Cytotoxic and DNA binding properties of aminoalkyl derivatives of di- and triazaphenanthrenes.

A series of mono- and dicationic derivatives of various di- and triazaphenanthrenes were synthesized and evaluated against both wild-type and amsacrine-resistant P388 leukemia in vitro. Monocationic derivatives of the fully-aromatic benzo[c][1,8]naphthyridine chromophore showed moderate and equal cytotoxicity in both cell lines, suggestive of efficacy against both the alpha and beta isozymes of mammalian DNA topoisomerase II. Derivatives of both the benzo[c][1,8]naphthyridine and benzo[c][1,8]naphthyridine-3(4H)-one chromophores also showed significant in vivo activity against wild-type P388 leukemia.     

Isothiazolopyridones: synthesis, structure, and biological activity of a new class of antibacterial agents

We report the syntheses of first-generation derivatives of isothiazolopyridones and their in vitro evaluation as antibacterial agents. These compounds, containing a novel heterocyclic nucleus composed of an isothiazolone fused to a quinolizin-4-one (at C-2 and C-3 of the quinolizin-4-one), were prepared using a sequence of seven synthetic transformations. The solid-state structure of 7-chloro-9-ethyl-1-thia-2,4a-diazacyclopenta[b]naphthalene-3,4-dione was determined by X-ray diffraction. The prepared derivatives of desfluoroisothiazolopyridones exhibited (a) antibacterial activity against Gram-negative and Gram-positive organisms, (b) inhibitory activities against DNA gyrase and topoisomerase IV, and (c) no inhibitory activity against human topoisomerase II.     

Synthesis and biological activity of pyrimido[2,1-b][1,3]thiazine, [1,3]thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine derivatives and thiazole analogues.

Some series of thiazolo[3,2-a]pyrimidine, pyrimido[2,1-b] [1,3]thiazine, thiazolo[3,2-a]purine, [1,3]thiazino[3,2-a]purine, thiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine derivatives, variously functionalized, were prepared. The compounds were tested for antimicrobial and antimycotic activity on a number of strains, namely: E. coli, Proteus vulgaris, P. mirabilis, Pseudomonas aeruginosa, Salmonella sp., Staphylococcus aureus, S. faecalis, Bacillus subtilis, Sarcina lutea, Candida albicans, C. tropicalis, Aspergillus sp., and for antiviral activity on Herpes simplex virus Type 1, Vesicular stomatitis virus and Coxsackievirus B5. The compounds proved to be devoid of activity against viruses and gram-negative bacteria, while some of them exhibited modest activity against gram-positive bacterial strains.     

Synthesis and biological activities of 10-substituted benzo[b][1,5]naphthyridines.

Eight 10-substituted benzo[b][1,5]naphthyridine derivatives containing N-(pyrrolidino)alkylamines, methanesulfonanilides, and aminoacetanilides were prepared, and their binding with DNA was studied by (a) Tm measurements and (b) the effect on DNA-dependent RNA polymerase in vitro. In addition, they were evaluated as antineoplastic agents in the P-388 test. None of the compounds exhibited anti-cancer activity.     

Synthesis,antibacterial evaluation,and DNA gyrase inhibition profile of some new quinoline hybrids

Antibiotic‐resistant bacteria continue to play an important role in human health and disease. Inventive strategies are necessary to develop new therapeutic leads to challenge drug‐resistance problems. From this perception, new quinoline hybrids bearing bioactive pharmacophores were synthesized. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against nine bacterial pathogenic strains. The results revealed that most compounds exhibited good antibacterial activities. Seven compounds ( 2b , 3b , 4 , 6 , 8b , and 9c,d ) displayed enhanced activity against methicillin‐resistant Staphylococcus aureus compared to ampicillin. These compounds were subjected to an in vitro S. aureus DNA gyrase ATPase inhibition study, which revealed that compounds 8b , 9c , and 9d showed the highest inhibitory activity with IC₅₀ values of 1.89, 2.73, and 2.14 μM, respectively, comparable to novobiocin (IC₅₀, 1.636 μM). Compounds 2a–c , 3a , 7c , 9c,d , and 10a,b revealed half the potency of levofloxacin in inhibiting the growth of Pseudomonas aeruginosa. As an attempt to rationalize the observed antibacterial activity for the most active compounds 8b , 9c , and 9d , molecular docking in the ATP binding site of S. aureus gyrase B was performed using Glide. Such compounds could be considered as promising scaffolds for the development of new potent antibacterial agents.     

Synthesis, antimalarial activity, and molecular modeling of new pyrrolo[1,2-a]quinoxalines, bispyrrolo[1,2-a]quinoxalines, bispyrido[3,2-e]pyrrolo[1,2-a]pyrazines, and bispyrrolo[1,2-a]thieno[3,2-e]pyrazines

Three pyrrolo[1,2-a]quinoxalines, 15 bispyrrolo[1,2-a]quinoxalines, bispyrido[3,2-e]pyrrolo[1,2-a]pyrazines, and bispyrrolo[1,2-a]thieno[3,2-e]pyrazines were synthesized from various substituted nitroanilines or nitropyridines and tested for their in vitro activity upon the erythrocytic development of Plasmodium falciparum strains with different chloroquine-resistance status. Bispyrrolo[1,2-a]quinoxalines showed superior antimalarial activity with respect to monopyrrolo[1,2-a]quinoxalines. The best activity was observed with bispyrrolo[1,2-a]quinoxalines linked by a bis(3-aminopropyl)piperazine. Moreover, it was observed that the presence of a methoxy group on the pyrrolo[1,2-a]quinoxaline nucleus increased the pharmacological activity. Drug effects upon beta-hematin formation were assayed and showed similar or higher inhibitory activities than CQ. A possible mechanism of interaction implicating binding of pyrroloquinoxalines to beta-hematin was supported by molecular modeling.     

Antimycobacterial and phototoxic evaluation of novel 6-fluoro/nitro-4-oxo-7-(sub)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid

Several newer 6-fluoro/nitro-4-oxo-7-(sub)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids (10-11a-q) were synthesised from 3,4-difluoro aniline and 3-fluoro-4-nitro aniline by nine-step synthesis. The compounds were evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multidrug-resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC2) as well as being tested for their ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the synthesised compounds, 7-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-nitro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (11l) was found to be the most active compound in vitro, with minimum inhibitory concentrations (MICs) of 0.09 microM and <0.09 microM against MTB and MTR-TB, respectively. Compound 11l was found to be 4 times and >506 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in vivo animal model, 11l decreased the bacterial load in lung and spleen tissues by 30% and 42%, respectively, at a dose of 50 mg/kg body weight.     

Benzo[c][2,7]naphthyridine-5-yl-arylamines-phenol Mannich bases of the amodiaquine-, cycloquine- and pyronaridine-type

2,5-Dichloro-4-methyl-benzo[c][2,7]naphthyridine (1) reacted with aromatic amines selectively by substitution at the 5-position to yield the amidines 2. The 4-aminophenol 2c could also be synthesized by cleavage of the ether 2b. The structure of 2c was proved by X-ray crystal analysis. Aminomethylation of 2c yielded the amodiaquine analogue 3. The mono- and bisaminomethylated derivatives 4 and 5 were obtained by reaction of compound 1 with phenol Mannich base hydrochlorides. Compounds 3-5 were tested in vitro for antimalarial activity using chloroquine-sensitive and resistant Plasmodium-falciparum strains. The highest activities were shown by the pyronaridine-type compounds 5a and 5b with IC50 values of approximately 200 nM.     

Synthesis and antibacterial activity of a novel series of potent DNA gyrase inhibitors. Pyrazole derivatives

We have previously found that a pyrazole derivative 1 possesses antibacterial activity and inhibitory activity against DNA gyrase and topoisomerase IV. Here, we synthesized new pyrazole derivatives and found that 5-[(E)-2-(5-chloroindol-3-yl)vinyl]pyrazole 16 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases. Many of the synthesized pyrazole derivatives were potent against clinically isolated quinolone- or coumarin-resistant Gram-positive strains and had minimal inhibitory concentration values against these strains equivalent to those against susceptible strains.     

Quinolone antibacterials: preparation and activity of bridged bicyclic analogues of the C7-piperazine

A series of quinolone and naphthyridine antibacterial agents possessing as the C7-heterocycle bicyclic 2,5-diazabicyclo[n.2.m]alkanes, where n = 2, 3 and m = 1, 2, and a series including 4-aminopiperidine and 3-amino-8-azabicyclo[3.2.1]octanes have been prepared and evaluated in vitro and in vivo for antibacterial activity against a variety of Gram-negative and Gram-positive organisms. These compounds were also tested against the target enzyme bacterial DNA gyrase. All the examples investigated are nearly equipotent with the parent 7-piperazinyl analogues. Only endo-7-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-1-cyclopropyl-6,8-difluoro- 1,4- dihydro-4-oxo-3-quinolinecarboxylic acid displays activity that surpasses that of the piperazine parent.     

Synthesis and biological evaluation of some pyrimidine, pyrimido[2,1-b][1,3]thiazine and thiazolo[3,2-a]pyrimidine derivatives

4,6-Diamino-1H-pyrimidine-2-thione (1) was used for the preparation of pyrimidine derivatives 2-5. Compound 5 was cyclized to produce pyrimido[2,1-b][1,3]thiazine derivative 6 which was condensed with p-chlorobenzaldehyde to give compound 7. The latter compound was reacted with hydroxylamine to give isoxazolo[4,5-d]thiazino[2,3-a]pyrimidine 8. Compound 8b was treated with 2-chloroethyl methyl ether to afford compound 9. Similarly, compound 3 reacted with chloroacetic acid to give thiazolo[3,2-a]pyrimidine 10, which was condensed with p-chlorobenzaldehyde to give compound 11. Compound 11 was condensed with hydroxylamine to give isoxazolo[4,5-d]thiazolo[2,3-a]pyrimidine 12. Compound 12b was treated with 2-chloroethyl methyl ether to afford compound 13. Biological evaluation of some prepared products showed that many of them revealed promising antimicrobial activity.     

Fluoronaphthyridines and quinolones as antibacterial agents. 2. Synthesis and structure-activity relationships of new 1-tert-butyl 7-substituted derivatives

A number of 7-substituted-1-tert-butyl-6-fluoroquinolone-3-carboxylic acids and 7-substituted-1-tert-butyl-6-fluoro-1,8-naphthyridine-3-carboxylic acids have been prepared and tested for antibacterial activities. Among those the 7-aminopyrrolidinyl 20b and the 7-diazabicyclo naphthyridine 18b are the most potent compounds in vitro and in vivo. Physicochemical data and acute toxicity are also discussed. Compound 18b, BMY 40062, exhibits the most favorable overall properties, considering in vitro and in vivo microbiological activity, its low toxicity, and pharmacokinetic profile, and was selected for clinical evaluation.     

Synthesis and antibacterial activity of 1-(2-fluorovinyl)-7-substituted-4-quinolone-3-carboxylic acid derivatives, conformationally restricted analogues of fleroxacin

The novel 1-(2-fluorovinyl)-4-quinolone-3-carboxylic acid derivatives Z-15a-c, E-15a-c, Z-16a-c, and E-16a-c, conformationally restricted analogues of fleroxacin (5), were synthesized, and their in vitro antibacterial activity was evaluated. A dehydrosulfenylation of a 2-fluoro-2-[(4-methoxyphenyl)sulfinyl]ethyl group was employed as a key step for the construction of a 2-fluorovinyl group at the N-1 position. It appeared evident that the Z-isomers Z-15a-c and Z-16a-c exhibited 2- to 32-fold more potent in vitro antibacterial activity than the corresponding E-isomers E-15a-c and E-16a-c. Furthermore, since Z-15b showed in vitro antibacterial activity and DNA gyrase inhibition comparable to that of 5, it was hypothesized that the conformation of Z-15b would be equivalent to the active conformer of 5. The results revealed that the antibacterial Z-1-(2-fluorovinyl)quinolone derivatives carry the novel N-1 substituent of the fluoroquinolones.     

Studies on pyridonecarboxylic acids. 1. Synthesis and antibacterial evaluation of 7-substituted-6-halo-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3- carboxylic acids.

A series of [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids and their esters were prepared and evaluated for antibacterial activity. The derivatives with a hydrogen or methyl group at C-1, fluorine at C-6, and piperazinyl or 4-methyl-1-piperazinyl group at C-7 showed superior in vitro antibacterial activity, and the derivatives with 4-methyl-1-piperazinyl group at C-7 had potent in vivo activity. Compound 29a (NM394) showed excellent in vitro antibacterial activity and low toxicity but poor absorption from the gastrointestinal tract. Compound 29ee (NM441), an N-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl] derivative of 29a, was found to possess a favorable pharmacokinetic profile and oral activity superior to that of ciprofloxacin in experimental animals.     

New structure-activity relationships of the quinolone antibacterials using the target enzyme. The development and application of a DNA gyrase assay

A series of 60 newly synthesized and known quinolone antibacterials, including quinoline- and 1,8-naphthyridine-3-carboxylic acids, pyrido[2,3-d]pyrimidine-6-carboxylic acids, and some monocyclic 4-pyridone-3-carboxylic acids, were tested and compared in a newly established, easy to perform, DNA gyrase assay. The results were correlated with minimum inhibitory concentrations (MICs) against a variety of organisms. Among the known quinolones were 14 clinically significant drugs (oxolinic acid, norfloxacin, ciprofloxacin, enoxacin, etc.) which were used as standards and compared side-by-side. The study focused on the changes in DNA gyrase inhibition brought about by certain features of the molecules, namely, the C6-fluorine or the nature of the C7 substituent. The intrinsic gyrase inhibition of the fused parent rings, quinoline vs. naphthyridine vs. pyrido[2,3-d]pyrimidine, was also explored. In all cases, loss of enzyme inhibition produced poor MICs, but some compounds with good DNA gyrase inhibition did not correspondingly inhibit bacterial growth. Possible explanations for this phenomena and the benefits of a DNA gyrase-MIC strategy for developing future structure-activity relationships are discussed.     

Design,synthesis, and pharmacological profile of novel fused pyrazolo[4,3-d]pyridine and pyrazolo[3,4-b][1,8]naphthyridine isosteres: a new class of potent and selective acetylcholinesterase inhibitors

A new family of tacrine (THA) analogues (7-9, 12), containing the azaheterocyclic pyrazolo[4,3-d]pyridine or pyrazolo[3,4-b][1,8]naphthyridine systems as isosteres of the quinoline ring of THA, has been synthesized. The compounds were tested in rat brain cholinesterases using Ellman's method, and all were fully efficacious in inhibiting the enzymes. Compounds 9 and 12b were the most potent against acetylcholinesterase (AChE), showing IC(50) of 6.0 and 6.4 microM, and were less active against rat brain butyrylcholinesterase, showing selectivity indexes of 5.3 and 20.9, respectively. Compounds 7-9 and 12 were also tested for their acute neurotoxicity in vitro, using cultured rat cortical cells. Compounds 7 and 8 were not significantly toxic; 9 was toxic at 500 microM, but not at 100 microM. The naphthyridine derivatives 12a and 12b showed a significant concentration-dependent neurotoxicity, being able to kill most cells at 500 microM. Molecular dynamic simulation using the X-ray crystal structure of AChE from Torpedo californica was used to explain the possible binding mode of these new THA isosteres.     

Synthesis of certain substituted quinoxalines as antimicrobial agents (part II)

Several fused triazolo and ditriazoloquinoxaline derivatives such as 1-aryl-4-chloro-[1,2,4]triazolo[4,3-a]quinoxalines (3a-d), 4-alkoxy[1,2,4]triazolo[4,3-a]quinoxalines (4a,b), 4-substituted-amino-[1,2,4] triazolo[4,3-a]quinoxalines (5a-h), 1-(aryl)-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-thione (6), 4-(arylidenehydrazino)1-phenyl-[1,2,4]triazolo[4,3-a]quinoxalines (10a-e) and [1,2,4]ditriazolo[4,3-a:3',4'-c]quinoxaline derivatives (11-13) have been synthesized and some of these derivatives were evaluated for antimicrobial and antifungal activity in vitro. It was found that compounds 3a and 9b possess potent antibacterial activity compared to the standard tetracycline.     

Synthesis and pharmacological properties of benzothienothiadiazolopyrimidine derivatives. III

2-Substituted derivatives of 5H-benzothieno [3,2-d] [1,3,4]-thiadiazolo [3,2-a]pyrimidin-5-one and of 10H-benzothieno [2,3-d] [1,3,4]-thiadiazolo [3,2-a]pyrimidin-10-one have been synthesized. The analgesic, antiinflammatory and ulcerogenic activities of these derivatives were evaluated. Some derivatives showed an analgesic activity similar to or a little lower than that of indomethacin, and much higher than that of mefenamic acid, acetylsalicyclic acid and phenylbutazone, with a lower acute toxicity and a better gastric tolerance.     

Synthesis and antimicrobial evaluation of new nitric oxide‐donating fluoroquinolone/oxime hybrids

A new series of nitric oxide‐donating fluoroquinolone/oximes was prepared in this study. The nitric oxide release from the prepared compounds was measured using a modified Griess colorimetric method. The antitubercular evaluation of the synthesized compounds indicated that ketone derivatives 2b and 2e and oximes 3b and 3d exhibited somewhat higher activity than their respective parent fluoroquinolones. Mycobacterial DNA cleavage studies and molecular modeling of Mycobacterium tuberculosis DNA gyrase were pursued to explain the observed bioactivity. More important, antibacterial evaluation showed that oximes 3c–e are highly potent against Klebsiella pneumoniae, with minimum inhibitory concentration (MIC) values of 0.06, 0.08, and 0.034 µM, respectively, whereas ketone 2c and oxime 4c are more active against Staphylococcus aureus than ciprofloxacin (MIC values: 0.7, 0.38, and 1.6 µM, respectively). Notably, the antipseudomonal activities of compounds 2a and 4c were much higher than those of their respective parent fluoroquinolones.     

Synthesis and cytostatic properties of some 6H-Indolo[2, 3-b][1, 8]naphthyridine derivatives

The new and efficient synthesis of the title heterocyclic ring system is described starting from suitable 2-chloro-1, 8-naphthyridines. The synthesized 6H-indolo[2, 3-b][1, 8]naphthyridine derivatives were tested in vitro on 55 tumor cell lines for their anticancer properties. The presence of the acetylamino moiety at position 3 in the main ring system proved to be crucial for the cytostatic activity of this class of compounds.