1995,559.6 Barker A C, Barlow J J, Copeland R J, Nicholson S &Taylor P J, J Chern Res (s), 1994, 248.7 Gaur V B, Shah V H, Parikh A R, J lnst Chern (India), 63,1991,219.8 Bamela S B & Seshadri S, Indian J Chern, 23B, 1984, 161.9 Paudler W W & Lee J, J Org Chern, 36, 1971, 3921.10 Abdel-Rahman R M, Seada M, Fawzy M & EI-Baz J,Pharrnazie,49, 1994,729.II Abdcl-Rahman R M, PakJ Scient & lnd Res, 30,1987,290.12 Abdel-Rahman R M, Indian J Chern, 27B, 1988,548.13 Mackie T J & Cartheny, J E Mac, Prac Med Microbiology,Vol. 2 (Churchill Livingstono, Edinburgh, London & NewYork), 1989,30.

Synthesis and biological activities of some new fully fused quinazoline derivatives

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Synthesis and biological activities of some new fully fused quinazoline derivatives

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