Synthesis of 1,4-dihydro-4-oxopyrrolo[1,2-b]pyridazine-3-carboxylic acids and 1,4-dihydro-4-oxoimidazo[1,5-b]pyridazine-3-carboxylic acids as potential antibacterial agents

To check the antibacterial potential of two families of aza analogues of the quinolones, 1,4-dihydro-4-oxopyrrolo[1,2-b]pyridazine-3-carboxylic acids and 1,4-dihydro-4-oxoimidazo[1,5-b]pyridazine-3-carboxylic acids, we have prepared a few derivatives in theses families using N-aminopyrrole and N-aminoimidazole derivatives as starting building blocks and the classical pathways of the quinolone series. The compounds showed no interesting antibacterial activity.     

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.     

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.     

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.     

Synthesis of 8-cyano-1,4-dihydro-4-oxopyrrolo[1,2-a]pyrimidine-3-carboxylic acids as potential antimicrobial agents

The preparation of a variety of 8-cyano-1,4-dihydro-7-phenyl-4-oxopyrrolo[1,2-a]pyrimidine-3-carboxylicacids and 8-cyano-1,4-dihydro-7-p-fluorophenyl-4-oxopyrrolo[1,2-a]pyrimidine-3-carboxylic acids is 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.     

Synthesis of 1,4-dihydro-4-oxopyridazino[1,6-a]indole-3-carboxylic acids and 1,4-dihydro-4-oxopyrido[3′,2′:4,5]pyrrolo[1,2-b]-pyridazine-3-carboxylic acids as potential antibacterial agents

A few aza analogues of the quinolones have been prepared in the two families of the 1,4-dihydro-4-oxopyridazino[1,6-a]indole-3-carboxylic acids and the 1,4-dihydro-4-oxopyrido[3′,2′:4,5]pyrrolo[1,2-b]-pyridazine-3-carboxylic acids to check their antibacterial potential. One compound 6c shows antibacterial activities of the level of nalidixic acid and represents a new lead structure differing from the classical quinolones.     

Direct monobromination of substituted 4-oxoquinoline-3-carboxylic acid derivatives

N-Bromosaccharin in the presence of pyridinium poly(hydrogen fluoride) can be used for monobromination of ethyl esters of 6- and 7-substituted-4-oxo-1,4-dihydroquinoline-3-carboxylic acids. The reactions take place at the C₆ or C₈ positions, depending on the types and positions of the substituents.     

The synthesis of a series of 7-amino-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylic acids as potential antibacterial agents

A series of 7-amino-1-cyclopropyl-1,4-dihydro-8-fluoro-4-oxo-1,6-naphthyridine-3-carboxylic acids has been prepared and evaluated for antibacterial activity. These compounds were prepared by the displacement of the chloro substituent from 7-chloro-1-cyclopropyl-1,4-dihydro-8-fluoro-4-oxo-1,6-naphthyridine-3-carboxylic acid employing the requisite nitrogen nucleophile to produce the title compounds. The naphthyridine acid was synthesized in ten steps from ethyl 2,4-dihydroxy-3-nitro-5-pyridinecarboxylate. The key step in the sequence was a Schiemann reaction carried out using the hexafluorophosphate salt of the diazonium ion derived from ethyl 3-amino-2,4-dichloro-5-pyridinecarboxylate.     

Studies on antibacterial agents. I. Synthesis of substituted 6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acids

A series of substituted 6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acids was synthesized and tested for antibacterial activities. Among them, 9-fluoro-6,7-dihydro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-1H,5H- benzo[i,j]quinolizine-2-carboxylic acid (OPC-7241) exhibited potent antibacterial activity against gram-positive and -negative bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa, and 9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1H, 5H-benzo[i,j]quinolizine-2-carboxylic acid (OPC-7251) showed potent activity characteristically against Propionibacterium acnes.     

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) .     

Synthesis and reactions of 7-substituted 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids as an antibacterial agent

1-Cyclopropyl- and 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivatives having a sulfinyl or sulfonyl group at C-7 were synthesized from 2,6-dichloro-5-fluoronicotinic acid derivatives by the route involving the Dieckmann-type cyclization. The displacement reactions of these compounds with pyrrolidine and piperidine gave mainly the 7-(1-pyrrolidinyl)- and 7-(1-piperidinyl)-1,8-naphthyridine derivatives 24-27 , respectively. Enoxacin, a potent antibacterial agent, was also synthesized with the analogous route.     

Studies on quinoline derivatives and related compounds. III. A novel pyridine synthesis to give substituted 1,4-dihydro-4-oxonicotinic acids

A variety of 5-mono- and 5,6-disubstituted 1,4-dihydro-4-oxonicotinates were prepared by a novel pyridine synthesis which involves thermal cyclisation of enaminomethylenemalonates 9. The intermediates 9 were readily prepared through a few steps from commercially available starting materials.     

Synthesis and antibacterial activity of new 5-substituted 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids

The 5-hydroxymethyl and the 5-formyl-1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids have been prepared via a 5-trimethylsilyl group and were tested in vitro as potential antibacterials.     

The synthesis of 3,4-dihydro-2-methyl-3-oxo-2H-benzo-1,4-thiazine-2-carboxylic acids

The synthesis of 3,4-dihydro-2-methyl-3-oxo-2H-benzo-1,4-thiazine-2-carboxylic acids 4a, b, 6a -e is presented. After the condensation of o-aminothiophenols with diethyl 2-bromo-2-methylmalonate in the presence of KF as a catalyst the nitrogen in the fused derivatives 3a, b , was alkylated to provide 5a-f , the corresponding esters 3a, b, 5a-f were hydrolysed.     

The synthesis of l-alkyl-1,4-dihydro-4-quinolone-2-carboxylic acids

A general method tor the preparation of 1,4-dihydro-4-quinolone-2-carboxylic acids, especially those which carry alkyl substituents on the ring N-atom, is described.     

Synthesis of substituted 1,2,3,4-tetrahydroquinoline-4-carboxylic acids

Reduction of some substituted quinoline-4-carboxylic acids was studied. The reduction of 2-alkylquinoline-4-carboxylic acids with Raney nickel in aqueous alkali was stereoselective, and the resulting 2-alkyl-1,2,3,4-tetrahydroquinoline-4-carboxylic acids were individual cis isomers. Original Russian Text ? Yu.A. Zhuravleva, A.V. Zimichev, M.N. Zemtsova, Yu.N. Klimochkin, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 4, pp. 622–625.