Novel Anti-bacterials Against MRSA: Synthesis of Focussed Combinatorial Libraries of Tri-Substituted 2(5H)-Furanones

Lattmann, Eric; Sattayasai, Nison; Schwalbe, Carl S.; Niamsanit, Suwanna; Billington, David C.; Lattmann, Pornthip; Langley, Chris; Singh, Harjit; Dunn, S. Patrick

doi:10.2174/157016306778108857

Cited by 45 publications

(30 citation statements)

References 14 publications

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“…It is reported that butalactin exhibits moderate antibacterial activity against Gram-positive bacteria [4]. Based on this findings, some derivatives of g-butyrolactone (5-alkoxy-4-aminofuran-2(5H)-one) showing good antibacterial activity against multiresistant Staphylococcus aureus were reported [5]. Recently, we focused our efforts to synthesize enamines with gbutyrolactone-core for antibacterial activity screening.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of 3-(4-fluorophenyl)-4-hydroxyfuran-2(5H)-one, C10H7FO3

Xiao¹,

Zhu²,

Jiang³

et al. 2010

Zeitschrift Für Kristallographie - New Crystal Structures

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C 10 H 7 FO 3 ,monoclinic, P12 1 /c1(no. 14), a =7.584(2) Å, b =8.863(2) Å, c =12.707(3) Å, b =90.64(1)°, V =854.1 Å 3 , Z =4,R gt(F) =0.041, wRref(F 2 ) =0.107, T =296 K. Source of materialAs olution of 2-ethoxy-2-oxoethyl 2-(4-fluorophenyl)-acetate (0.96 g, 4mmol) in dry THF was added dropwise to asuspension of NaH in dry THF in an ice cold bath. The stirring was maintained at room temperature for 5h.Water was added and the solution was extracted twice with ethyl ether. The aqueous phase was cooled to 0°Cand then acidified with concentrated hydrochloric acid to give asolid precipitate. The title compound was crystallized from ethanol-water (2:1, v/v)t og ive the colorless blockshaped crystals suitable for single-crystal structure determination. DiscussionCompounds with g-butyrolactone-core (furanone) show diverse biological activities such as antitumor and anti-inflammatory activity [1][2][3]. It is reported that butalactin exhibits moderate antibacterial activity against Gram-positive bacteria [4]. Based on this findings, some derivatives of g-butyrolactone (5-alkoxy-4-aminofuran-2(5H)-one) showing good antibacterial activity against multiresistant Staphylococcus aureus were reported [5]. Recently, we focused our efforts to synthesize enamines with gbutyrolactone-core for antibacterial activity screening. In the title crystal structure, the bond length d(C7-C10) = 1.346(2) Å is in the range of atypical double bond (1.32 -1.38 Å), and the title compound was therefore identified as afuran-2(5H)-one not afuran-2(3H)-one. Because C9 attaches to adouble bond, s-p hyperconjugation occurring between C9-H9A (H9B) and C7-C10 slightly shortens C9-C10 bond from about 1.53 to 1.490(2) Å.C10-O3 (1.316(2) Å)bond length is shorter than the standard C-Osingle bond (1.41 -1.44 Å), but longer than C-O double bond (1.19 -1.23 Å). This clearly indicated that an sp 3 orbital of O3 is conjugated with the p molecular orbital of C7=C10 double bond, which was supported by the small torsion angle (-1.5(2)°)ofC1-C7-C10-O3. The stereochemistry of the double bond in lactone ring was assigned as (E)-configuration (figure, top). The butyrolactone moiety makes ad ihedral angle of 17.86(6)°with the 4-fluorophenyl group. In the title compound, the two independent hydrogen bonds generate at wo-dimensional layer of edge-fused centrosymmetric rings running parallel to (100), with R 2 2 (8) rings built from pairs of C-H···Fhydrogen bonds centred at (0,3n/2 +1,-1n/2), where n represents an integer, and with the R 6 6 (44) rings built from pairs of C-H···Fa nd O-H···Oh ydrogen bonds centred at (0,3n/2+1, 1n/2), where n again represents an integer (figure, bottom). The resulted layer has azigzag pattern in the cross section, running along the [010] direction. In al ayer, each R 6 6 (44) ring runs through by other two R 6 6 (44) rings which are from other two layers, respectively, and these layers (three) therefore interweave each other to form al ayered tablet. The title ompound extends further to its final three-dimensional network through ...

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Section: Discussionmentioning

confidence: 99%

Crystal structure of 3-(4-fluorophenyl)-4-hydroxyfuran-2(5H)-one, C10H7FO3

Xiao¹,

Zhu²,

Jiang³

et al. 2010

Zeitschrift Für Kristallographie - New Crystal Structures

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“…Fore xample,s omed erivatives of gbutyrolactone (5-alkoxy-4-aminofuran-2(5H)-one) showing good antibacterial activity against multiresistant Staphylococcus aureus were reported [2].4-Alkylamino or 4-arylamino derivatives of 3-arylfuran-2(5H)-one are potent inhibitors against tyrosyl-tRNA synthetase (TyrRS) [1,3], one of the aminoacyltRNA synthetases(aaRSs). In the title compound, the bond C7-C10 (1.375(4) Å) was assigned as ad ouble bond [4,5], and the title compound was thereforeidentified as afuran-2(5H)-one, notafuran-2(3H)-one.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of 3-(4-bromophenyl)-4-(4-chloro-phenylamino)furan-2(5H)-one, C16H11BrClNO2

Peng¹,

Wu²,

Wang³

et al. 2012

Zeitschrift Für Kristallographie - New Crystal Structures

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Source of material3-(4-Bromophenyl)-4-hydroxyfuran-2(5H)-one (127 mg, 0.5 mmol) was prepared according to [1],and was added into a mixture of 4-chloroaniline (76 mg, 0.6 mmol) and p-toluene sulphonic acid (3.4 mg,0.02 mmol). The resulting mixture was heated to 363 Kfor 10 min. 5mLoftoluene were then added and refluxed for 4h.After toluene was removed under reduced pressure, the residue was purified by columnc hromatography on silica gel, eluting with EtOAc/petroleum ether (v/v =1/1). Experimental detailsThe Hatom bonded to N1 was located in difference Fourier map. The configuration of N1 could help to explain why d(C10-N1) is shorter than d(C11-N1). The Flack parameter is 0.016(8). DiscussionMany compounds of g-butyrolactone-core (furanone) show diverseb iologicala ctivities. Fore xample,s omed erivatives of gbutyrolactone (5-alkoxy-4-aminofuran-2(5H)-one) showing good antibacterial activity against multiresistant Staphylococcus aureus were reported [2].4-Alkylamino or 4-arylamino derivatives of 3-arylfuran-2(5H)-one are potent inhibitors against tyrosyl-tRNA synthetase (TyrRS) [1,3], one of the aminoacyltRNA synthetases(aaRSs). In the title compound, the bond C7-C10 (1.375(4) Å) was assigned as ad ouble bond [4,5], and the title compound was thereforeidentified as afuran-2(5H)-one, notafuran-2(3H)-one. Butyrolactone moiety and the attached amino group (H1,N 1, C10 and C11)a re nearly co-planar with ad ihedral angle of 5.2(2)°, indicating theconjugation of p orbitalofN1withthe p molecular orbital of C7-C10,which shortens the bond distance of C10-N1. Additionally, d(C10-N1) is further shortened to 1.342(3) Åbythe strong electron withdrawing effect of the carbonyl group (C8-O1), which is intermediated by p molecular orbital of C7-C10.However, C11-N1 is atypical single bond with the bond length of 1.433(3) Å. The dihedral angle of amino group and 4-chlorobenzene ring is quite large (58.5(2)°). The significant tilting of the amino group therefore breaks the conjugation with its attached 4-chlorobenzene ring. The bond distance d(C7-C10) =1 .355(3) Åi sm uch shorter than d(C7-C8) = 1.450(4) Å. This significantly increases the steric strain between 4-(4-chlorophenylamino) group and 3-(4-bromophenyl) group, whichleads to an increase in angle ÐC1-C7-C10 =129.4(2)°in comparison with ÐC1-C7-C8 =1 23.3(2)°. In the packing, the three independent hydrogen bonds generate at wo-dimensional layer running parallel to (010), in which two kinds of hydrogen bonding patterns could be observed with R 4 3 22 () and R 4 4 21 () rings built from C-H×××Oa nd N-H×××Oh ydrogen bonds. On the one hand,eachmolecule utilizes thetwo Oatoms of lactonemoiety as acceptorsand is hydrogen-bonded to threeothers.Onthe other hand, the same molecule utilizes C5, C16 and N1 as donors and forms hydrogen bonding interactions with another three molecules. Theabove mentioned layers are stacked by van der Waals forces.

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“…The 5-arylated 2(5H)-furanones reacted selectively in the ester position and no reaction in the 4-position was observed. Previously the substitution in the 4-position was described for pseudoesters 14 , and here a ring -opening ring -closure mechanism for the formation of hydroxyl-pyrrolones is proposed in scheme 2.…”

Section: Synthesismentioning

confidence: 97%

Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease

et al. 2017

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Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from muco-chloric acid and optimised as CCK 2 selective ligands using radiolabelled binding assays. CCK antagonism was confirmed for the ligands in isolated tissue preparations. DSS (dextran sulfate sodium) induced inflammation was analysed for derivative 7 and PNB-001 with L-365,260 as standard. The IC 50 of PNB-001 was determined as 10 nM. Subsequent in vivo evaluation confirmed anti-inflammatory activity with respect to IBD assays. The best molecule, PNB-001, showed analgesic activity in the formalin test and in the hotplate assay the analgesic effect of 1.5 mg/kg PNB-001 was equivalent to 40 mg/kg tramadol. The CCK 2 selective antagonist PNB-001 protected rats against indomethacin induced ulceration at similar doses. The GI protection activity was found more potent than the 10 mg/kg dose of prednisolone, which served as standard.

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Novel Anti-bacterials Against MRSA: Synthesis of Focussed Combinatorial Libraries of Tri-Substituted 2(5H)-Furanones

Cited by 45 publications

References 14 publications

Crystal structure of 3-(4-fluorophenyl)-4-hydroxyfuran-2(5H)-one, C10H7FO3

Crystal structure of 3-(4-fluorophenyl)-4-hydroxyfuran-2(5H)-one, C10H7FO3

Crystal structure of 3-(4-bromophenyl)-4-(4-chloro-phenylamino)furan-2(5H)-one, C16H11BrClNO2

Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease

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