Synthesis and biological evaluation of tetracyclic fluoroquinolones as antibacterial and anticancer agents

A simple and efficient synthesis of 6-fluoro-4-oxopyrido[2,3-a]carbazole-3-carboxylic acids (13a–e) and a structurally related 6-fluoro-4-oxothieno[2′,3′:4,5]pyrrolo[3,2-h]quinoline (13f) was achieved via Stille arylation of 7-chloro-6-fluoro-8-nitro-4-oxoquinoline-3-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. The ability of 13a–f to inhibit the activity of DNA gyrase and topoisomerase IV was also investigated. The thieno isostere (13f) emerged as the most active antibacterial, while the 9-fluoro derivative (13e) was the most potent against multidrug-resistant staphylococci. Compounds 13a, 13c–f displayed growth inhibition against MCF-7 breast tumor and A549 non-small cell lung cancer cells coupled with an absence of cytotoxicity toward normal human-derm fibroblasts (HuDe). Compound 13e was the most active anticancer against MCF-7 cells, with greater potency than ellipticine (IC₅₀ 0.8 and 1.6 μM, respectively). The most active compounds in this series show promise as dual acting anticancer and antibacterial chemotherapeutics.     

An efficient synthesis of 3-fluoro-5-thio-xylofuranosyl nucleosides of thymine, uracil, and 5-fluorouracil as potential antitumor or/and antiviral agents

1,2:5,6-Di-O-isopropylidene-alpha-D-glucofuranose by the sequence of mild oxidation, reduction, fluorination, periodate oxidation, borohydride reduction, and sulfonylation gave 3-deoxy-3-fluoro-1,2-O-isopropylidene-5-O-p-toluenesulfonyl-alpha-D-xylofuranose (5). Tosylate 5 was converted to thioacetate derivative 6, which after acetolysis gave 1,2-di-O-acetyl-5-S-acetyl-3-deoxy-3-fluoro-5-thio-D-xylofuranose (7). Condensation of 7 with silylated thymine, uracil, and 5-fluorouracil afforded nucleosides 1-(5-S-acetyl-3-deoxy-3-fluoro-5-thio-beta-D-xylofuranosyl) thymine (8), 1-(5-S-acetyl-3-deoxy-3-fluoro-5-thio-beta-D-xylofuranosyl) uracil (9), and 1-(5-S-acetyl-3-deoxy-3-fluoro-5-thio-beta-D-xylofuranosyl) 5-fluorouracil (10). Compounds 8, 9, and 10 are biologically active against rotavirus infection and the growth of tumor cells.     

Synthesis and characterization of novel 6-fluoro-4-piperidinyl-1,2-benzisoxazole amides and 6-fluoro-chroman-2-carboxamides: antimicrobial studies

Novel derivatives of 6-fluoro-4-piperidinyl-1,2-benzisoxazole amides 4(I-VI) were obtained by the condensation of different acid chlorides with 6-fluoro-3-piperidin-4yl-benzo[d]isoxazole. Also, 6-fluoro-chroman-2-carboxamides 6(I-III) were synthesized by using nebulic acid chloride with different amines in presence of triethylamine as acid scavenger and dichloroethane as solvent. The synthesized compounds were characterized by IR, 1H NMR, and CHN analysis. These molecules were evaluated for their efficacy as antimicrobials in vitro by disc diffusion and microdilution method against pathogenic strains such as Bacillus substilis, Escherichia coli, Pseudomonas fluorescens, Xanthomonas campestris pvs, X. oryzae, Aspergillus niger, A. flavus, Fusarium oxysporum, Trichoderma species, F. monaliforme, and Penicillum species. Compounds 4I, 4IV, 4V, 6I, 6II and 6III showed better inhibitory activity than compared to standard drugs. Among these compounds, 4IV and 6III showed potent inhibitory activity against all the strains and found to be nonstrain dependent. The title compounds represent a novel class of potent antimicrobial agents.     

Novel ofloxacin derivatives: synthesis, antimycobacterial and toxicological evaluation

Thirty novel 9-fluoro-2,3-dihydro-8,10-(mono/di-sub)-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acids were synthesized from 2,3,4,5-tetrafluoro benzoic acid and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from mycobacteria. Among the synthesized compounds, 10-[2-carboxy-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active compound in vitro with MIC99 of 0.19 microM and 0.09 microM against MTB and MTR-TB, respectively. In the in vivo animal model also the same compound decreased the bacterial load in lung and spleen tissues with 1.91 and 2.91--log10 protections, respectively, at the dose of 50mg/kg body weight. Compound 10-[(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active in the inhibition of the supercoiling activity of DNA gyrase with an IC(50) of 10.0 microg/mL. The results demonstrate the potential and importance of developing new oxazino quinolone derivatives against mycobacterial infections.     

Synthesis, characterization and evaluation of benzimidazole derivative and its precursors as inhibitors of MDA-MB-231 human breast cancer cell proliferation

A novel series of trisubstituted benzimidazole and its precursors (3-7) were synthesised and characterized by using 1H NMR, LC/MS, FTIR and elemental analysis techniques. The title compounds were evaluated for inhibition against MDA-MB-231 breast cancer cell proliferation. The results revealed that the compound N-(4-cyano-3-(trifluoromethyl) phenyl)-4-fluoro-3-nitrobenzamide (3) was the potent inhibitor.     

The synthesis and biological evaluation of a novel series of C7 non-basic substituted fluoroquinolones as antibacterial agents

A series of non-basic building blocks was synthesized and introduced to the C7 position of the quinolone nucleus 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid to afford the corresponding fluoroquinolones in 46–85% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. The sulfur-containing quinolone, 7-(2-thia-5-azabicyclo[2.2.1]heptan-5-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid exhibited a superior antibacterial activity against quinolone-susceptible and multidrug-resistant strains in comparison with the clinically used fluoroquinolones ciprofloxacin and vancomycin, especially to the Streptococcus pneumonia and multidrug-resistant S. pneumonia clinical isolates.     

Biochemical Characterization,Phytotoxic Effect and Antimicrobial Activity against Some Phytopathogens of New Gemifloxacin Schiff Base Metal Complexes

String of Fe(III), Cu(II), Zn(II) and Zr(IV) complexes were synthesized with tetradentateamino Schiff base ligand derived by condensation of ethylene diamine with gemifloxacin. The novel Schiff base (4E,4′E)-4,4′-(ethane-1,2-diyldiazanylylidene)bis{7-[(4Z)-3-(aminomethyl)-4-(methoxyimino)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid} (GMFX-en) and its metal complexes were identified and confirmed by elemental analyses, FT-IR, UV/VIS, ¹H-NMR spectra, magnetic susceptibility, conductometric measurements and thermal analyses. The FT-IR spectral data showed the chelation behavior of GMFX-en toward the metal ions through oxygen of carboxylate group and nitrogen of azomethine group. In the light of all spectral data, these complexes presumably have octahedral geometry configurations. Thermal analysis specified that the decaying of the metal complexes exist in two or three steps with the final residue metal oxides. Antimicrobial activity of the new prepared metal complexes was screened against some common phytopathogens and their mode of action has been also discussed. The potential phytotoxic effectiveness of the new complexes was furthermore inspected on two commonly experimental plants. The complexes showed significant antimicrobial and phytotoxic effects against the majority of tested phytopathogens and the two tested plants, respectively. The potential antimicrobial activity of the complexes proved their possibility to be used successfully in agropharmacutical industry to control many serious phytopathogens. The phytotoxicity of the studied complexes also indicated their possibility as potential bio-based herbicides alternatives to weed control in crop fields.     

Synthesis and biological activity of 5-fluorotubercidin

The electrophilic fluorination of 4-chloropyrrolo[2,3-d]pyrimidine (1) was studied culminating a 59% conversion of compound 1 to 4-chloro-5-fluoropyrrolo[2,3-d]pyrimidine (2) using Selectfluor. This transformation proceeded via the 4-chloro-5,6-dihydro-5-fluoro-6-hydroxypyrrolo[2,3-d]pyrimidine (3) in a 9:1 trans:cis ratio. The trans isomer of compound 3 was studied by 1H NMR and 19F NMR, and the 5-H tautomer (4) was observed as another intermediate. A modified Vorbruggen procedure of compound 2 and tetra-O-acetylribose gave 4-chloro-5-fluoro-7-(2,3,5,-tri-O-benzoyl-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (6) in a 65% yield. Treatment of compound 6 with ammonia (l) in dioxane gave 5-fluorotubercidin (7). No antibacterial activity was observed. An MTT assay (Promega) against Huh-7 liver cells, normal mouse spleen cells stimulated with Con A (a T-cell mitogen), and normal mouse spleen stimulated with LPS (a B-cell mitogen) showed no significant toxicity. Increased activity of 7 over tubercidin was observed against L-1210 cells and toxicity in fibroblast cells was reduced.     

Synthesis and biological properties of substituted 1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acids

A series of substituted 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinoline carboxylic acids was synthesized and tested for their in vitro and in vivo antibacterial activity. The introduction of a methyl group at the 5-position of quinoline nucleus enhanced characteristically the antibacterial activity against Gram-positive bacteria, including Streptococcus pneumonia, which is a major pathogen in the respiratory tract infection, while retaining Gram-negative activity. Among them, 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride (grepafloxacin) exhibited potent in vitro antibacterial activity against Gram-positive bacteria such as Streptococcus pneumoniae and high in vivo efficacy on the experimental systemic infections caused by the Gram-positive and -negative bacteria tested. It also showed a high distribution to the lung and bronchoalveolar lavage fluid in comparison to reference drugs and is now undergoing clinical evaluation.     

Egyptian propolis: 1-antimicrobial activity and chemical composition of Upper Egypt propolis

The antimicrobial activity of four propolis samples collected from Upper Egypt against Staphylococcus aureus; Escherichia coli and Candida albicans was evaluated. There was a variation in the antimicrobial activity according to the propolis origin. Banisweif propolis showed the highest antimicrobial activity against Staphylococcus aureus, Escherichia coli and Candida albicans, but Fayoum propolis had moderate activity against all tested pathogens. Propolis collected from Assiut and Souhag gave lower antimicrobial activity. Propolis samples were investigated by GC/MS, 71 compounds were identified, 14 being new for propolis. Banisweif propolis is characterized by the presence of 7 caffeate esters and 4 triterpenoids. Fayoum propolis showed the highest amount of lactic acid and the presence of 3 chalcones. But Assiut propolis is characterized by the presence of 4 prenylated coumarates. Souhag propolis is characterized by the presence of 5 aliphatic dicarboxylic acids and some other new compounds to propolis.     

Substituted 3-((Z)-2-(4-nitrophenyl)-2-(1H-tetrazol-5-yl) vinyl)-4H-chromen-4-ones as novel anti-MRSA agents: synthesis, SAR, and in-vitro assessment

In search for a new antibacterial agent with improved antimicrobial spectrum and potency, we designed and synthesized a series of novel 3-((Z)-2-(4-nitrophenyl)-2-(1H-tetrazol-5-yl) vinyl)-4H-chromen-4-ones 7a-h by convergent synthesis approach. All the synthesized compounds were assayed for their in-vitro antibacterial activities against gram-negative and gram-positive bacteria. The preliminary structure-activity relationship, to elucidate the essential structure requirements for the antimicrobial activity that results into anti-MRSA (methicillin-resistant S. aureus) potential, has been described. Amongst the synthesized compounds 7d, 7e, 7f and 7h were found to possess activity against methicillin-resistant S. aureus in addition to the activity against other bacterial strains such as E. faecalis, S. pneumoniae, and E. coli.     

SYNTHESIS OF SOME 2′-FLUORO-2′-DEOXY-3′-C-ETHYNYL AND 3′-C-VINYL-β-D-LYXOFURANOSYL NUCLEOSIDES

1-(2-Fluoro-2-deoxy-β-D-arabinofuranosyl)uracil (5) and 1-(2-fluoro-2-deoxy-β-D-arabinofuranosyl)cytosine (6) were synthesized as reported earlier. Both of these compounds were converted into 2′-fluoro-2′-deoxy-3′-C-ethynyl and 3′-C-vinyl-β-D-lyxofuranosyl nucleosides (16–19) by a multistep sequence. All these new nucleosides were evaluated against seven human tumor cell lines in vitro.     

Binding of the carcinogens 5-fluoro-7-hydroxymethyl-12-methylbenz(a)anthracene and its acetate ester to DNA in vitro

Binding of 5-fluoro-7-hydroxymethyl-12-methylbenz(a)anthracene to calf thymus DNA was negligible (1.2 μmole hydrocarbon/mole DNA-P) in the absence of microsomal enzymes whereas in the presence of liver microsomes from unpretreated rats or from rats pretreated with 3-methylcholanthrene binding was greatly enhanced (11.6 and 16.2 μmole hydrocarbon/mole DNA-P respectively). In contrast, the acetate ester of 5-fluoro-7-hydroxymethyl-12-methylbenz(a)anthracene readily bound to DNA non-enzymatically (9.1 μmole hydrocarbon/mole DNA-P). In the presence of a 3′-phosphoadenosine-5′-phosphosulfate (PAPS) generating system, the binding of 5-fluoro-7-hydroxymethyl-12-methylbenz(a)anthracene was independent of sulfate ion. ATP enhanced non-enzymatic binding of 5-fluoro-7-hydroxymethyl-12-methylbenz(a)anthracene to DNA whereas CTP, β,γ-methylene-ATP, and ADP were much less effective suggesting a certain specificity for adenosine in addition to a high energy triphosphate for high binding. These observations suggest that 5-fluoro-7-hydroxymethyl-12-methylbenz(a)anthracene may be converted to a phosphate ester which, like 5-fluoro-7-acetoxymethyl-12-methylbenz(a)anthracene, readily binds to DNA.     

Synthesis and antimycobacterial evaluation of various 7-substituted ciprofloxacin derivatives

Tuberculosis continues to be a major cause of morbidity and mortality all over the world. Various 7-substituted ciprofloxacin derivatives were synthesized and evaluated for antimycobacterial activity in vitro and in vivo against Mycobacterium tuberculosis and for inhibition of the supercoiling activity of DNA gyrase from Mycobacterium smegmatis. Preliminary results indicated that most of the compounds demonstrated better in vitro antimycobacterial activity against M. tuberculosis than ciprofloxacin. Compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[[N4-[1'-(5-methylisatinyl-beta-semicarbazo)]methyl]N1-piperazinyl]-3-quinoline carboxylic acid (3h) decreased the bacterial load in spleen tissue with 0.76-log10 protections and was considered to be moderately active in reducing bacterial count in spleen. The results demonstrated the potential and importance of developing new quinolone derivatives against mycobacterial infections.     

Synthesis and antimycobacterial evaluation of newer 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(substituted secondary amino)-8-methoxy-5-(sub)-4-oxoquinoline-3-carboxylic acids

Thirty-four newer 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(substituted secondary amino)-8-methoxy-5-(sub)-4-oxoquinoline-3-carboxylic acids were synthesized from 1,2,3,4-tetrafluoro benzene and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC(2)) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase. Among the synthesized compounds, 7-(1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinolin-2(1H)-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylic acid (13n) was found to be the most active compound in vitro with MIC of 0.16 and 0.33 microM against MTB and MDR-TB, respectively. In the in vivo animal model 13n decreased the bacterial load in lung and spleen tissues with 2.54 and 2.92-log10 protections, respectively, at the dose of 50mg/kg body weight. Compound 13n also inhibited the supercoiling activity of mycobacterial DNA gyrase with IC(50) of 30.0 microg/ml.     

Synthesis and antimicrobial activity of 7 alpha-amino-23,24-bisnor-5 alpha-cholan-22-ol derivatives

A series of 7 alpha-aminobisnorsteroids were synthesized and their in vitro antimicrobial activity was evaluated regarding Gram-positive and Gram-negative bacteria. The stereoselective reductive amination of 7-ketosteroid 3 with NH(4)OAc, in the presence of NaBH(3)CN, afforded a high yield of 7 alpha-aminosteroid 4. The 3,7-diaminobisnorsteroids were obtained by the reductive amination of 4 with NH(4)OT(f), Boc-spermidine, and Boc-spermine. 3 alpha,7 alpha-Diaminobisnorsterol dihydrochloride 15 showed the highest antimicrobial activity against Streptococcus pyogenes 308 A with a MIC value of 1.6 microg/mL. Hemolytic activities of the compounds 13-20 were determined. Compound 13 showed MHC value at 100 microg/mL.     

Solid-phase synthesis of 4,8-disubstituted-8,9-dihydropyrazino[2,3-g]quinazolin-7(6H)-ones

An approach for the solid-phase synthesis of 4,8-disubstituted-8,9-dihydropyrazino[2,3-g]quinazolin-7(6H)-ones from 4-chloro-7-fluoro-6-nitroquinazoline scaffold is described. A chemoselective reaction of resin-bound arylamines (3) with 4-chloro-7-fluoro-6-nitroquinazoline (8) yielded resin-bound 4-arylamino-7-fluoro-6-nitroquinazolines (4), which were reacted with amino acid methyl esters to afford the corresponding resin-bound compound (5). Following the reduction of nitro group and intramolecular cyclization of 5, resin-bound 4,8-disubstituted-8,9-dihydropyrazino[2,3-g]quinazolin-7(6H)-one (6) was yielded. The desired products (7) were obtained in good yields and purities after cleavage from the resin.     

Synthesis and antibacterial activity of novel 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-4-oxoquinoline-3-carboxylic acids bearing cyclopropane-fused 2-amino-8-azabicyclo[4.3.0]nonan-8-yl substituents at the C-7 position

A series of novel 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-4-oxoquinoline-3-carboxylic acids bearing cyclopropane-fused 2-amino-8-azabicyclo[4.3.0]nonan-8-yl substituents at the C-7 position were synthesized to obtain potent drugs for the treatment of Gram-positive infections. Some compounds exhibited excellent antibacterial activity, and potent inhibitory activity against bacterial DNA topoisomerase IV. In addition, some of the potent compounds showed reduced inhibitory activity against human DNA topoisomerase II compared with the corresponding noncyclopropane-fused compounds.     

Alumina-supported synthesis of antibacterial quinolines using microwaves

7-(5'-Alkyl-1',3',4'-thiadiazol/oxadiazol-2'-ylthio)-6 -fluoro-2,4-dimethylquinolines and 3-formyl-2-(2'-hydroxy- 1',4'-naphthoquinon-3'-yl)-4-methyl/6-methyl/7-quinolines have been synthesised by the reaction of 5-alkyl-1,3,4-thiadiazol/oxadiazol-2-thiols with 7-chloro-6-fluoro-2,4-dimethylquinoline and by the reaction of 2-hydroxy-1,4-naphthoquinone with 2-chloro-3-formyl-4-methyl/6-methyl/7-methyl/8-methylquinolines respectively on basic alumina using microwaves, the reaction time has been brought down from hours to seconds with improved yield as compared to conventional heating. The compounds were tested for their in vitro antibacterial activity. All compounds showed promising antibacterial activity. The best activity was observed by compounds 3a and 3f.     

N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: A novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors

A series of N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC₅₀ values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.