Background: The Cinnoline moiety and Sulphonamide moiety both have good antimicrobial properties. Methods: In the present study both the moieties were condensed to synthesize substituted cinnoline sulphonamide derivatives using intramolecular cyclization followed by diazotization in order to get synergistic activity. Results: These derivatives particularly halogen substituted cinnoline derivatives showed potent antimicrobial activity. Conclusion: Further investigations are required to find out possible mechanism of action.Keywords: Cinnoline, Antibacterial, Antifungal

Darbhamulla, S

Vikas, S

AJOL - African Journals Online

African Health Sciences Vol 9 No 4 December 2009 275Synthesis, characterization and biological activities of substitutedcinnoline culphonamides*Vikas S1, Darbhamulla S21. Indian Veterinary Research Institute, Surgery Division, India2. NGSM-IPS, Pharmaceutical Chemistry, Manglore -574160, IndiaAbstractBackground: The Cinnoline moiety and Sulphonamide moiety both have good antimicrobial properties.Methods: In the present study both the moieties were condensed to synthesize substituted cinnoline sulphonamidederivatives using intramolecular cyclization followed by diazotization in order to get synergistic activity.Results: These derivatives particularly halogen substituted cinnoline derivatives showed potent antimicrobial activity.Conclusion: Further investigations are required to find out possible mechanism of action.Keywords: Cinnoline, Antibacterial, AntifungalAfrican Health Sciences 2009; 9(4):275-278IntroductionA simple and good yielding method for the synthesisof substituted cinnoline sulphonamide derivatives bythe condensation of p-amino-benzene sulphonylchloride with various substituted 4-amino cinnolineFigure 1: Scheme*Correspondence author:Saxena VikasIndian Veterinary Research InstituteSurgery DivisionIzatnagar -243122, IndiaEmail: vikasvicky17@rediffmail.com3-carboxamides which was obtained by theintramolecular cyclization of the hydrazone whichin turn obtained by coupling with cyanoacetamidein aqueous ethanolic solution containing sodiumacetate followed by diazotisation. They werecharacterized by spectral data. All the synthesizedcompounds were screened for their anti-microbialactivity. Among the compounds tested Bromo andChloro substituted products showed significantantimicrobial activity.African Health Sciences Vol 9 No 4 December 2009276[ In 1 (a-j)  R : a = o-nitro, b = p-chloro, c = o-methyl, d = p-nitro, e = p-bromo, f  = 3,4-dinitro, g= m-chloro, h = o-fluoro, i = 2,3-di-chloro ]Materials and MethodsAll the reactions were carried out under prescribeslaboratory conditions. The products were purifiedby recrystallisation. Melting points were determinedin open capillaries and are uncorrected. Purity ofthe compounds was verified by pre coated TLCplates (E. MERCH kieselgel 60 F254). IR spectrawere recorded using KBr pellets on a NICOLETTIMPACT400 CDCl3 Spectro- photometer. 1HNMR on a JEOLJMS D-300 spectrometer in usingTMS as internal standard and mass spectra wererecorded on SHIMADZU GC-MS at 70evspectrometer. The new series of  title, compoundswere synthesized diazotization of substituted anilines1a-i followed 2 by coupling with cyanoacetamide 3in aqueous ethanolic solution containing sodiumacetate, afforded the corresponding hydrazone 4a-i.Intramolecular cyclization of the hydrazone withanhydrous Alcl3 in chlorobenzene resulted in theformation of  substituted phenyl 4-amino cinnoline3-carboxamide 5a-i. Crude p-acetamido benzenesulphonyl chloride was treated with dilute ammoniafollowed by hydrolysis. P-amino benzene sulphonylchloride 6 obtained was refluxed with DMF andsubstituted 4- amino cinnoline -3-carboxamide,resulted in the formation of  substituted 4-(p-aminophenyl sulphonamide) cinnoline 3-carboxamide 7a-i (Scheme-1). Physical data of final products is givenin Table-1.Table 1: Physical data of  compounds preparedCompound R1R2Physical state      M.P    Yield     Mol Formula (M.wt)    (ÚC)     (%)7a NO2H Pale green crystals     192     68 C15H12N6SO57b Cl H Creamish white crystals          282     66 C15H12CIN5SO37c CH3H White crystals     252     66 C16H15N5SO37d H NO2Creamish white crystals          248     67 C15H12N6SO57e H Br Pale brown crystals     242     79 C15H12BrN5SO37f NO2NO2Pale yellow crystals     232     65 C15H11NaN6S2O87g Cl H Pale orange crystals     230     69 C15H12CIN5SO37h F H Pale yellow crystals     219     70 C15H11FCIN5SO37i Cl Cl Pale yellow crystals     198     70 C15H11Cl2N6SO5Synthesis of substituted phenyl hydrazono(cyano) acetamide (4a-i)The substituted aniline (0.195 mole) was dissolved amixture of conc Hcl (7.5ml) and water (7.5ml) andcooled to 0° to 5° c in an ice bath. To this a coldsaturated solution of sodium nitrite (0.19mole) wasadded slowly. Soon after the addition, the fumes ofnitrous acid were liberated, a pinch of sulphamicacid / thiourea is added, stirred till the fumes wereceased. The diazonium salt thus formed was filteredin to a cooled solution containing cyanoacetamide(0.195 mole), water (350ml), 10 gm of CH3COONaand 15 ml of alcohol. The mixture was kept stirringup to 6 hrs at room temperature, the solid wascollected and recrystallized from methanol.Synthesis of substituted 4-amino cinnoline 3-carboxamide (5a-i)To the anhydrous Alcl3 (0.111mole) thechlorobenzene 150ml was added and nitrogen gaswas passed for half  an hour. This mixture was addedto the substituted phenyl hydrazono cyano acetamidethen nitrogen was passed for 10 min, the mixturewas then refluxed for 2hrs. It was cooled, dilute Hcl(20ml) was added to it. It was then heated on waterbath cooled, filtered, washed twice with diluteNaoH solution and filtered. The product wasrecrystallized from methanol, water 10:1.Synthesis of p-aminobenzene sulphonylchloride6Transfered 20 gm of  crude p-acetamido benzenesulphonyl chloride to a 500ml flask added 10ml ofconc Hcl and 30ml of  water. Boiled the mixturegently under reflux for 30-45min. The solution, whencooled to room temperature no solid amide wasdeposited, if a solid separated, heated for a furthershort period. Treated the cooled solution with 2 gmof activated charcoal, heated the mixture to boiling,and filtered under suction through a hardened filterpaper. Place the filtrate (a solution of  p-aminobenzene sulphonyl chloride) in a litre beaker  andAfrican Health Sciences Vol 9 No 4 December 2009 277cautiously added 16 gm (approximately) of solidsodium bicarbonate in portions with stirring. Afterthe evolution of gas was subsided, tested thesuspension with litmus paper and if it is still acidadded more sodium bicarbonate until neutral.Cooled in ice, filtered off the paminobenzenesulphonyl chloride under suction and dried.Recrystallised from water.Synthesis of substituted 4-(p-amino phenyl-sulphonamide) cinnoline 3-carboxamide (7a-i)Substituted 4-amino cinnoline 3-carboxamide(0.05mole) was taken in 25 ml of DMF and P-aminobenzene sulphonyl chloride (0.01 mole) wasadded and refluxed for 2hrs.The mixture was pouredin to the crushed ice and filtered, and recrystallisedwith alcohol.Antimicrobial activityThe synthesized derivatives were screened forantibacterial and antifungal activity using disk diffusionmethod (Modified Kirby-Bauer Method). Muller-Hinton broth and Sabourauds agar media were usedas growth media for bacteria and fungi respectively.Pseudomonas aeruginosa, Escherichia coli, Bacillussubtilis, Staphylococcous aureous, Candida albicansand Aspergillus niger were the organism used forthe screening.ResultsIR spectra revealed the important functional groups.1H NMR spectra of the products indicate theformation of  the substituted cinnoline sulphonamidederivatives. The mass spectral data indicated stablemolecular ion peak for all the synthesized products.The halogenated compounds showed the expectedisotopic ion peaks in the mass spectra. All thecompounds were screened for their anti-bacterialactivity against both gram-positive and gram-negativebacterias and also for their anti-fungal activity againstC. albicans and A. niger and found to be active asshown in the Table-2.Table 2: Antibacterial and antifungal activities of  the synthesized compoundsSl.No. Compound No.                  Diameter of zone of inhibition (mm)P. aeruginosa E. coli B.subtilis S. aureus C. albicans   A. niger1 7a 12 14 16 15 18 172 7b 17 19 20 18 17 183 7c 13 16 15 16 20 224 7d 14 15 17 18 17 155 7e 15 14 12 13 16 176 7f 12 15 15 16 15 147 7g 19 20 22 19 19 208 7h 18 22 21 20 21 229 7i 13 14 16 15 18 1710 Norfloxacin 20 23 24 22 - -11 Griseofulvin - - - - 22 2412 DMF - - - - - --Indicates no inhibitionThe antibacterial and antifungal activities were carriedout by the disk diffusion method. It is concludedthat substituted cinnoline sulphonamide derivativescan be synthesized successfully in the laboratory. Theresults from antimicrobial activities studies showedthat some of the substituted cinnoline sulphonamidederivatives (7b, 7g, 7h) posses good antibacterialactivities and compounds (7a, 7c, 7d, 7e, 7f, 7i)showed moderate to good activities when compareto the standard drug norfloxacin.Whereascompounds (7c, 7g, 7h) showed good antifungalactivity and compounds (7a, 7b, 7d, 7e, 7f, 7i)showed moderate to good activities when comparedto the standard drug Griseofulvin. Spectral evidencefor some of the representative substituted cinnolinessulphonamide derivatives are given below.8-Nitro 4-(p-amino phenyl sulphonamide)cinnoline 3-carboxamide:7aPale green crystals m.p. 192° C (68.26%) IR (KBr,cm-1): 3481 (-NH), 3361-3218 (-NH2), 3106 (-CH),1631 (-CO).1H NMR (CDCl3)ä :7.85 (3H, d), 7.5(4H, m, Ar-H), 8.1 (1H, s, NH), 8.3 (2H, d, NH2),8.7 (2H, s,CONH2). MASS: The peak at m/z 388corresponds to the parent compoundC15H12N6SO5. Base peak was observed at m/zAfrican Health Sciences Vol 9 No 4 December 2009278139 and the important fragment ion peaks areobserved at m/z 156 and m/z 142.6-chloro -4 (p-amino phenyl sulphonamide)cinnoline 3-carboxamide:7bCreamish white crystals m.p. 288° C (66.28%), IR(KBr, cm-1): 3464 (-NH), 3394- 3245 (-NH2), 3108(-CH), 1681(-CO), 1H NMR (CDCl3)ä :7.9 (3H,d), 7.3 (4H, m, Ar-H), 8.0 (1H, s, -NH), 8.1 (2H,d,NH2), 8.5 (2H, s,CONH2). MASS: The peak atm/z 377 corresponds to the parent compoundC15H12ClN4SO3. Base peak was observed at m/z 329 and the important fragment ion peaks areobserved at m/z 156 and m/z 142.8-Methyl 4-(p-amino phenyl sulphonamide)cinnoline3-carboxamide:7cwhite crystals m.p. 252°C (66.60%), IR (KBr, cm-1): 3465 (-NH), 3388-3290 (-NH2), 3106 (-CH),1629(-CO).1H NMR (CDCl3)ä :7.9 (3H, d ), 7.4(4H, m, Ar-H), 2.3 (3H, s, CH3), 8.1 (1H, s, -NH),8.2 (2H, d, NH2), 8.6 (2H, s, CONH2). MASS: Thepeak at m/z 357 corresponds to the parentcompound C16H15N5SO3. Base peak wasobserved at m/z 154 and the important fragmention peaks are observed at m/z 156 and m/z 142.DiscussionEvaluation of antimicrobial activity for substitutedCinnoline Sulphonamide derivatives exhibits potentantimicrobial activity. All derivatives demonstratedsignificantly activity, while some derivatives mainlyhalogen substituted derivatives not onlydemonstrated approximately same zone ofinhibition as reference drug but also show potentactivity on lesser concentration, this might be due tothe reason that cinnoline ring system is identical toring system found in ciprofloxacin and similarly it isproved that sulphonamides are active bacterial PABA(Para amino benzoic acid) inhibitor. In conclusion,the combination of two active moieties displayedprofound antimicrobial activity. Further, it would beinteresting to obtain the possible mechanism ofaction and their in vivo trial in experimental animals.AcknowledgementThe authors wish to thanks Nitte Education Trust,Mangalore for providing all the facilities and HeadRSIC, CDRI Lucknow and Head, RSIC, PunjabUniversity, Chandigarh for the spectral data.References1. Pattan SR, Patel RB, Ali M. Shamrez, Butle SRand Pattan S, Synthesis of  some substituted 2-amino/acetamido-4-aryl thiazolyl5- substitutedsulphides and sulphones and their antibacterialand antifungal activity. Indian J Het. Chem. 13:265  2682. Vingkar KS, Bobade AS and Khadse BG,Synthesis and Antimicrobial activity of 6Chlorocinnolino thiazoles. Indian J. Het. Chem 11:35-38.3. Katritzky AR and Pozharskii AF, Hand bookof  Heterocyclic chemistry. 2; 629- 630.4. Abbady MS, Sh M, Radwan and Bakhite EA,Synthesis and antimicrobial activity of somecinnoline derivatives containing sulphonamidogroup Indian. J Chem 32 (B): 1281  12845. Stefaska Barbara et al, Synthesis and biologicalevaluation of 2, 7-Dihydro3Hdibenzo [de,h]cinnoline3,7-dione derivatives and theiranticancer activity, Bioorganic and Medicinal chemistry11(4): 561-576. Fusco, Raffaello, Piselli, Fulvio L, Boschi, PierM, A process for the preparation of antibacterial1-alkyl-3-carboxyl-4 cinnolines, Chem. Abstr,110,75540.

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Synthesis, characterization and biological activities of substituted cinnoline culphonamides

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Synthesis, characterization and biological activities of substituted cinnoline culphonamides

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