Studies on 8-methoxyquinolones: synthesis and antibacterial activity of 7-(3-amino-4-substituted)pyrrolidinyl derivatives

A series of 8-methoxyquinolones bearing 3-amino-4-methylpyrrolidines or 3-amino-4-fluoromethylpyrrolidines at the C-7 position was synthesized and their physicochemical and biological properties were evaluated. All of the compounds synthesized showed more potent activity than LVFX (3) against both gram-positive and negative bacteria. Increases in lipophilicity of these compounds had desirable effects on their potency of single intravenous toxicity and pharmacokinetic profiles in animals. Among the compounds synthesized, 1-fluorocyclopropyl derivatives 17 and 20, and 7-(cis-3-amino-4-fluoromethylpyrrolidinyl) derivative 19 (DC-756h) showed negative responses in the micronucleus test in mice while 1-cyclopropyl-7-(3-aminopyrrolidinyl) derivative 16 showed a positive response. These results suggested that the introduction of a fluorine atom into the 3-aminopyrrolidinyl substituent resulted in favorable influence on genetic toxicity as well as into the N-1 cyclopropyl substituent.     

Glycosylation of o-acylamino derivatives of 4-methyl-7-hydroxy-coumarin

Certain glycopyranosides of o-acylamino-4-methyl-7-hydroxycoumarin were studied. They have potential application as fluorogenic substrates for a number of enzymes in biochemical diagnostics of hereditary diseases.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 603–606, May, 1987.     

Synthesis of 2-substituted-7-azaindoles from 2-amino-3-picolin

An easy route to the synthesis of 2-substituted-7-azaindole derivatives has been developed. The carbinol intermediate dissolved in DMF undergoes cyclization upon treatment with sodium hydride, trifluoroacetic anhydride, and trifluoroacetic acid at 120 °C in a straightforward and one-pot step. An alternative methodology using (CF₃SO₂)₂O in acetonitrile in basic media followed by the addition of CF₃COOH affords the expected 2-substituted azaindole in best yields.     

A concise synthesis of 3-substituted-7-amino-6-carboxyl-8-azachromones

We report on an approach to truncate the tricyclic 5H-chromeno[2,3-b]pyridin-5-one core of amlexanox, an approved drug under investigation for the treatment of obesity, to the bicyclic 4H-pyrano[2,3-b]pyridin-4-one (8-azachromone) core. A short, concise synthesis generates a key intermediate with requisite functionality on the pyridyl A-ring and iodo functionality on the 4-pyrone B-ring upon which palladium-catalyzed cross-coupling and subsequent reactions generate representative analogues. One of these shows a 14.2-fold increase in aqueous solubility over amlexanox.     

Studies on chemotherapeutics I. Synthesis of 5-substituted-4-oxo-1,4-dihydro-3-pyridinecarboxylic acid derivatives

Ethyl 5-substituted-4-oxo-1,4-dihydro-3-pyridinecarboxylates were synthetized by reacting 1,3,5-triazine with 4-substituted ethyl acetoacetate derivatives in ethanol, in the presence of sodium ethoxide. The l-alkyl-5-substituted-4-oxo-1,4-dihydro-3-pyridinecarboxylic acids required for the antimicrobial studies were prepared by N-alkylation (with triethyl phosphate or alkyl halides) and alkaline hydrolysis of the pyridone esters.     

Synthesis and antibacterial activity of novel 7-substituted-6-fluoro-1- fluoromethyl-4-oxo-4H-[1,3thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives

A series of 7-substituted-6-fluoro-1-fluoromethyl-4-oxo-4H- [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives (2a-1) was prepared and evaluated for antibacterial activity. These compounds were obtained by deacylation of 4-benzoyloxy-2-(1-chloro-2-fluoroethyl)thio-6,7- difluoroquinoline-3-carboxylate (10) and subsequent intramolecular cyclization followed by substitution with cyclic amines and then hydrolysis. The intramolecular cyclization reaction of 18, one of the diastereomers (17, 18) revealed that the cyclization reaction proceeded through an inversion to afford (-)-11a in good chemical and optical yield. The enantiomers of 2a were prepared from the enantiomers of 11a, which were obtained by the optical resolution of the racemate using high-performance liquid chromatography (HPLC). Compounds 2a,b showed excellent in vitro and in vivo antibacterial activity against both gram-negative and gram-positive bacteria including quinolone and Methicillin-resistant Staphylococcus aureus.     

Design, synthesis and antiproliferative activity of novel 2-substituted-4-amino-6-halogenquinolines

Two series of novel 2-substituted-4-amino-6-halogenquinolines 8a-l and 13a-h were designed, synthesized and evaluated for their antiproliferative activity against H-460, HT-29, HepG2 and SGC-7901 cancer cell lines in vitro. The pharmacological results indicated that most compounds with 2-arylvinyl substituents exhibited good to excellent antiproliferative activity. Among them, compound 8e was a considered promising lead for further structural modifications with IC?? values of 0.03 μM, 0.55 μM, 0.33 μM and 1.24 μM, which was 2.5- to 186-fold more active than gefitinib and compound 1.     

Studies on pyridonecarboxylic acids . 2. Synthesis and antibacterial activity of 8-substituted-7-fluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acids

A series of 8-substituted-7-fluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acids was prepared and evaluated for antibacterial activity. These compounds were synthesized from ethyl 2-mercaptoquinoline-3-carboxylates 17 which were obtained from anilines 11 by a route involving an intramolecular cyclization reaction.     

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 of some new 2-substituted-4-sulfamoylphenylazo-thiophene and/or thiazole derivatives as antibacterial agents

Benzoylacetone has been reacted with phenyl isothiocyanate to afford two different thiocarbamoyl derivatives (α-phenylthiocarbamoyl benzoylacetone and benzoyl thioacetanilide) depending upon the base used to perform the reaction. Several new 2-substituted-4-sulfamoylphenylazo-thiophene and/or thiazole derivatives were synthesized by heterocyclization of the thiocarbamoyl derivatives with various halogenated reagents. The synthesized compounds were screened for their antibacterial activities; they showed accepted activities with respect to the control drugs.     

Facile synthesis of 5-amino- and 7-amino-6-azaoxindole derivatives

An efficient approach for the formation of 5-amino- and 7-amino-6-azaoxindole derivatives was developed. 2-Amino-4-chloro-3-nitropyridine (8), and its 5-nitro-substituted regioisomer (9), respectively, were obtained by reaction with ethyl malonate. The resulting 2-amino-3/5-nitropyridine derivatives substituted in the 4-position with malonic acid diethyl ester (10, 11) were subjected to reductive cyclization yielding 3-ethoxycarbonyl-6-azaoxindole derivatives 4a and 5a. Protection of the amino function was not required. Intermediates 10 and 11 could also be converted to the corresponding 4-acetic acid ethyl esters 12 and 13 by dealkoxycarbonylation with LiCl, and subsequently cyclized under reductive conditions yielding 3-unsubstituted 5-/7-aminooxazindoles.     

Synthesis of novel coumarin substituted amide derivatives and their antibacterial activities

A series of novel coumarin substituted amide derivatives were synthesized and evaluated for their antibacterial activities. Result indicated that compounds 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n, 3o and 3q exhibited excellent antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas citri subsp. Citri (Xcc) in vitro, which were better than those of commercial agricultural antibacterial thiodiazole-copper. The title compounds with electron-withdrawing group showed better antibacterial activities than those of compounds with electron-donating group, and the title compounds bearing the same substituent group exhibited better antibacterial activities against Xcc than antibacterial activities against Xoo.     

A general approach for the synthesis of 5-substituted-4-amino-pyrrolidin-2-ones and 5-substituted-4-amino-3-pyrrolin-2-ones

Short stereoselective syntheses of both 5-substituted-4-amino-pyrrolidin-2-ones and 5-substituted-4-amino-3-pyrrolin-2-ones from natural α-amino acids are described.     

Synthesis of new derivatives of 4-amino-2,4-dihydro-1,2,4-triazol-3-one as potential antibacterial agents

Thirty new 2-substituted-4-amino-5-alkyl or aryl-2,4-dihydro-1,2,4-triazol-3-ones and ten 2-substituted-5-alkyl or aryl-4-(5-nitro-2-furfurylidene)amino-2,4-dihydro-1,2,4-triazol-3-ones were synthesized and characterised by their sharp melting points, elemental analysis, ir and ¹H nmr spectra. These new derivatives of 5-nitro-2-furaldehyde were screened for their antibacterial activities. Most of the compounds showed good activity against one test organism, Staphylococcus aureus. For a few compounds, C.M.I. ranged from 4 to 8 μg/ml (higher results than nitrofurantoin).     

Synthesis, characterization and antifungal evaluation of 5-substituted-4-amino-1,2,4-triazole-3-thioesters

A series of 5-substituted-4-amino-1,2,4-triazole-3-thioesters was synthesized by converting variously substituted organic acids successively into the corresponding esters, hydrazides, 5-substituted-1,3,4-oxadiazole-2-thiols, 5-substituted-1,2,4-triazole-2-thiols and 5-substituted-1,3,4-oxadiazole-2-thioesters. Finally the target compounds were obtained by refluxing 5-substituted-1,3,4-oxadiazole-2-thioesters in the presence of hydrazine hydrate and absolute alcohol. The structures of the synthesized compounds were established by physicochemical and spectroscopic methods. The synthesized compounds were evaluated for their in vitro antifungal activity. Some of the evaluated compounds possessed significant antifungal activity as compared to a terbinafine standard.     

Microwave assisted synthesis,spectroscopic and antibacterial studies of titanocene chelates of Schiff bases derived from 3-substituted-4-amino-5-hydrazino-1,2,4-triazoles

The reactions of bis(cyclopentadienyl)titanium(IV) chloride with a new series of Schiff bases (LH₂), derived by condensing 3-(phenyl/2-chlorophenyl/4-nitrophenyl)-4-amino-5-hydrazino-1,2,4-triazoles with salicylaldehyde or 2-hydroxyacetophenone, have been studied both by conventional stirring method and also by using microwave technology. The products of type [(η⁵-C₅H₅)₂Ti(L)] have been isolated in both cases. Tentative structural conclusions are drawn for the reaction products based upon physico-chemical and spectroscopic methods. The ligands behave as dibasic, tetradentate chelating agents and a six-coordinated structure have been assigned to these derivatives. Studies were conducted to assess the growth inhibiting potential of the free Schiff bases and their complexes against various bacterial strains.