The Synthesis and Cytotoxic Activity of D-Ribofuranosides and 2-Deoxy-D-Ribofuranosides of Substituted Bis(indolyl)furan, Bis(indolyl)pyrrole, and Indolo[2,3-a]carbazole Derivatives

1-(2,3,5-Tri-O-acetyl)--D-ribofuranosyl indole, the key compound in the synthesis of glycosides with the bis(indole) aglycone, was obtained for the first time by the indoline–indole method. There were synthesized 3-(1-methylindol-3-yl)-4-(1-glycosylindol-3-yl)furan(or pyrrole)-2,5-diones containing the residue of -D-ribofuranose or 2-deoxy--D-ribofuranose and analogous glycosides of indolo[2,3-a]furano(or pyrrolo)[3,4-]carbazol-5,7-diones, which are structurally relative to the antitumor antibiotic rebeccamycin. Their cytotoxicities toward a number of human tumor cell lines were studied in vitro, and the carbazole N-glycosides were shown to be more active than the bis(indole) glycosides. At the same time, the ribofuranosides were found to be less active than the corresponding ribopyranosides synthesized previously.     

Synthesis and anticonvulsant activity of new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones

Twenty-two new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones were synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens in mice. Several compounds were tested additionally in the 6-Hz psychomotor seizure model. The neurotoxicity was determined applying the rotarod test. Excluding one compound, all other molecules were found to be effective in at least one seizure model. The most active were 1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (14), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3-methylpyrrolidine-2,5-dione (17), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3,3-dimethylpyrrolidine-2,5-dione (23) and 3,3-dimethyl-1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (26). These compounds showed high activity in the 6-Hz psychomotor seizure test as well as were active in the maximal electroshock and subcutaneous pentylenetetrazole (14 and 23) screens. Initial SAR studies for anticonvulsant activity have been discussed.     

Structure-based design, synthesis, and biological evaluation of novel 1,4-diazepines as HDM2 antagonists

Crystallographic analysis of ligands bound to HDM2 suggested that 7-substituted 1,4-diazepine-2,5-diones could mimic the alpha-helix of p53 peptide and may represent a promising scaffold to develop HDM2-p53 antagonists. To verify this hypothesis, we synthesized and biologically evaluated 5-[(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-7-phenyl-1,4-diazepin-1-yl]valeric acid (10) and 5-[(3S)-7-(2-bromophenyl)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-1,4-diazepin-1-yl]valeric acid (11). Preliminary in vitro testing shows that 10 and 11 substantially antagonize the binding between HDM2 and p53 with an IC(50) of 13 and 3.6 microM, respectively, validating the modeling predictions. Taken together with the high cell permeability of diazepine 11 determined in CACO-2 cells, these results suggest that 1,4-diazepine-2,5-diones may be useful in the treatment of certain cancers.     

N1-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives are potent and selective 5-HT6 receptor antagonists

A series of N(1)-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)indole derivatives was designed and synthesized. These compounds were shown to have high affinity for the 5-HT(6) receptor. Two analogs, 4-[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-1-sulfonyl]-phenylamine 15g and 4-[3-(1,2,3,6-tetrahydropyridin-4-yl)-5-methoxy-1H-indole-1-sulfonyl]-phenylamine 15y, had 0.4 and 3.0 nM affinity, respectively, and antagonized the production of adenylate cyclase at sub-nanomolar concentrations.     

Retinoic acid metabolism inhibition by 3-azolylmethyl-1H-indoles and 2, 3 or 5-(alpha-azolylbenzyl)-1H-indoles

Among a library of 70 azoles, 8 indole derivatives substituted in the 2-, 3- or 5- position with an azolylmethyl or alpha-azolylbenzyl chain were evaluated for retinoic acid (RA) metabolism inhibitory activity. The most active inhibitors identified in this study were 5-bromo-1-ethyl-3-methyl-2-[(phenyl)(1H-1,2,4-triazol-1-yl)methyl]-1H-indole (3) (68.9% inhibition) and 5-bromo-1-ethyl-2-[(4-fluorophenyl) (1H-1,2,4-triazol-1-yl)methyl]-3-methyl-1H-indole (6) (60.4% inhibition). At the same concentration (100 microM) ketoconazole exerted similar inhibitory effect (70% inhibition).     

Identification and characterization of 4-[4-(3-phenyl-2-propen-1-yl)-1-piperazinyl]-5H-pyrimido[5,4-b]indole derivatives as Salmonella biofilm inhibitors

A screening of a small-molecule library was conducted, in search of Salmonella biofilm inhibitors active in a broad temperature range, both in prevention and in eradication of biofilms. Moreover, the inhibitors were selected not to influence the planktonic growth of Salmonella to diminish the selective pressure and to prevent or slow down resistance development. Out of the 20,014 compounds screened at 16 and 37 °C, 140 hits were identified. After characterization of the most promising hits at a broader set of temperatures (16, 25, 30 and 37 °C), we identified 7-methoxy-4-[4-(3-phenyl-2-propen-1-yl)-1-piperazinyl]-5H-pyrimido[5,4-b]indole as an interesting preventive anti-biofilm compound. A first structure-activity relationship of this compound was delineated, revealing 8-fluoro-4-[4-(3-phenyl-2-propen-1-yl)-1-piperazinyl]-5H-pyrimido[5,4-b]indole as a promising analogue in the prevention of Salmonella biofilms.     

The synthesis of 2- and 3-aryl indoles and 1,3,4,5-tetrahydropyrano[4,3-b]indoles and their antibacterial and antifungal activity

A series of 2- and 3-aryl substituted indoles and two 1,3,4,5-tetrahydropyrano[4,3-b]indoles were synthesized from indole and 5-methoxyindole. The 2-aryl indoles were synthesized from the 1-(phenylsulfonyl)indole derivatives using magnesiation followed by iodination. The 2-iodinated compounds were then subjected to Suzuki–Miyaura reactions. In addition, the 3-aryl indoles were made from the corresponding 3-bromoindoles using Suzuki–Miyaura reactions. The 1,3,4,5-tetrahydropyrano[4,3-b]indoles were also synthesized from 1-(phenylsulfonyl)indole by magnesiation followed by treatment with allylbromide. The product was then converted into [2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl]methanol which upon exposure to Hg(OAc)₂ and NaBH₄ afforded tetrahydropyrano[4,3-b]indoles. A number of the 2- and 3-aryl indoles displayed noteworthy antimicrobial activity, with compound 13a displaying the most significant activity (3.9 μg/mL) against the Gram-positive micro-organism Bacillus cereus.     

Synthesis and anticonvulsant activity of new N-Mannich bases derived from 3-(2-fluorophenyl)- and 3-(2-bromophenyl)-pyrrolidine-2,5-diones. Part II

Synthesis and anticonvulsant activity of new N-Mannich bases of 3-(2-fluorophenyl)- and 3-(2-bromophenyl)-pyrrolidine-2,5-diones have been described. Initial anticonvulsant screening was performed in mice after intraperitoneal administration in the maximal electroshock seizure test (MES) and subcutaneous pentylenetetrazole seizures test (scPTZ). The neurotoxicity was determined applying the rotarod test. The in vivo results in mice showed that majority of compounds were effective in the MES test. Only seven molecules showed protection in the scPTZ test. The quantitative evaluation in the MES seizures after oral administration into rats showed that the most active were 1-[{4-(4-fluorophenyl)-piperazin-1-yl}-methyl]-3-(2-bromophenyl)-pyrrolidine-2,5-dione (14) with ED(50) of 7.4mg/kg and 1-[{4-(3-bromophenyl)-piperazin-1-yl}-methyl]-3-(2-bromophenyl)-pyrrolidine-2,5-dione (16) with ED(50) of 26.4mg/kg. These molecules were more potent and also less neurotoxic than phenytoin which was used as reference antiepileptic drug.     

Synthesis of 6- or 4-functionalized indoles via a reductive cyclization approach and evaluation as aromatase inhibitors

Two new series of benzonitrile derivatives on position 6 or 4 of indole ring were successfully synthesized via a Leimgruber-Batcho reaction. All the compounds were evaluated in vitro on the inhibition of aromatase (CYP19) and 17alpha-hydroxylase-C17,20-lyase (CYP17). The racemate, 4-[(1H-imidazol-1-yl)(1H-indol-4-yl)methyl]benzonitrile 9, showed high level of inhibitory activity towards CYP19 (IC(50)=11.5 nM).     

Mefloquine-oxazolidine derivatives, derived from mefloquine and arenecarbaldehydes: In vitro activity including against the multidrug-resistant tuberculosis strain T113

Ten new mefloquine-oxazolidine derivatives, 4-[(1S,8aR)-3-(aryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline (1: aryl=substituted phenyl) and 4-[(1S,8aR)-3-(heteroaryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline [2: heteroaryl=5-nitrothien-2-yl (2a); 5-nitrofuran-2-yl (2b) and 4H-imidazol-2-yl) (2c)], have been synthesized and evaluated against Mycobacterium tuberculosis. Compounds 1f (aryl=3-ethoxyphenyl), 1g (Ar=3,4,5-(MeO)(3)-C(6)H(2)) and 2c were slightly more active than mefloquine (MIC=33μM) with MICs=24.5, 22.5 and 27.4, respectively, whereas compounds 1e (aryl=3,4-(MeO)(2)-C(6)H(3)) and 2a (MICs=11.9 and 12.1μM, respectively) were ca. 2.7 times more active than mefloquine, with a better tuberculostatic activity than the first line tuberculostatic agent ethambutol (MIC=15.9). The compounds were also assayed against the MDR strain T113 and the same MICs were observed. Thus the new derivatives have advantages over such anti-TB drugs as isoniazid, rifampicin, ethambutol and ofloxacin, for which this strain is resistant. The most active compounds were not cytotoxic to Murine Macrophages Cells in a concentration near their MIC values.     

Substituted furo[3,2-b]pyridines: novel bioisosteres of 5-HT 1F receptor agonists

Synthesis and evaluation of a series of 2,3,5- and 3,5-substituted furo[3,2-b]pyridines were undertaken in order to investigate their utility as bioisosteres of 5-HT(1F) receptor agonist indole analogues, 1-3. The replacement proved to be effective, providing compounds with similar 5-HT(1F) receptor affinity and improved selectivity when compared with the indole analogues. Through these studies we identified 4-fluoro-N-[3-(1-methyl-piperidin-4-yl)-furo[3,2-b]pyridin-5-yl]-benzamide (5), a potent and selective 5-HT(1F) receptor agonist with the potential to treat acute migraine.     

Retinoic Acid Metabolism Inhibition by 3-Azolylmethyl-1H-indoles and 2, 3 or 5-(α-Azolylbenzyl)-1H-indoles

Among a library of 70 azoles, 8 indole derivatives substituted in the 2-, 3- or 5- position with an azolylmethyl or α-azolylbenzyl chain were evaluated for retinoic acid (RA) metabolism inhibitory activity. The most active inhibitors identified in this study were 5-bromo-1-ethyl-3-methyl-2-[(phenyl)(1H-1,2,4-triazol-1-yl)methyl]-1H-indole (3) (68.9% inhibition) and 5-bromo-1-ethyl-2-[(4-fluorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-3-methyl-1H-indole (6) (60.4% inhibition). At the same concentration (100 μM) ketoconazole exerted similar inhibitory effect (70% inhibition).     

Side chain modifications of (indol-3-yl)glyoxamides as antitumor agents

New series of analogues of N-(pyridin-4-yl)-2-[1-(4-chlorobenzyl)-indol-3-yl]glyoxamide D-24851 were synthesized, characterized and tested for their in vitro anticancer properties. In the first series, an amino acid spacer was introduced in the glyoxamide chain of D-24851. In the second series, the glyoxamide chain was moved to positions 4 and 5 of indole skeleton. These new compounds were tested on four cancer cell lines (KB, SK-OV-3, NCI-H460 and SF-268), with promising activity for the glycine derivative.     

Synthesis and antimycobacterial activity of some alkyl [5-(nitroaryl)-1,3,4-thiadiazol-2-ylthio]propionates

Two series of 2- and 3-[5-(nitroaryl)-1,3,4-thiadiazol-2-ylthio, sulfinyl and sulfonyl] propionic acid alkyl esters were synthesized and screened for antituberculosis activity against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system. The MIC values for the compounds showing more than 90% inhibition were determined. The result of comparison between two groups of data exhibited that among the synthesized derivatives, the compound propyl 3-[5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-ylthio]propionate was the most active one (MIC=1.56 microgml(-1)).     

Evaluation of Antituberculosis Activity and in Silico Properties of Oxymethylene-cyclo-1,3-diones

Tuberculosis is a leading infectious disease that has infected one-third of the world's population and is more prevalent among people belonging to developing countries such as India and China. In the present study, a series of substituted oxymethylene-cyclo-1,3-diones was synthesized and screened for anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv (M. tuberculosis). The compounds were synthesized by condensation of 1,3-cyclicdione, substituted phenols/ alcohols and triethyl orthoformate. The synthesized compounds were screened for anti-tuberculosis activity against M.tuberculosis H37Rv using Middlebrook 7H9 broth assay. Results demonstrated that among the synthesized library of molecules, two compounds 2-(2-hydroxyphenoxymethylene)-5,5-dimethylcyclohexane-1,3-dione and 5,5-dimethyl-2-(2-trifluoromethylphenoxymethylene)cyclohexane-1,3-dione were found to be most active against M. tuberculosis (MICs of 1.25 μg/mL⁻¹). The MICs of 2-(2,4-difluoro-phenoxymethylene)-5,5-dimethylcyclohexane-1,3-dione and 2-(2-bromophenoxymethylene)-5,5-dimethylcyclohexane-1,3-dione were found to be 5 and 10 μg mL⁻¹, respectively. Data from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that all the four most active compounds did not exhibit cytotoxicity against human cell lines. Molecular docking studies revealed that the most active compound targets mycobacterial InhA enzyme. In summary, the present study demonstrates the methodology for the synthesis of oxymethylene-cyclo-1,3-diones and identified two potential anti-tuberculosis compounds.     

Antimycobacterial activity: a facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines

A series of twelve dispiropyrrolidines were synthesized using [3+2]-cycloaddition reactions. The synthesized compounds were screened for their antimycobacterial activity against M. tuberculosis H(37)Rv and INH resistant M. tuberculosis strains using agar dilution method, four of them showed good activity with MIC of less than 1 μM. Compound 4'-[5-(4-fluorophenyl)pyridin-3-yl]-1'-methyldispiro[indan-2,2' pyrrolidine-3',2″-indan]-1,3,1″-trione (4b) was found to be the most active with MIC of 0.1215 and 5.121 μM, respectively.     

Side chain modifications of (indol-3-yl)glyoxamides as antitumor agents

New series of analogues of N-(pyridin-4-yl)-2-[1-(4-chlorobenzyl)-indol-3-yl]glyoxamide D-24851 were synthesized, characterized and tested for their in vitro anticancer properties. In the first series, an amino acid spacer was introduced in the glyoxamide chain of D-24851. In the second series, the glyoxamide chain was moved to positions 4 and 5 of indole skeleton. These new compounds were tested on four cancer cell lines (KB, SK-OV-3, NCI-H460 and SF-268), with promising activity for the glycine derivative.     

Inhibitory effects of multi-substituted benzylidenethiazolidine-2,4-diones on LDL oxidation

Multi-substituted benzylidenethiazolidine-2,4-diones 3a-h were synthesized by Knoevenagel condensation of di- or tri-substituted 4-hydroxybenzaldehydes [or 1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone] 1 with thiazolidine-2,4-dione (2) and evaluated for antioxidant activities of Cu(2+)-induced oxidation of human low-density lipoproteins (LDL). Among compounds 3a-h, 3a was superior to probucol in LDL-antioxidant activities and found to be ninefold more active than probucol. Due to its potency, compound 3a was tested for complementary in vitro investigations, such as TBARS assay (IC(50) = 0.1 microM), lag time (240 min at 1.5 microM), relative electrophoretic mobility (REM) of ox-LDL (inhibition of 83% at 10 microM), fragmentation of apoB-100 (inhibition of 61% at 5 microM), and radical DPPH scavenging activity on copper-mediated LDL oxidation. In macrophage-mediated LDL oxidation, the TBARS formation was also inhibited by compound 3a.     

Design, synthesis, and biological evaluation of 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones and related compounds as antifungal and antibacterial agents

A series of (S)-N-(3-chloro-1,4-naphthoquinon-2-yl)-alpha-amino acid ethyl esters 3 and 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones 6-23 were synthesized and evaluated for antifungal and antibacterial activities. The structure-activity relationship of these compounds was studied and the results show that the compounds 3a and 3b exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii whereas compounds 12 and 22 showed in vitro antibacterial activity against Klebsiella pneumoniae and Escherichia coli.     

Synthesis and in vitro biological activity of new 4,6-disubstituted 3(2H)-pyridazinone-acetohydrazide derivatives

New 3(2H)-pyridazinone derivatives containing a N'-benzyliden-acetohydrazide moiety at position 2 were synthesized. The structures of these newly synthesized compounds were confirmed by IR, 1H NMR, and MS data. These compounds were tested for their antibacterial, antifungal, antimycobacterial, and cytotoxic activities. The compounds 2-[4-(4-chlorophenyl)-6-(morpholin-4-yl)-3-oxo-(2H)-pyridazin-2-yl]-N'-(4-tert-butylbenzyliden)acetohydrazide and 2-[4-(4-chlorophenyl)-6-(morpholin-4-yl)-3-oxo-(2H)-pyridazin-2-yl]-N'-(4-chlorobenzyliden) acetohydrazide exhibited activity against both Gram-positive and Gram-negative bacteria. Most of the compounds were active against E. coli ATCC 35218. The preliminary results of this study revealed that some target compounds exhibited promising antimicrobial activities.