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  • Synthesis and Antibacterial Activity Studies of 2,4-Di Substituted Furan Derivatives

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    Ratnakaram Venkata Nadh
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    2,4 disubstitiuted furan derivatives (8A–8M) were prepared from furan-4-carboxylic acid ethyl ester (1). Antibacterial activity of new 2,4 di substituted furan derivatives was studied against Gram (+) and Gram () bacteria. 8F, 8E, 8D and 8J were found to be effective against Gram () bacteria whereas, 8A and 8L were effective against Gram (+) bacteria. Least MIC value was found as 100 mg/ml against Escherichia coli (for 8D and 8F), and Proteus vulgaris (for 8E and 8F). Antibacterial activity is correlated with different substituents. Products exhibited better antibacterial activities especially towards Streptococcus pyogenes, Proteus vulgaris, and Escherichia coli.

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    2,4 disubstitiuted furan derivatives (8A–8M) were prepared from furan-4-carboxylic acid ethyl ester (1). Antibacterial activity of new 2,4 di substituted furan derivatives was studied against Gram (+) and Gram () bacteria. 8F, 8E, 8D and 8J were found to be effective against Gram () bacteria whereas, 8A and 8L were effective against Gram (+) bacteria. Least MIC value was found as 100 mg/ml against Escherichia coli (for 8D and 8F), and Proteus vulgaris (for 8E and 8F). Antibacterial activity is correlated with different substituents. Products exhibited better antibacterial activities especially towards Streptococcus pyogenes, Proteus vulgaris, and Escherichia coli.

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    6 visualizações9 páginas

    Synthesis and Antibacterial Activity Studies of 2,4-Di Substituted Furan Derivatives

    Enviado por

    Ratnakaram Venkata Nadh
    2,4 disubstitiuted furan derivatives (8A–8M) were prepared from furan-4-carboxylic acid ethyl ester (1). Antibacterial activity of new 2,4 di substituted furan derivatives was studied against Gram (+) and Gram () bacteria. 8F, 8E, 8D and 8J were found to be effective against Gram () bacteria whereas, 8A and 8L were effective against Gram (+) bacteria. Least MIC value was found as 100 mg/ml against Escherichia coli (for 8D and 8F), and Proteus vulgaris (for 8E and 8F). Antibacterial activity is correlated with different substituents. Products exhibited better antibacterial activities especially towards Streptococcus pyogenes, Proteus vulgaris, and Escherichia coli.

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    © All Rights Reserved
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    Sinalizar o conteúdo como inadequado
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    ensue! University Jounal of 8st and Applied Slences 6 (2017) 345-355 ELSEVIER Content lists available at SclonceDirest Beni-Suef University Journal of Basic and Applied Sciences journal homepage: www.elsevier.com/locate/bjbas Full Length Article Synthesis and antibacterial activity studies of 2,4-di substituted furan derivatives Sireesha Malladi*”, R. Venkata Nadh“*, K, Suresh Babu‘, P. Suri Babu® *peporment of Scene and Humans, vgnan's Unversy, Valamud 522215, td Deparment of hes. JN Anamaps Is CHAM Universy Benge Campus Karo S123 Inia ‘Deparonent of Chemisty. MalaredayBugnering Coleg, Hyerabed. naa “achary Magara Univesity, Magna Naga. Cn 522510. a, ARTICLE INFO ABSTRACT ‘rte istry Received ia tevted fot 27 une 2017 Accented 12 August 2017 24 disubstituted furan derivatives ‘Anibacterial activity of new 24 i substituted furan derivatives was studied against Gr bacteria. BF, SE. SD and 8) were found tobe effective against Gram (~) bacteria whereas, BA and BL tive agaist Gram (+) bacteria, Least MIC value was fund as 100 pil against Escherichia ol BF), and Proveusvulgori (for 8 and SE} Antibacterial atvtyiscorelated with diferent sub- :A-SM) were prepare from luran-4-cazbonylic aid ethyl este (1), and Gra stituents. Products exhibited better antibacterial activities especially towards Steptococus pyogenes postbacea cty Stricrre-actnty elatonehip ‘Proteus vulgar, and Fsoheicia ca 2017 BeseSuef University, reduction and hosting by Elsevier BV, Tiss an open acces atti under ‘the CC BY-NC-ND license (itp |/cteativeconimensatglicenses/by-nc-nd/4.) 1 Introduction LI. Importance of furans Heterocyclic compounds containing oxygeninitrogen atoms have received significant attention in view of their spectrum of effective pharmacological activities (Ahmad eta), 2013). signifi cant and enduring area of research interest for chemists is synthe- sis of substituted furans as furan ring is an imperative structural unit in various biologically active and natural products Joule and ‘Mill, 2070; Sniady al. 2008), Extensive gamut of insecticidal and phytocidal activities are exhibited by furan derivatives (Wakita et al, 2003; Shimokawatoko and Yamada, 2006). Theit diverse array of encouraging pharmacological properties helps to use them antidepressant, antimicrobial and ant-inlammatory agents (Such et al, 1980). The lofty therapeutic properties of furan derivatives encourage synthesizing a number of chemother- apeutic agents as they operate on different receptorsjtargets (Banerjee et al, 2012} 7 Gorespondngsethor maf oddrerersicerhs malaiyshoocosn(S. Mala, dctormsdh0y hoo out (RV. adh), babuicyilcm (RS. Babu) suspathpaadzinal com aba 2514-85350 2017 Ben-suel Utes. Peducton and hosting by Eee BY. Thi fan open aces ale der the CC AYCNCOND lene ("> esteem 1.2, Methodologies for synthesis of furans and need for new drugs Furan is a versatile synthon (Wright, 2005) and Zheng et al (2011) reported that furan ring has shown better antimicrobial Activity compared to other substituents, Different synthetic routes ‘were reported in literature for synthesis of molecules incorporated with furan moiety (Salem, 2016). Substituted furans are synthe- sised by two key approaches, In the first approach, Foran ring is raised by an array of various strategies which include cycloisomer- iaation (Pridmore et al, 2005), cyclization (Wang et al. 2010), Intramolecular couplings and ring closing metathesis (Woran and Rodriguez, 2012). The second strategy involves functionalization of existing furan rings. In classical approaches furans are syathe- sised by cyclization suitable precursors in presence of strong min- eral acids (Paal-Knorr reaction) (Li, 2014) or metal catalysts (ponick et al, 2009; Gabriele et al, 2010), Substituted furan derivatives were synthesized with involvement of transition metal salts (Sumit et al, 2007), in the presence of a gold (1) catalyst by 2 Claisen-type rearrangement (Florin and Fabien, 2011), under continuous-flow conditions (York, 2011). New synthetic routes were established for the preparation of 2.4-disubstituted furans (Ka‘viteky et a, 2004), 2,3-disubsttuted furans by ortho lithiation (Toft et 21, 2005), Synthesis and biological activity studies of furan erivatives were reviewed by Logogl et al. (2010) and Zheng etal. (2010). lenses 06 6407 In the subtropical regions of the world, around 20,000 deaths per year were due to parasitic bacterial infections (Nani et al 2015). In spite of availability of several antibiotics in the market, there is an ample requirement for novel anti-bacterial agents in view of rapid developing of antibiotic resistant bacteria (Shelshar, 2010}, 13, Objectives of study ‘The present study is aimed at synthesis of2.4-disubsticuted fur- ans having different substituents on aromatic ting in order to lunderstand their antibacterial activities as they are widely dis tributed in nature (Cheng et al, 2010) and the existence of furan ring could significantly enhance the antibacterial activity {Jumina and Zulkarnain, 2002) 2. Materials and methods Melting points were determined using open glass capillar- les on a Mel-temp apparatus and are uncosvected. Thin layer et Suef Ue Basie ApS. 6 (2017) 35-52 chromatography (TLC) was performed on E Merk AL silica gel GO F254 plates and visualized under UV light. The IR spectra were recorded on a Perkin Elmer FI-IR spectrometer The "HNMR spectra were recorded on a Varian EM-360 spectrometer (400MFHz). All chemical shifts were reported in 8 (ppm) using TMS as an internal standard, The mass spectra were recorded on Agilent ion trap MS. Analytical and Laboratory Reagent gratle chemicals of Merck India Co. Led, were used in the present study. MIC (Minimum Inbibi- tory Concentration) values of tested compounds against bacterial strains were determined by broth microdilution method (CLS, 2012), 13 Experimental part 31, Scheme and procedure for synthesis of 24 disubstituted furan derivatives ‘Synthetic route implied to prepare compounds (8A-8M) is out- lined in the given below scheme. “DEST by =, same om Bt OHO Le “ho 5 Mla Bent Sue Ue |. Base Ape 6 (2017) 345-353 Pa 3.2. Procedure forthe synthesis of compounds 2 to 8 Representative procedure for the intermediates ang final prod- ucts involved in the above given synthetic route is briefed below. 4.2.1. S-Formaylfuran-3-carboxylic acid ethyl ester (2) To the sted mixture of POC! (34ml) and DMF (37 mi). compound 1 (40g, 285 mmol) was added in three portions ‘Then the mixture was heated under reflux conditions for 14h. The contents were cooled by quenching with water and ethyl acetate was used to extract the product. Water and satu- rated NaCl were employed to wash the extracted organic layer. ‘Then MgSO, crystals were added to dry the organic layer, fl- tered and evaporated in vacuum. A pale yellow liquid (compound-2, 264 g, 55%) was obtained by purifying the resi- ddue with flash column chromatography (silica gel, 3:1 hexane] ethyl acetate). 3.22 5-Hydroxymethyl-furan-3-carboxylic acd ethyl ester (3) ‘To the stired solution of compound 2 (8 g, 47 mmol) in THE (60 ml), sodium borohydride was added in two portions and mix- ture was stirred at —10 °C to —5°C for 1h, A pale yellow liquid (compound-3, 526 g, 65%) was obtained by repeating the above processes viz, quenching, extracting with ethyl acetate, washing. frying. evaporation and purification by flash column chromatography. 323. 4-(Ethoxy carbonylfuran-2-y))methy! methane sulfonate (4) To the stirred solution of compound 3 (5 g) in THF (50 ml), ‘TEA was added at 0°C and then methane sulfonyl chloride was added slowly at same temperature. Stirring was continued for another 2h at room temperature. For further step, the crude product was taken 3s such which was obtained by repeating the above processes (viz, quenching, extracting with ethyl acetate, washing, drying ‘and evaporation) co the reaction mixture. 3.24, Ethyl 5-((methyl amino methyl }furan-3-carboxplate (5) Crude compound 4 (53 g) in THF (30 mL) was cooled to °C and then 2.0 M MeNH was slowly added with continuous sttring. The ‘mixture was stirred in sealed tube for 16h at room temperature. Then THF was distilled off completely ané crude compound was taken into next step, 3.25. Ethyl 5-[(Benzene sulfonyl-methyl-amino}-methyll-furan-3- carboxylate (6) ‘The mixture of compound 5 (5.8 g), and TEA (3.0 eq) was taken in DCM (607ml), Then benzene sulfonyl chloride (4.45 g) was added drop wise to the mixture at O°C. The solution was stirred for 6h at room temperature, Water was added and organic layer was extracted with ethyl acetate (3 + 10 mL) which was washed with water. The solid product was dried to afford compound § asa white solid (5.08 g) 3.26. 5-[(Benzene sulfonyL-methyl-amino)-methyl-furan-3- carboxylic acid (2) ‘To a stirred solution of compound 6 (5 g) in THF, LIOH was added and then heated to 70-80°C for 6h. To the mixture, water was added and then pH was adjusted to 2.0 using hydrochloric acid. A white soli (2.08 g, Yield: 98%) was obtained by washing the collected precipitae with water followed by drying 5.22. Synthesis of amides (8A-8M} ‘Amides were synthesized using activating reagent (EDCHCI: N- (B-dimethylaminopropy!)-N-ethyl carbodiimide hydrochloride), base (TEA: Triethyalamine), solvent (CH,Cly: dichloromethane) and additive (HOB: 1-hydroxybenzotriazole hydrate) To 2 solu- tion of dichloromethane containing compound-7 (500 mg) and amine (A-M), added EDC. HCI (1.5 eq) and HOBE (1.269) at 0°C Finally TEA (2.eq) was added and stirred overnight at RT. After completion of the reaction, the reaction mixture was distilled and the obtained crude compound was dissolved in EtOAc, washed with water, brine solution, dried over Na,SOs, filtered and evaporated under vacuum to obtain the crude amide derivatives ‘which were purified by column chromatography. 23, Characterization of synthesized compounds The synthesized compounds were characterized by melting point. spectral data of IR, 7H NMR, "°C NMR and MS. The data is siven below. 33:1. 5-Formayl-furan-3-carboxylic acid ethyl ester (2) ‘Apale yellow liquid, bp 268-270 °C. IR spectrum (KB), v.em * 3030 (Ar-H str), 2625 (C—H str), 2720 (aldehyde—C—H st), 1724 (ester—C=0 ste), 1692 (aldehyde—C=0 ste), 1521 (Ar—C=C str), 1400 (C=H bend), 1212 (Ar—C=0 str), 1085 (ester—C—0), 45 (furar—C—H ben) em": 7H NMR spectrum (CDCl, 300 MHz} 8, ppm (Hz): 9.7 (1H, s, CHO), 8.2 (1H, s, Furan—H), 7.58 (1H, 5, Furan-H), 44 (2H, q, J=7.12 Hz, —CH,). 14 (3H. tJ=7.12 Hr, —CH,); PC NMR (CDCI, 200 Mz) 4, ppm: 178.1 (—CHO), 159.4 (ester C=0), 154.3 (Furan—C), 148.8 (Furan—), 1208 (Franc) 1165 (Furan—C), 60.9 (—CH;,—ester), 14.1 (C1); Mass spectrum (EL, 70 eV): Found. mz: 168.1 [MI". CH40q. Calculated, m/z 168.5. 33.2, 5-Hydroxymethy!-furan-3-carboxylic acid ethyl ester (3) AA pale yellow liquid, bp. 310-314°C. IR spectrum (KBr, », cm: 3076 (ACH str), 2985, 2844 (CH str), 1717, 1702 (C0 str), 1548, 1449 (Ar—C=C str), 1335 (S=0 str, 1226 (Ar—C—O st), 1159 (ester—C=0 str). 772 (“Hl ben) ems 1H NM spectrum (300 MHz, CDCL,) 4, ppm (J, Hz): 80 (1H. Furan—H), 6.6 (1H, s, Furan—H), 4.65 (2H, d, J=7.12 Ha, CH= hydroxy). 43 QH, gq, J=7.12 Hz, —CHj—ester), 14 GH, J=7.12 Mz, “CH; #C NMR spectrum (200 MHz, CDCI) 8, ppm 163.1 (C=O), 155.3 (Furan—C), 147.5 (Furan—C, 1200 (Furan—, 1075 (Furan—C), 60.9 (—CH,-ester), $7.1(—CH,—hydroxy), 14.2 (CHa); Mass spectrum (EI, 70 eV): Found, mz: 170 [M)", 171 [M. *HT CoHicOy Calculated, m/z: 170.08, 333. Ethyl S.((methyl amino}metty)furan-3-carboxylate (5) ‘A Pale yellow syrupy liquid, b.p. 292-295 °C IR spectrum (KBr), vy, cmm 7: 3349 (NH str), 2870 (CH str), 1715 (C=0 ste), 1548, 1447 (Ar—C=C str), 1021 (C—O str), 863 (furan—CH ben) cm” 3H NMR spectrum (CDCl, 400 M2) 8, ppm U Hz): 81 (1H, s Furan—H), 6.6 (1H, s, Furan-H), 45 (2H, s, CHN). 43 2H, q, J= 7.8 Ha,—CH—ester), 14 (3H, J» 7.8 Hz, CH); °CNMR spec ‘rum (CDC, 100 MHz} 4, ppm: 160.5 (C0), 1498 (Furan—C), 14500 (Furan—C), 118.9 (Furan—C), 106.7 (Furan—c), 609 (—CH,- ester), 52.4 (NCH). 33.4 (NACH). 14.1 (OCH): Mass spectrum (El, 70 eV): Found, mjz: 183 MI’. CoH,,NO,. Calculated, mje: 1832. 334, Ethyl 5:[(Renzene sulfonyl-methyl-amine)-methyl}-furan-2. carboxylate (6) ‘A white solid, mp. 116-119°C. IR spectrum (KBr), y, em” 3076 (AI—~C—H str), 2985, 2944 (CH str), 1717, 1702 (C=0 st), 1548, 1449 (AI—C=C str}, 1335 (S=0 str), 1226 (Ar—C—O st), 1159 (ester—C—0 str), 772 (CH ben) em”; "HNMR spectrum (DMSO-d,) 5, ppm Q, Hz): 80 (IH, s, Furan—H), 7.6 2H, 6, J= 72 Hz, SAH), 7.2 (1H, J= 7.6 Hz, SAH}, 6.6 (1H, 5, FuranH), 43 (2H, dJ=8Hz, -N-CH—), 28 GH, s, NCH}: PC NMR spectrum (CDCI, 100 MHz) 8, ppm: 162.7 (C=0}, 150.5 (Furan—C), 1475 (Furan—C), 1375 (SAC), 1327 (SAC), 1290 (SAL), 1273 (S-ANHO, 1202 (Furan—O), 109.2 (Fran), 604 (—CH,—ester), 454 (N-CH.—), 346 (NCH), 142 (—CH,}; Mass spectrum (El, 70 eV): Found, mz: 323 [MP C\sH7NOs, Calculated, mjz: 323.3, et Suef Ue Basie App Sa. 6(2017) 35-52 3.35. 5-[(Benzene sulfonyl-methyl-amino}-methylJuran- carboxylic acid (7) ‘A white solid, mp, 199-201 °C. IR spectrum (KBr, ¥, em”? 3442 (OH str), 3158, 3067 (Ar—C—H str), 2927, 2820 (C“H st), 1692, 1677 (C=0 str), 1605, 1551 (Ar—C=C str}, 1225 (Ar—C—O str), 1161 (C=O str), 934 (ACH ben) em”*; 'H NMR spectrum (DMSO-de) 5, ppm G, 2): 82 (1H, s, Fura): 78 (2H, d.J=72 He, SCAP-H): 7.7 (1H, t, J=76 Hz, ArH), 765 (2H, m, J= 755 He, ArH), 6.6 (1H, 5, Furan—H), 43 (2H, 6, J=8 Hz, NCH), 24 (3H, 5, NACH): PC NMR spectrum (CDCI, 100 Mit2) 8, ppm: 166.5 (C=0), 151.2 (Furan—€), 148.9 (Furae—), 1376 (S-AMC), 1228 (SAMO), 1291 (SAMO), 1274 (Sar), 119.1 (Furan—C), 1093 (Furan—C), 465 (NCH), 347 (CN-CH,); Mass spectrum (El, 70eV): Found, mjz: 294 IM. C.sH1sNO,S. Calculated, m/z: 295.05 3.36 5-(Benzene sulfony-methyl-amino}-methy|-furan- carboxylic acid phenyl amide (8A) Yield: 63%, a pale yellow solid, mp. 191-193 °C. IR spectrum (KBr), y, cm 3379 (NH str), 2923 (CH str), 1646 (C=0 str), 1547, 1443 (ArC=C str), 1334 (SO ste), 1162 (C—O str), 936 (Ar—CK ben) cm-; "HNMR spectrum (DMSO-ds) 4, ppm (J, Hz}: 9:90 (1H, br. s. NH): 8.30 (1H, s, Furan—#): 7.80 2H, o. J=7.2z, Nr); 7.80-7.60 (SH, m, J= 8.6 Hz, S—Ar—H): 7.40 (2H, t. J= 7.6 Hz, N-Ar—; 710 (1H. &,J=8 Hz, NAH): 6.80 (1H, s, FuranH); 430 (2H, s, -N—CH,); 2.67 (3H, , “NCH. Yc NMR spectrum (DMSO-<,, 100 MHz) 8, ppm: 160.0 (C=0), 1503 (Furan—C); 1459 (Furan—C); 1387 (N—At<); 1368 (SAO); 133.0 (SAMO); 1283 (SAC); 128.6 (Furan—<) 1272 (SAC); 1235 (NAME), 1235 (NAC). 120.1 (NAO); 108.9 (Furan—C); 46.1 (NCH); 34.6 (-N—CH,) Mass spectrum (EI, 70 eV): Found, mjz: 371.1 [MMH] CisHsaNOe- 5. Calculated, mz: 370.1 337, 5|(Benzene sufonyl-methy-amino}-methyl-furan- carboxylic acid (2-methoxy-phenyl)-amide (8B) Yield: 63%, 4 pale yellow solié, mp. 153-155°C. IR spectrum (KBr), v, cm": 3323.9 (NH str), 3130 (ArH str), 2935 (CH str), 1652 (C=0 str, 1546, 1487, 1460 (AT—C=C str), 1340 (S=0 sir), 1156 (C—O str), 938 (Ar—C—H ben) em '; 'H NMR spectrum (DMSO-d,) J, Hz): $20 (1H, br. s, N40), 8.32 (1H, s, Furan-H), 7.80 (2H, 4, J=7.6 Hz, SAH). 770 (1H, tJ =7.6 Hz, NATH). 1.68-7.6 (34, m, J=3 He, S—Ar—H), 720 (1H, tJ = 8 Hz, NATED, 7.10 (1H, dJ=5.2 Hz, NACH), 690 (1H, tJ = 8.8 Hz, N-AIH). 685 (IK, 5, Furen—H), 430 GH, s, NCH, 380 GH. s —O-CH,), 2.68 (3H, s, NACH.) PC NMR spectrum (CDCI, 100 MHz) s, ppm: 160.0 (C0), 151.4 (Furan—C), 150.2 (N—Ar—C), 1458 (Furan—C), 1368 (SAr—C), 1330 (SAC), 1293 (SAO), 1272 (NAO), 1262 (SAC), 125.7 (Furan—), 1247 (NATO), 1233 (NEATC), 1201 (NEATO), 1113 (N—Ar—0), 108.9 (Furan—C), 55.6 (—O-CH), 46.0 (-N—CH—), 5346 (N—CHi); Mass spectrum (EI, 70 eV): Found, mz: 407.1 [M HY. CzlfgoN;OsS. Calculated, mjz: 400.1 3.3.8. 5-(Benzene sulfonyl-methyl-anino}-methyl]-furan-3 carboxylic acid (4-methoxy-phenyl)-amide (8) Yield: 60%, 2 pale yellow solid, mp. 122-135°C. IR spectrum (KBr), vem": 2323.9 (NH sts), 2130 (PCH st), 2935 (CH str), 1652 (C—O str). 1546, 1487, 1460 (Ar—C=C str), 1340 (S=O str), 1186 (C—O str), 938 (Ar—C—H ben) em *; "H NMR spectrum (DMSO-d.) 4, ppm J, Hz}: 9.79 (1H, br. s, N-H), 825 (1H, s, Furan—H), 7.8 2H, d J= 68 Hz, S~Ar-H), 7.65 (2H. m,/=8.3 He, N-Ar-H), 7.60-7.50 (3H, m, [= 8.03 Hz, SAH). 60 (2H, m, J>882H2, N-AMH), 430 (2H, s, NCH), 374 GH, 5, 0-H). 2.68 (3H, 5, “N—CHs): PC NMR spectrum (DMSO-d, 100 MEi2) 8, ppm: 159.1 (C=0). 15533 (N—Ar—C), 150.2 (Furan—C), 5 Mla Benue Un. Basic Arp. Sc. 62017) 345-353 xe 1458 (Furan—C), 1368 (SAMC), 13303 (SAMO), 1293 (S-Ar-0), 1272 (NANO), 1262 (SAC), 125.7 (Furan—C), 1247 (NAMC), 1233 (N-AMC}, 1201 (NANO), 1113 (N—Ar=C), 106.9 (Furan—C), 55.6 (—O-CH,}, 45.05 (NCH), 34.6 (NCH); Mass spectrum (EI, 70 eV): Found, mjz: 401.2 [M HY", CagHsoNa05S, Calculated, mj 400.1 3.39, $(Benzene sulfonyl-methyl-amino}-methy}-furan-2- carboxylic acid (3-methoxy-pheny)-amide (8D) Yield: 64%. a pale yellow solid, mp. 165-167 °C. IR spectrum (KBr), v, cm: 3363.9 (N—H st), 3145 (ACH st), 2924 (CHL Str), 1728, 1660 (C=0 str. 1543, 1453 (AI—C=C str). 1328 (S=0 si), 1216 (S=O ste), 1160 (CO str), 936 (ACI ben) em’ TCNMR spectrum (DMSO-d,) 8. ppm J, Hz): 887 (IH, br. s N-H), 8.29 (1H, s, Furan—H), 7.80 (2H, d, J=7.2 Hz, SAH) 7.70 (1H, d, J= 72 Hie, SAH), 7.60 (2H, (J =7.6 Hz, S~AIH) 7.4 (IK, s, NATH), 7:30-7:20 (2H, m, J= 1.6 Hz, NACH), 6.90 (14, 5, Foran), 668 (1H, dd J= 1.6, Hz, NATH). 43 (2H. s, NCH}, 3.74 GH, 5, OCH), 2.68 (3H, 5, “N—CH): PC NMR spectrum (DMSO-de, 100MHz) 5, ppm: 160.1 (C=O), 1594 (NArC), 1503 (Furan—C), 1459 (Furan—C), 139.9 (NAT), 1368 (SAC), 133.0. (SAC), 1293 (SAO), (S-Ar—O), 123.5 (NAO), 1123 (NAC), 109.0 (NAL) 1088 (N-Ar—C), 105.8 (Furan—<), 545(-0-CH,), 45.098 (CN=CH.=), 34.621 (—N—CHl,): Mass spectrum (EI, 70 eV): Found. Imjz: 401.2 [Mell]. CayoNs0sS. Calculated. mz: 400.1. 3.3.10, 5.|(Benzene sulfonyl-methyl-amino)-methyl] furan carboxylic acid (2..-dimethoxy-phenyl)-amide (8E) Yield: 72%, a pale yellow solid, mp. 102-105 °C. IR spectrum (kB), v, em *: 3322 (NH str), 3123 (APC ste), 2960 (CH Str), 1651 (C=0 str), 1600. 1547, 1485 (Ar—C=C str) 1328 (S=O str, 1224 (S=O str), 1161 (CO str), 936 (ACH ben) cm "HNMR spectrum (DMSO-d:) 6. ppm (J, Hz): 930 (1H, br. s N=), 830 (1H, 5, FuranH), 78 (2K, d, J=7.2 Hz, S-Ar—H), 7.70 (18, [= 7.2 He, SAP), 7.60 (2H, t [= 7.6 Hz, APH, 7239 (1H, da, J=2, 68 He, N-Ar—H), 7.0 (1H, d, J= 12 Hz, NATH), 580 (IH, s, Furan—H), 6.70 (IH, dd, J= 1.8, Bz, N-AT—H), 43 QH, s, NACH), 38 (3H. s, —O-CH), 3.74 GH, s, ~0—CHy) 2.68 (3H, s, -N—CH,); "°C NMR spectrum (DMSO-d, 100 M2) 3, pm: 160 (C=0), 159 (NAIC), 150 (Furan—<), 145.8 (N—Ar—C). 1368 (SAIC), 133.03 (S—A/—C), 129.368 (Furan~<), 127.2 (S-Ar—0), 126.22 (SAO), 128.7 (Furen—C), 1247 (NAC) 1233 (NUAMC), 1201 (N-AMC), 11136 (NAO), 1069 (Furan—O), $5.6 (—O-CH,), 46.08 (NCH), 346 (NCH) Mass spectrum (El, 70 eV): Found, mjz: 431.2 [M4] CasHaNOy- S.Caleulated, mz: 430.12, 3.3.11, 5-(Benzene sulfony-methy-amino)-methyl furan carboxylic acid (2:6-dimethoxy-phenyl)-amide (BF) Yield: 74%, a pale yellow solid, mp. 164-155°C. IR spectrum (KBr), v, em: 3454 (NH str). 3307.8 (NH sit), 2929 (CH str), 1729 (C=0 str). 1654, 1474 (Ar—C=C str), 1332 (S=0 st 1257 (S=0 str), 1115 (CO str), 938 (Ar—C—H. ben) cm='; "HL NMR spectrum (DMSO-d) 6. ppm J, Hz): 9.0 (1H, s, br, NCH). 8.18 (1H, br. S, Furan—H). 7.80 (2H, d, J=7.2 Hz, S—Ar—I0), 7.70 (3H, m, J=803 Hz, S“AT-H), 720 (1H, m, J= 8.18 Hz, NAH. 680 (1H, m. J= 8.18 Hz) 6:70 (2H, d, J=7.2Hz, NArH), 420 (2H, s, “NCH, 3.70 (GH, s, ~O-CH,), 268 (3H, s, NCH) We 'NMR spectrum (DMSO-d, 100 MHz) 3, ppm: 160.0 (C—O) 1562 (NAC), 1500 (Furan—C), 145.6 (Furan—C), 1368 (Sar), 1330 (SAC), 1293 (S-AMC), 1278 (SA), 127.2 (Furan—C), 1233 (NAP), 114.1 (NATO), 109.1 (Furan—C), 104.3 (N-Ar—C), 55.6 (—O-CH;), 46.1 (-N-CH;-), Sais (NCH); Mass spectrum (EL 70 eV) Found mjz. 4912 Mt THY GnaNiO6s Caletated mlz 43012 3.3.12, 5.{(Benzene sulfonyl-methyl-amino}-methy]-furan-2- carboxylic acid (2,4-dimethoxy-pheny)-amide (86) Yield: 76%, a pale yellow soli, mp. 131-133 °C. IR spectrum (er), v, em: 3322 (NH str), 3123 (ACH str}, 2960 (CH str), 1651 (C=O str), 1600, 1547, 1485 (Ar—C=C str}, 1328 (S=O str), 1224 (S=0 str}, 1161 (C0 str), 936 (ArC—H ben) em; UNM spectrum (DMSO-d) 8, ppm (J, Hz): 9.0 (1H, br. NI), 830 (1H, s, Furan—H), 7.80 (2H, d, J= 7.2 He, S—ArH), 7.60 (2H, (J=7.6 Hz, S—AIH), 740 (1H, d,J= 8 Hz, SAH). 6.90 (1H, d 2, NoArH), 6.60 (IH. d, J= 6.8 Hz, NATH), 6.70 (1H, da Je24, 877 z, NAH), 642 (HHL, s, FuranH), 430 2H. s NCH), 38 GH, 5, -O-CH,), 3.74 GH s. -0—CH,). 268 (BH, 5, NCH); MCNMR spectrum (DMSO-d, 100 Miz}, ppm: 1603 (C=O), 159.1 (N-ArC), 1505 (NAO), 1458 (Furan—O), 138.1 (NAC), 1368 (SAC), 133.03 (SAIC). 1293 (SAMO), 1272 (SAC), 1262 (SAO), 1257 (Furan—O), 1247 (NAC), 1233 (NOAMO), 120.1 (NAC), 11136 (Furan—c), 1089 (Furan—C), 35.6 (—O-CH;), 46.05 (AACH.A), 345 (N—CH): Mass spectrum (H1, 70 eV): Found, mje; 431.2 [Mol] CasHaN0,5, Calculated, mjz: 430.12 3.3.13, 5-(Benzene sulfonyl-methyl-amino}-methyl}furan-3- carboxylic acid (3.45-timethoxy-phenyl)-amide (8H) Yield 78%, a yellow soli, mp. 165-167 °C. IR spectrum (KB, v cm": 3351 (NOH str), 2637 (CH str), 1655 (C=0 str), 1603, (AIM-C=C st1), 1338 (SHO str), 1224 (S=0 str), 1151 (C0 st 939 (Ar—C—H ben) cm *: HNMR (DMSO-d,) d, ppm (J. Hz): 9.80 (1H, be. 5, NOH), 830 (11, s, Fura), 780 (2H, d, J=7.2 Hz S-ArH), 770 (UH, t, J=72, SAH). 7.65 (QH, t J= 7.6 He S-Ar—H), 7.16 (2H. s, NATH), 6:90 (1H, 5, NAIH). 4.30 (24, 5, N-CH.—), 3.76 (3H, s, -O-CH,). 3.71 (3H. s, -O-CH,). 3.60 GH. 5, -O-CH,), 26 GH, 5, NCH); YC NMR spectrum (DMSO-d, 100Miz) 4, ppm: 1602 (C=), 1525 (NAC). 1508 (Furan—C), 1463. (Furan—C), 1366 (N-ArC), 1352 (SAO), 1344 (SAC), 1307 (SAPO), 128.3 (N-AT—C), 1257 (Furan—C) 1086 (Furan—C), 603 (—O-CH,), 55.5 (-O-CHi) 460 (NCH), 34.6(N-CHL): Mass spectrum (EL eV): Found, mjz: 461.2 [MH CzHaN0>S. Calculated, mz 460.13 3.3.14, 5.[(Benzene sulfonyl-methyl-amino)-methy]-furan-2- ‘carboxylic acid (4-hydroxy-pheny)-amide (81) Yield: 67%, a yellow solid, mp. 225-227 °C-IR spectrum (KB, v cm: 3454 (OTH str), 3378 (NH str), 3124 (Ar—C—H str), 1647 (Co str, 1548 (ACC str), 1205 (S=0 str), 149 (C0 st 1938 (Ar—C—H ben) em *: HNMR (DMSO-d,) 4, ppm {J Hz): 98.70 (1H, br, 5, NH, 92 (1H, br. 5, Ar—O—H), 8.20 (1H, 5, Furan—H), 7.80 (2H, d.J~ 7.2 Hz, SAH), 7.65 (3H, m, J~7.2 Hz, S-ArH). 7.40 (2H. mJ = 8.8 Hz, N-APH), 6.90 (1H, m,J = 8,7 Hz, NATH), 1.70 (1H, m.J= 8.7 Hr, N-Ar—H), 4.30 (2H, s, -N—CH,—),2.68 (3H, 5, -N—CH,}; °C NMR spectrum (DMSO-d, 100 MH} 8: 1595 (C=0), 1535 (N—Ar—C), 150.1 (Furan—C), 1455 (Furan—C), 136.8 (SAPO), 133.03 (SAO), 1302 (NAIC), 1293 (SAIC) 1272 (SAPO), 123.6 (Furan—O), 1221 (NAP. 1150 (NAO), 108.8 (Furan—C), 46.1 (NCH) 346 (NCH) Mass spectrum (El, 70 eV): Found, mjz: 387.1 [M+H|.C,oHygN.05- S. Calculated, mz: 386.08. 3.3.15, 5.[(Benzene sulfonyl-methyl-amino}-methy)-furan-3- carboxylic acid (2-chloro-4-hydroxy-phenyl)-amide (8)) Yield: 63%, a thick yellow solid, mp. 124-125:C. IR spectrum (KBr), 9, em *: 3460 (0-H str), 3369 (N-H ste), 1727 (C=0 str), 1626, 1499 (Ar—C=C str), 1342 (S=0 str), 1195 (CO str), 575 (C= str) em”; "HNMR spectrum (DMSO-4,) 8, ppm (J. Hz) 8.50 (1H, s, Furan—H), 7.80 (2H, d, J= 7.2 Hz, S-ArH), 7.72 (1H, J 8.0 Hz, SAH), 7.66 (2H. & J=7.2 He, SAP-H), 7.13 (1H. 4.J=S4Hz, NATH), 690 (1H, dd, J=28, 88 Hz, NOAH), 68 (1H, d, J= 88 He, N-Ar-H), 6:75 (TH, br. §, Furan—H), 429 (2H, 5, (NICH), 2.65 (3H, s, (NOCH): #C NMR spectrum (DMSO- de, 1OOMHz) 4, ppm: 161.0 (C=O), 1512 (N—Ar—C), 149.6 (Furan—C), 142.8 (Furan—C), 1398 (S—Ar—O), 1367 (S-Ar—<), 1330 (SAC), 1294 (NAC), 1271 (SAC), 122.2 (Furan—0), 121.2 (NAC), 1185 (NAIC), 1153 (NAO), V151 (NOAP—O), 1094 (Furan—C), 458 (NCH), 346 (“N—CH,); Mass spectrum (EL, 70 eV): Found, m2: 421.1 [MoH CysHtyNi0sS. Calculated, mjz: 420.05. 3.3.16, 5-{(Benzene sulfonyl-methyl-amvino)-methyl-furon~ carboxylic acid (2-chloro-5-methoxy-phenyl)-amide (8K) Yield: 81%, a thick yellow solid, m p. 136-140°C. IR spectrum (KBr), v, cm 3446, 3231 (NH str), 2929 (C-H str), 1649, (ArC=C str), 1340 (S=0 str), 1223 ($0 str), 1163 (CO str), 933 (A—C-H ben) cm; "HNMR spectrum (OMSO-de) 3, ppm (. Hz): 8.16 (1H, s, Furan—H), 7.9-7.80 (2H, d.J = 7.2 Hz, S—ATH), 7.60 (1H, m, J= 7.5 Ha, S~AIH), 7.56 (2H, &,J=7.6 Hz, SAH), 728 (iH, t J=82 Hz, NAD, 667 (IH, dd, J=4, 12H, N-AH), 650 (s, HH, Furan-H), 430 (2H, s, -N—CH~), 3.80, GH, s, “0-CH,). 2.80 GH, s, —N—CH), PC NMR spectrum (DMSO-d, 100MHz) 4, ppm: 1589 (C=O), 1588 (N—Ar—<), 1815 (Furn—€). 1453 (Furar—), 1375 (SAMO), 1348 (SAMO), 1328 (N-AMC), 1291 (SAC), 127.3 (SAM), 1236 (Fura), 1138 (NAC), 1113 (N-AMC), 1074 (NAC), 105.3 (Furan—C), $5.6 (—O-CH,), 46.5 (NCH) 349 (—N—CH,); Mass spectrum (EI, 70 eV): Found, mz: 452. Ci HieNzO45, Caleulated, mjz: 449.9, 3.3.17, 5.{{Benzene sulfonyl-methyl-amiino)-methylf-furan- carboxylic acid (2-hydroxy-4-ftuoro-phenyl)-amide (BL) Yield: 71%, a light brown solid, mp. 200-203 °C. IR spectrum (ir), v, em fs 3343 (NH str), 3115 (Ar—C—H str), 2924 (CH Str), 1651 (C=0 str), 1608 (Ar—C=C str}, 1325 (S=0 st), 1161 (C0 ste}, 933 (ACH ben) em * "HNMR spectrum (DMSO- 4g) 6, ppm U, Hz): 1021 (1H, br. §, Ar-O-H), 9.29 (1H, br. 5, NH), 830 (1H, s, Furan—H), 780 (2H, d, J=7.5Hz, SmArH), 770 (1H, t. Jn 7.6 Hz, ArH), 7.66 (2H, t, J= 8 Hz, SAH), 7.49 (1H, t= 68 Hz, N—Ar—H), 680 (1H, s, Furan—H), 672-6 61 H, m9, J= 5.0 Hz, N-AP—H), 4.30 (5, 2H, (NCH, 2.74 (3H, 5, 2-methoxy > 345tri methoxy > unsubstituted > 25-dimechoxy> 3 methoxy > 2.4-dimethoxy > 4 methoxy. = 2-Chloro, 4-hydroxy > 4-hydroxy = 2-hloro, 5-methoxy > 2.5-di methoxy + flydroxy, 4-uoro > 246-44 Muoro In the present case, the presence of methoxy, chloro-, and fu oro groups on phenyl group improved the antibacterial activity of synthesized compounds and a similar observation was reported in isoxazoline derivatives (Shah and Desai, 2007), Poor activity was shown by 5-|(Benzene sulfonyl-methyl-amino)-methy|- arboxylic acid (4-methoxy-pheny!)-amide (8C) against tested bac- teria compared to the reference campound. Exceptionally high antibacterial activity was shown by 5 [(Benzene sulfonyl-methyl-amino}-methyl|-furan-3-carboxylic ack 4-(2.6 dimethoxy-pheny!)-amide (8F) compared to the other com- pounds which can be attributed to the two ortho substitutions of methoxy on phenyl groups. The methoxy group affects the charge distribution which confers significant improvement in biological effect. The enhanced inhibition observed in the presence of meth- oxy group is then more likely due to its interaction with some intracellular target. The presence of a strong electron- ‘withdrawing group must alter the nature ofthe compound in such a way as to promote binding to the target(s) (Waring et al. 2002). Fagroddin et al, (2012) reported that electron releasing groups such as methoxy and naphthyl groups on 1-(2"4"-dichlorophe nyl)-3-{substituted aryl)-2-propene-t-ones exhibited maximum anti bacterial activity having against gram positive bacteria (Bacil- lus subtilis) and gram negative bacteria (Escherichia co), Similarly, slectron- releasing substitutions present in 1,4-naphthoquinones at position 2 or 3 increased (Riel etal, 2002). Alkoxy substitution (viz, 4-0CH, and 3.45-(0CH,),) on (4-0x0-thiazolidinyl) ‘quinazolin-4(3H) ones of 2-(2,6-Dichlorophenyl)amino}phenylace tic acid exhibited good antibacterial activity (Patel and Patel, 2007), In most ofthe biologically important derivatives of furans, sub- stitutions at 2- and 5-positions are commonly observed in nature (Salem, 2016). Out of the synthesized 25-disubstituted com- pounds on phenyl group in the present case, better antibacterial activity of 5-[(Benzene sulfonyl-methyl-amino)-methyl|-furan-3- catboxylic acid (2-chloro,S-methoxy-phenyl)-amide (BK) com- pared to 5-|{Henzene sulfonyl-methyl-amino)-methy!|furan-3-car boxylic acid (2.5-dimethoxy-phenyl)-amide (8E) might be due to the attachment of chloro group to phenyl. This result suggested that the introduction of halogen substituent increased the hydrophobicity of the synthesized compounds leading to the increase of the antibacterial activity (Wan et al, 2010), Electron ‘withdrawing groups like halogens will increase bactericiéal poten- tial, According to Prasac et al, (2008) designing the compounds bearing electron withdrawing substituents and with high degree of binding linearity with groups results in high molecular weights ‘which increase antibacterial activity. Literature survey reveals that lipophilicity ofthe test compounds is amended by the presence of electron withdrawing or donating groups, which in turn alters per- meabiliy across the bacterial cell membrane. 4-Amino-N-(13- Benzothiazol-2-yl)benzene sulphonamide derivatives with elec- tron withdrawing substituents like chlorofeatboxy substitutions have shown prominent antibacterial activity (Jshusati et al et Sun jBasie App Sa 6 (2017) 35-52 2008) Moreover, the presence of electron withdrawing. groups reduces electron density and hence helps the faster diffusion through the bacterial body leading to an increased antimicrobial activity (Hania, 2009). Wan etal, (2010) demonstrated that halo- gen substitution on the benzotriazoylpropanone improved the hydrophobicity and hence showed higher antibacterial activity against 8, subrilis, Electron withdrawing functional groups lke halo sroups an the phenyl group possess antibacterial activity in the case of (Z)-1-benzojb furan-2-y-3-Substituted phenyl)prop-2- en-I-one derivatives (Raj et al, 2012), 1-phenyl-3-(4-(4-Dutano loxy)pheny!)-S-aryl-i-pyrazoles (Goyal and Jain, 2012), chal- cones (Zangade et al, 2011), 4-Substituted-imino-methyltetra zolo{1,5-x}guinoline derivatives (Bava and Kumar, 2009) and ben- zotriazoles (Nuala and Ratnakaram, 2014), Bali studies reveal thatthe presence of electron withdrawing functional groups on the phenyl group at para position exhibit enhanced antibacterial activ- ity in (Z)-1-benzo[b|furan-2-y1-3-(Substituted phenyl)prop-2-en- T-one derivatives (Raj etal, 2012), T-phenyl-3-(4-(4- butanoloxy) pheny!)-5-aryl-1H-pyrazoles (Goyal and Jain, 2012), 2-Amino-4-(substituted)-64(3°-thienyl)pyrimidines and. 1,3,5-Tr substituted-2-pyrazolines (Anupama et al, 2012a, 2012b). How= ever in the present case, higher activity is observed with chlorine substituent at ortho position 43, Higher activity towards Gram (+) bacteria In the present study itis observed that inhibition displayed by synthetised 2,4-disubstituted furans against all the studied Gram () bacteria is higher than Gram (~) bacteria (Tables 1 and 2). ‘The differential activities of the synthesized compounds against these two types of bacteria can be elucidated taking into account oftheir cel outer layers In the case of Gram (+) bacteria, cell outer barzier is made up of peptidoglycan layer which is ineffective and permeable. Hence, drug constituents are permeable through the cell wall of Gram (+) bacteria. However, in Gram (-~) bacteria, cell Wallis made up of multilayered peptidoglycan and phospholipidic ‘membrane which is impermeable to drug constituents (Kumar val, 2011), Hence, 24-disubstituted furans have preferable activ- ity against Gram (+) bacteria 5. Conclusion In conclusion, the proposed methodology provides better yields compared to previous reports in synthesis of 24-di substituted fur- ans, Highest antibacterial activity was exhibited by the compound having methoxy substitution on two ortho positions. Both electron ‘withdrawing and donating groups on phenyl group have shown, improved antimicrobial activity on Gram (-) bacteria. Better antibacterial activities of synthesized compounds were observed against Streptococcus pyogenes, Proteus vulgaris, and Escherichia cl References “ely of seme ew 135-subsitted-pyrazlise Int Res. Phat “nd aitincobial act of some new 2a6cascsttutee pyridines. Ine) es. Pam, chem 9 (2, 231-235, Aponic AL C¥. Maing, Marques, 2009. Aa extremely ale syahess of Turan: poles, abd thepnenes by te ehyaraive evezauen of propel lesbos Org tet 1120, 4526-4627. BaneieR. Kas HA. Bapenee NC. 2012. Medicinal sigueance of furan “erates Arse nt) ev life 2) Foe 5 Ma Benue Un. asc Arp. 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