Studies on antibacterial agents. II. Synthesis and antibacterial activities of substituted 1,2-dihydro-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acids

A series of substituted 1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acids for the treatment of systemic infections was synthesized via 7-bromo-3-ethylthio-4,5-difluoro-2-methylindole (3), which was prepared by Gassman's indole synthesis in excellent yield. The synthesized pyrroloquinolines were tested for their antibacterial activities. 8-Fluoro-1,2-dihydro-2-methyl-9-(4-methyl-1-piperazinyl)-6-oxo-6H- pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid showed a potent antibacterial activity against gram-positive and gram-negative bacteria.     

Synthesis and antibacterial activity of 1-(substituted-benzyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acids and their 6,8-difluoro analogs

Alkylation of 6,7-difluoro-4-hydroxyquinoline-3-carboxylic acid ethyl ester with substituted-benzyl chlorides gave 1-(substituted-benzyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl esters. Their treatment with piperazine or N-methylpiperazine in pyridine yielded 1-(substituted-benzyl)-6-fluoro-1,4-dihydro-4-oxo-7-(l-piperazinyl)quinoline-3-carboxylic acid ethyl esters which were hydrolyzed with aqueous sodium hydroxide and then acidified with hydrochloric acid afforded the desired 1-(substituted-benzyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-iperazinyl)quinoline-3-carboxylic acids. The 6,8-difluoro analogs were prepared similarly using 6,7,8-trifluoro-4-hydroxyquinoline-3-carboxylic acid ethyl ester as a starting material. Some of these quinolones demonstrated fairly good antibacterial activities. Among them, 6-fluoro-1-(4-fluorophenylmethyl)-1,4-dihydro-7-(1-iperazinyl)-4-oxoquinoline-3-carboxylic acid ( 7d ) and 6,8-difluoro-1-(3-fluorophenylmethyl)-1,4-dihydro-7-(1-piperazinyl)-4-oxoquinoline-3-carboxylic acid ( 8c ) are two of the best.     

Synthesis of fluorinated 2,6-heptanediones and 2-oxa-6- azabicyclo[2.2.2]octanes from 1,4-dihydropyridines

Electrophilic fluorination of Hantzsch-type 1,4-dihydropyridines with Selectfluor^® led to the formation of new fluorinated 2,6-heptanediones - dialkyl 2,4-diacetyl-2,4-difluoro-3-phenylpentanedioates. Novel 2,6-heptanedione derivatives in reaction with hydrazine hydrate easily form 6-amino-4,7-difluoro-3-hydroxy-1,3-dimethyl-5-oxo-8-phenyl-2-oxa-6-azabicyclo[2.2.2]octanes instead of the corresponding diazepine derivatives. The obtained 2-оxa-6-azabicyclo[2,2,2]octanes are thermally stable at the temperatures below 50°С. At higher temperatures rearrangement of 2-oxa-6-azabicyclo[2,2,2]octanes offers new fluorine-containing pyrazolinone derivatives - alkyl esters of 2-fluoro-2-((4-fluoro-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)(phenyl)methyl)-3-oxobutanoates.     

Synthesis of Mono-and Di-fluorinated Benzimidazoles

Three efficient methods to synthesize mono‐ and di‐fluorinated benzimidazoles are reported. These methods provide 5‐amino‐6‐fluoro‐benzimidazoles ( 5 ), 5,7‐difluoro‐benzimidazoles ( 10 ), and 6‐fluoro‐benzimidazoles ( 13 ) starting from commercially available 1,5‐difluoro‐2,4‐dinitrobenzene (DFDNB), 2,3,4,5‐tetrafluoro‐6‐nitrobenzoic acid (TFNBA), and 2,4‐difluoro‐1‐nitrobenzene (DFNB), respectively.     

Synthesis of regioisomeric 6,9-(chlorofluoro)-substituted benzo[g]quinoline-5,10-diones,benzo[g] isoquinoline-5,10-diones and 6-chloro-9-fluorobenzo[g]quinoxaline-5,10-dione

Treatment of difluoro or chloro fluoro-substituted benzyl bromides 5a-c with zinc dust in tetrahydro-furan leads to the corresponding benzylic zinc bromides 6a-c. These organometallics on treatment with chlorosubstituted heterocyclic esters 4A and 4B mediated by nickel catalysis undergo couplings to yield dihalobenzyl substituted heterocyclic esters 7Aa-c and 7Ba-c. Treatment of 4c with 6c under Pd catalysis leads to 7Cc. The acids 8, prepared by hydrolysis of these esters, with treatment of fuming sulfuric acid undergo cyclizations and oxidations to yield the desired regioisomeric dihalo-substituted heterocyclic quinones 2.     

Fluorocinnoline derivatives. II. Synthesis and antibacterial activity of fluorinated 1-alkyl-1,4-dihydro-4-oxocinnoline-3-carboxylic acids

Chemical modification of cinoxacin was studied with the aim of improving its antibacterial activity and spectrum. Alkylation of ethyl 6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnoline-3-carboxylates (1 and 7) with alkyl iodide or dialkyl sulfate gave ethyl 1-alkyl-6,7,8-trifluoro- and 6,7-difluoro-1,4-dihydro-4-oxocinnoline-3-carboxylates (2 and 8), together with the isomeric anhydro-bases 3 and 9 of 2-alkyl-3-ethoxycarbonyl-6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnolinium hydroxides, respectively. Acid-catalyzed hydrolysis of the 1-alkyl derivatives 2 and 8 gave the corresponding carboxylic acids 4 and 10. The same treatment of 3 and 9, accompanied with decarboxylation of the inner salts 5 and 11, afforded the anhydro-bases 6 and 12 of 2-alkyl-4-hydroxycinnolinium hydroxides, respectively. Displacement reactions of 4 and 10 with nucleophiles such as amine, alkoxide and thiolate gave 7-substituted 1-alkyl-6,8-difluoro- and 6-fluoro-1,4-dihydro-4-oxocinnoline-3-carboxylic acids (13 and 17-35). Antibacterial activities of these compounds were evaluated and compared with those of cinoxacin and norfloxacin. Some compounds showed a broader spectrum and more potent activity than cinoxacin, but were considerably inferior in activity to norfloxacin.     

Chemistry of fluorinated quinones I. The Diels-Alder reactions of fluoranil

The Diels-Alder reaction of fluoranil with cyclopentadiene, 1,3-butadiene, and 1-acetoxy-1,3-butadiene gave 1,4, 5, 8-bis(methylene)-4a, 8a, 9a, 10a-tetrafluoro-1, 4, 4a, 5, 8, 8a, 9a, 10a-octahydroanthraquinone (I), 2, 3, 4a, 8a-tetrafluoro-4a, 5, 8, 8a-tetrahydro-1,4-naphthoquinone (III), and 5-acetoxy-2, 3, 4a, 8a-tetrafluoro-4a, 5, 8, 8a-tetrahydro-1,4- naphthoquinone (VI), respectively. Hydrogenation of I gave the expected saturated diketone(II). Hydrogenation of III afforded, with elimination of the two tertiary fluorines, 2,3-difluoro-5, 6, 7, 8-tetrahydro-1, 4- dihydroxynaphthalene (IV). In hydrogenation of VI, acetic acid and two moles of hydrogen fluoride were eliminated to give 2,3-difluoro-1, 4-dihydroxynaphthalene(VII). Both dihydroxy compounds IV and VII yielded on oxidation with ferric chloride the corresponding quinones, 2, 3- difluoro-5, 6, 7, 8-tetrahydro-1, 4-naphthoquinone (V) and 2, 3-difluoro-1, 4-naphthoquinone (VIII), respectively. Equivalent amounts of compounds IV and V gave a red-brown semiquinone IX, and a mixture of VI and VIII gave a dark-violet semiquinone X.     

Synthesis of 7-thio-substituted 4-oxoquinoline-3-carboxylic acids with antibacterial activity

A series of C-7 thio-substituted 1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids were prepared and tested for their antibacterial activity. Structure-activity relationships associated with the C-5 and C-7 substituents were discussed. Among the C-7 substituents including alkylthio, arylthio, heteroarylthio, and cyclic aminothio groups, a 2-aminoethylthio group was the best for enhancing in vitro antibacterial activity. The C-5 variants increased activity in the order OH less than F less than H less than NH2. Of compounds prepared in this work, 5-amino-7-(2-aminoethyl)thio-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4 -oxo-quinoline-3-carboxylic acid (18) was the most active.     

Synthesis and biological activity of novel amino acid-(N'-benzoyl) hydrazide and amino acid-(N'-nicotinoyl) hydrazide derivatives

The coupling reaction of benzoic acid and nicotinic acid hydrazides with N- protected L-amino acids including valine, leucine, phenylalanine, glutamic acid and tyrosine is reported. The target compounds, N-Boc-amino acid-(N;-benzoyl)- and N- Boc-amino acid-(N;-nicotinoyl) hydrazides 5a-5e and 6a-6e were prepared in very high yields and purity using N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl- methylene]-N-methyl-methanaminium hexafluorophosphate N-oxide (HATU) as coupling reagent. The antimicrobial activity of the Cu and Cd complexes of the designed compounds was tested. The products were deprotected affording the corresponding amino acid-(N;-benzoyl) hydrazide hydrochloride salts (7a-7e) and amino acid-(N;- nicotinoyl) hydrazide hydrochloride salts (8a-8e). These compounds and their Cu and Cd complexes were also tested for their antimicrobial activity. Several compounds showed comparable activity to that of ampicillin against S. aureus and E. coli.     

Synthesis of indan-based unusual alpha-amino acid derivatives under phase-transfer catalysis conditions

Conformationally constrained cyclic alpha-amino acid derivatives were synthesized under solid-liquid phase-transfer catalysis conditions. This methodology involves the bis-alkylation of ethyl isocyanoacetate with various alpha,alpha'-dibromo-o-xylene derivatives [alpha,alpha'-dibromo-o-xylene 5, 2,3-bis(bromomethyl)-1, 4-dimethoxybenzene 6, 1,2-bis(bromomethyl)-4,5-dibromobenzene 7, 2, 3-bis(bromomethyl)naphthalene 8, 1,8-bis(bromomethyl)-naphthalene 9, 6,7-bis(bromomethyl)-2,2-dimethyl-1H-phenalene-1,3(2H)-dione 10, 2, 3-bis(bromomethyl)-1,4-anthraquinone 11, 6, 7-bis(bromomethyl)quinoxaline 12, 3,4-bis(bromomethyl)furan 13, 1,2, 4,5-tetrakis(bromomethyl)benzene 28, and hexakis(bromomethyl)benzene 30] using potassium carbonate as a base and tetrabutylammonium hydrogensulfate as a phase-transfer catalyst to give corresponding isonitrile derivatives, which upon hydrolysis with HCl in ethanol gave amino esters. Using this method electron-deficient as well as electron-rich and halogen-substituted indan-based alpha-amino acids were prepared. The preparation of bis-indan as well as tris-indan alpha-amino esters is also described.     

Synthesis and antibacterial activity of some 7-substituted 1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acids: Ethers,secondary amines and sulfides as c-7 substituents

A series of 7-substituted 1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acids were prepared from 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8 . Those derivatives reported contain acyclic and heterocyclic substituents linked to the quinolone C-7 position via O, NH or S. The in vitro antibacterial data of some of these derivatives against 4 Gram positive and 4 Gram negative organisms are reported.     

An exceptional red shift of emission maxima upon fluorine substitution

The effect of perfluorination on photophysical properties was investigated through synthesis and photophysical characterization of two isostructural donor-acceptor-donor dye molecules. The synthesis of two versatile fluorinated benzene compounds, 1,4-difluoro-2,5-diperfluorooctylbenzene (1) and 1,4-dibromo-2,5-difluoro-3,6-diperfluorooctylbenzene (2), is presented. The X-ray structure of 2 has been determined and shows that the perfluorinated octyl chains segregate from the benzene rings in the solid state, giving rise to a layered structure. The further synthesis through Suzuki coupling reactions using 4-formylbenzeneboronic acid with (2) and 1,4-dibromo-2,5-dioctylbenzene (3) gave, respectively, 1,4' '-diformyl-2',5'-difluoro-3',6'-diperfluorooctyl-p-terphenylene (4) and 1,4' '-diformyl-2',5'-dioctyl-p-terphenylene (5). The condensation of the dialdehydes 4 and 5 with 9,10-phenanthrenequinone and ammoniumbicarbonate in glacial acetic acid gave the dye molecules 1,4' '-bis(1H-phenanthro[9,10-d]imidazol-2-yl)-2',5'-difluoro-3',6'-diperfluorooctyl-p-terphenylene (6) and 1,4' '-bis(1H-phenanthro[9,10-d]imidazol-2-yl)-2',5'-dioctyl-p-terphenylene (7), respectively. The UV-vis spectra of the two molecules are nearly identical, whereas the fluorescence spectra are very different. Compound 7 shows blue fluorescence with little solvent dependence (lambda(emission) = 410 nm in THF, CH2Cl2, and hexane), whereas compound 6 shows a highly solvent-dependent emission wavelength (lambda(emission) = 583 nm in THF, lambda(emission) = 560 nm in CH2Cl2, and lambda(emission) = 450 nm in hexane). The fluorescence red shift of compound 6 in a series of solvents with different polarity is discussed using the Lippert-Mataga equation. Fluorescence lifetime and quantum yields were also determined. Ultraviolet photoelectron spectroscopy (UPS) was performed on thin films of compound 6 and 7 on a gold substrate. The observed ionization potential was 6.15 eV for 6 and 5.85 eV for 7" [correction].     

(N-Isocyanimino)triphenylphosphorane-Mediated,One-Pot,Efficient Synthesis of Sterically Congested 1,1,1-Trifluoro-2-(5-aryl-1,3,4-oxadiazol-2-yl)-2-propanol Derivatives via Intramolecular Aza-Wittig Reaction

Reactions of (N-isocyanimino)triphenylphosphorane with 1,1,1-trifluoroacetone in the presence of aromatic (or heteroaromatic) carboxylic acids (3-methylbenzoic acid, 1-naphthalenecarboxylic acid, 2-naphthalenecarboxylic acid, 2-furancarboxylic acid, and 2-thiophenecarboxylic acid) proceed smoothly at room temperature and in neutral conditions to afford sterically congested 1,1,1-trifluoro-2-(5-aryl-1,3,4-oxadiazol-2-yl)-2-propanol derivatives in high yields. The reaction proceeds smoothly and cleanly under mild conditions, and no side reactions were observed.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

分离检测生物活性物质的荧光标记试剂与分子探针及其应用

作者结合自己的研究工作主要评述了用于分离检测氨基化合物（氨基酸、肽、蛋白质和生物胺等）、巯基化合物（谷胱甘肽、半胱氨酸和高半胱氨酸等）及NO等生物活性物质的荧光标记试剂和荧光分子探针的近期进展和应用。除了传统的的OPA、NDA、DNS、FMOC、FITC、NBD-F、AQC、Cy5等在HPLC和CE分离荧光检测应用新进展,还介绍了许多新的荧光分子探针和标记试剂的性能和应用。它们是N－羟基琥珀酰亚胺活性酯荧光标记试剂,6-氧-（N-琥珀酰亚胺乙酸酯）-9-（2'-甲氧羰基）荧光素（SAMF）,1,3,5,7-四甲基-8-苯基-（4'-O-（N-琥珀酰亚胺乙酸酯））-二氟化硼-二吡咯甲烷（TMPAB-Osu,）等和3-碘乙酰胺苯嵌蒽酮荧光探针及MCY5、DSTCY、DCDSTCY和DCTCY等花菁类近红外荧光探针等。     

A new synthetic route to 7-halo-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,an intermediate for the synthesis of quinolone antibacterial agents

Starting from m-fluorotoluene, 7-chloro-6-fluoro- and 6,7-difluoro-1-cyclopropyl-1,4-dihydro-4-oxoquino-line-3-carboxylic acids, 3 and 16 were synthesized. Compounds 3 and 16 are useful intermediates for the synthesis of a class of quinolone antibacterial agents. The synthetic route involves two processes; i) construction of the quinoline ring by an intramolecular cyclization accompanied by the elimination of a nitro group and ii) introduction of fluorine atom by replacement of a nitro group with potassium fluoride. 7-(3-Amino-1-pyrroli-dinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (18) was prepared from 3 or 16. The antibacterial activity of 18 compares favorably with that of ciprofloxacin (2) .     

Reaction of azole condensed quinoxaline N-oxides with acetic anhydride

The reaction of 7-chlorotetrazolo[1,5-α]quinoxaline 5-oxide 6a with acetic anhydride gave 7-chloro-5-(7-chlorotetrazolo[1,5-α]quinoxalin-4-yl)-4,5-dihydro-4-oxotetrazolo[1,5-α]quinoxaline 7a , while the reaction of 7-chloro-1,2,4-triazolo[4,3-α]quinoxaline 5-oxide 6b with acetic anhydride afforded 7-chloro-5-(7-chloro-1,2,4-triazolo[4,3-α]quinoxalin-4-yl)-4,5-dihydro-4-oxo-1,2,4-triazolo[4,3-α]quinoxaline 7b and 7-chloro-4,5-dihydro-4-oxo-1,2,4-triazolo[4,3-α]quinoxaline 8b . The reaction of compound 6a or 6b with acetic anhydride/acetic acid provided 7-chloro-4,5-dihydro-4-oxo-tetrazolo[1,5-α]quinoxaline 8a or compound 8b , respectively.     

Transformation of a spirobarbituric acid via aminobarbituric acid‐hydantoin rearrangement

A successful application of the aminobarbituric acid‐hydantoin rearrangement to produce a bicyclic carbamoylhydantoin from an intermediate spirobarbituric acid is reported. 7a‐Phenylcarbamoyl‐tetrahydro‐1H‐pyrrolo[1,2‐c]imidazole‐1,3(2H)‐dione ( 8 ) was obtained in a one‐pot multistep reaction of 1‐acetyl‐2,2‐bis(ethoxycarbonyl)pyrrolidine ( 5 ) and phenylurea in the presence of sodium ethoxide. Under less severe conditions, 5 and phenylurea were reacted to afford 1‐acetyl‐7‐phenyl‐triaza[4,5]decane‐6,8,10‐trione ( 6 ). The structural elucidation of the bicyclic hydantoin 8 and the spirobarbituric acid 6 was based on relevant nmr signals in accordance with those of reference compounds, i.e. monocyclic hydantoins 4a,b and acetamidobarbituric acids 2a‐c. The latter compounds were newly prepared from diethyl acetamidomalonates 1 and phenylurea.     

Syntheses, structures, and electrochemical properties of platinum(II) complexes containing di-tert-butylbipyridine and crown ether annelated dithiolate ligands

A series of new platinum(II) complexes containing both 4,4'-di-tert-butyl-2,2'-bipyridine (dbbpy) and the extended tetrathiafulvalenedithiolate ligands have been prepared and characterized. These complexes include [Pt(dbbpy)(C8H4S8)] (1; C8H4S82- = 2-{(4,5-ethylenedithio)-1,3-dithiol-2-ylidene}-1,3-dithiol-4,5-dithiolate), [Pt(dbbpy)(ptdt)] (2; ptdt = 2-{(4,5-cyclopentodithio)-1,3-dithiol-2-ylidene}-1,3-dithiol-4,5-dithiolate), [Pt(dbbpy)(mtdt)] (3; mtdt = 2-{(4,5-methylethylenedithio)-1,3-dithiol-2-ylidene}-1,3-dithiol-4,5-dithiolate), [Pt(dbbpy)(btdt)] (4; btdt = benzotetrathiafulvalenedithiolate), [Pt(dbbpy)(C8H6S8)] (5; C8H6S82- = 2-{4,5-bis(methylthio)-1,3-dithiol-2-ylidene}-1,3-dithiol-4,5-dithiolate), [Pt(dbbpy)(3O-C6S8)] (6; 3O-C6S82- = 2-{4,5-dithia-(3',6',9'-trioxaundecyl)-1,3-dithiol-2-ylidene}-1,3-dithiol-4,5-dithiolate), and [Pt(dbbpy)(4O-C6S8)] (7; 4O-C6S82- = 2-{4,5-dithia-(3',6',9',12'-tetraoxatetradecyl)-1,3-dithiol-2-ylidene}-1,3-dithiol-4,5-dithiolate). The crystal structures of a new ligand precursor (2-[4,5-dithia-(3',6',9',12'-tetraoxatetradecyl)-1,3-dithiol-2-ylidene]-4,5-bis(2-cyanoethylsulfanyl)-1,3-dithiole, IIIc) and complexes 5-7 have been determined by X-ray crystallography. Complexes 1-7 show intense electronic absorption bands in the UV-vis region due to the intramolecular mixed metal/ligand-to-ligand charge-transfer transition, and they display significant solvatochromic behavior. Redox properties of these compounds have been investigated by cyclic voltammetry, and complex 7 shows a significant response for Na+ ions with a large positive shift of ca. 45 mV.     

New antifungal 1,2,4-triazoles with difluoro(heteroaryl)methyl moiety

New 1,2,4-triazoles (1) having a difluoro(heteroaryl)methyl moiety were designed and synthesized via 1-aryl-2,2-difluoro-2-(heteroaryl)ethanones (2), which were prepared by two routes starting from the reaction of ethyl 2,2-difluoro(heteroaryl)acetate with phenyllithiums (Route A) and from the reaction of chlorodifluoro(heteroaryl)methane with benzaldehydes (Route B). The compounds 1 except for 1g show antifungal activities against yeasts and filamentous fungi in vitro, especially (+)-1f have equal or superior activities compared to those of itraconazole.     

The reaction of acetic acid 2‐selenoxo‐2H‐pyridin‐1‐yl esters with benzynes: A convenient route to Benzo[b]seleno[2,3‐b]pyridines

Benzyne and its 3,4,5,6‐tetraphenyl, 3‐ and 4‐methyl, 3‐methoxy and 4,5‐difluoro derivatives react with acetic acid 2‐selenoxo‐2H‐pyridin‐1‐yl esters 4a‐e to give benzo[b]seleno[2,3‐b]pyridines 10–15 in modest yields. The benzynes were generated by one or more of the following methods: diazotization of anthranilic acids 5a‐g with isoamyl nitrate; mild thermal decomposition of 2‐diazoniobenzenecarboxylate hydrochlorides 6a‐d treatment of (phenyl)[o‐(trimethylsilyl)phenyl]iodonium triflate (7) with tetrabutylammonium fluoride; and treatment of 2‐trimethylsilylphenyl triflates 8a‐c with cesium fluoride. In all the reactions, the corresponding 2‐(methylselenenyl)pyridines 16a‐d were also obtained suggesting that these reactions may involve selenium addition to benzyne via a SET (single electron transfer).