Synthesis, cytotoxicity, and anti-inflammatory evaluation of 2-(furan-2-yl)-4-(phenoxy)quinoline derivatives. Part 4

A number of 2-(furan-2-yl)-4-phenoxyquinoline derivatives have been synthesized and evaluated for anti-inflammatory evaluation. 4-[(2-Furan-2-yl)quinolin-4-yloxy]benzaldehyde (8), with an IC(50) value of 5.0 microM against beta-glucuronidase release, was more potent than its tricyclic furo[2,3-b]quinoline isomer 3a (>30 microM), its 4'-COMe counterpart 7 (7.5 microM), and its oxime derivative 13a (11.4 microM) and methyloxime derivative 13b (>30 microM). For the inhibition of lysozyme release, however, oxime derivative 12a (8.9 microM) and methyloxime derivative 12b (10.4 microM) are more potent than their ketone precursor 7 and their respective tricyclic furo[2,3-b]quinoline counterparts 4a and 4b. Among them, 4-[4-[(2-furan-2-yl)-quinolin-4-yloxy]phenyl]but-3-en-2-one (10) is the most active against lysozyme release with an IC(50) value of 4.6 microM, while 8 is the most active against beta-glucuronidase release with an IC(50) value of 5.0 microM. (E)-1-[3-[(2-Furan-2-yl)quinolin-4-yloxy]phenyl] ethanone oxime (11a) is capable of inhibiting both lysozyme and beta-glucuronidase release with IC(50) values of 7.1 and 9.5 microM, respectively. For the inhibition of TNF-alpha formation, 1-[3-[(2-furan-2-yl)quinolin-4-yloxy]phenyl]ethanone (6) is the most potent with an IC(50) value of 2.3 microM which is more potent than genistein (9.1 microM). For the inhibitory activity of fMLP-induced superoxide anion generation, 11a (2.7 microM), 11b (2.8 microM), and 13b (2.2 microM) are three of the most active. None of above compounds exhibited significant cytotoxicity.     

Design, synthesis, and evaluation of 3,4-disubstituted pyrazole analogues as anti-tumor CDK inhibitors

Two series of 3,4-disubstituted pyrazole analogues, 3-(benzimidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (2) and 3-(imidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (3), were synthesized as novel cyclin-dependent kinase (CDK) inhibitors. Representative compounds showed potent and selective CDK inhibitory activities and inhibited in vitro cellular proliferation in various human tumor cells. The design, synthesis, and preliminary biological evaluation of these pyrazole compounds are reported.     

2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727): a potent, orally active dipeptidyl peptidase IV inhibitor without mechanism-based inactivation of CYP3A

We report on the identification of 2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727) (7a) as a potent and orally active DPP-4 inhibitor without mechanism-based inactivation of CYP3A. Compound 7a showed good DPP-4 inhibitory activity (IC(50)=1.1 nM), excellent selectivity against related peptidases and other off-targets, good pharmacokinetic and pharmacodynamic profile, great in vivo efficacy in Zucker-fatty rat, and no safety concerns both in vitro and in vivo.     

New pyrrolopyrimidin-6-yl benzenesulfonamides: potent A2B adenosine receptor antagonists

A new series of 4-(1,3-dialkyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)benzenesulfonamides has been identified as potent A2B adenosine receptor antagonists. The products have been evaluated for their binding affinities for the human A2B, A1 and A3 adenosine receptors. 6-(4-{[4-(4-Bromobenzyl)piperazin-1-yl]sulfonyl}phenyl)-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (16) showed a high affinity for the A2B adenosine receptor (IC50=1 nM) and selectivity (A1: 183x; A3: 12660x). Synthesis and SAR of this novel class of compounds showing improved absorption properties is presented herein.     

Synthesis and antibacterial activity of egonol derivatives

Synthesis of egonol derivatives, 5-(3'-chloropropyl)-7-methoxy-2-(3',4'-methylenedioxyphenyl)benzofuran 1, 5-(3'-bromopropyl)-7-methoxy-2-(3',4'-methylenedioxyphenyl)benzofuran 2, 3-[2-(1,3-benzodioxol-5-yl)-7-methoxy-1-benzofuran-5-yl]propanal 3, 5-(3'-iodopropyl)-7-methoxy-2-(3',4'-methylenedioxyphenyl)benzofuran 4, 5-[3-(3'-bromopropyloxy) propyl]-7-methoxy-2-(3',4'-methylenedioxyphenyl)benzofuran 5, 3-[2-(1,3-benzodioxol-5-yl)-7-methoxy-1-benzofuran-5-yl]propylmethanoate 6, 3-[2-(1,3-benzodioxol-5-yl)-7-methoxy-1-benzofuran-5-yl]propyloleate 7, 5-[3'-hydroxypropyl]-6-bromo-7-methoxy-2-(3',4'-methylenedioxyphenyl)benzofuran 8, 4-[2-(1,3-benzodioxol-5-yl)-7-methoxy-1-benzofuran-5-yl]butanenitrile 9, 3-[2-(1,3-benzodioxol-5-yl)-7-methoxy-1-benzofuran-5-yl]propylbenzoate 10, 5-[3'-hydroxypropyl]-7-methoxy-3-nitro-2-(3',4'-methylenedioxyphenyl)benzofuran 11 and their antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Candida albicans and Escherichia coli are reported. The starting material egonol 5-[3'-(hydroxy)propyl]-7-methoxy-2-(3', 4'methylenedioxyphenyl)benzofuran was isolated from seeds of Styrax officinalis L. The structural elucidication of these compounds (1-11) was established using 1D ((1)H, (13)C), 2D NMR (HMBC, HMQC, COSY) and LCMS spectroscopic data. While egonol and some synthesised new compounds show similar antibacterial activity and MIC values against S. aureus, B. subtilis, C. albicans and E. coli, other new derivatives show different activity against S. aureus, B. subtilis, C. albicans and E. coli.     

Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and aza-oxindoles

The discovery, synthesis, potential binding mode, and in vitro kinase profile of 3-(3-bromo-4-hydroxy-5-(2'-methoxyphenyl)-benzylidene)-5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one, 3-[(1-methyl-1H-indol-3-yl)methylene]-1,3-dihydro-2H-pyrrolo[3,2-b]-pyridin-2-one as potent TrkA inhibitors are discussed.     

Antifungal and anthelmintic activity of novel benzofuran derivatives containing thiazolo benzimidazole nucleus: an in vitro evaluation

A novel series of thiazolo[3,2-a]benzimidazole derivatives containing benzofuran nucleus (5a–l) have been synthesized. The key intermediate, substituted benzimidazol-sulfanyl benzofuran ethanone (3a–d) was prepared by refluxing the mixture of substituted 2-acetyl benzofuran and substituted 2-mercaptobenzimidazole in acetic acid. The cyclisation of compounds (3a–d) using polyphosphoric acid furnished the corresponding 6-substituted benzofuran thiazolo[3,2-a]benzimidazoles (4a–d). Further, the cyclized compounds (4a–d) were subjected for Mannich reaction to give corresponding Mannich bases (5a–l). All newly synthesized compounds were screened for antifungal and anthelmintic activity. Amongst the tested compounds, 4b and 4d exhibited potential antifungal activity. From the anthelmintic activity data, it was found that the compounds 3a, 3b and 5i were found to be more effective against the tested earthworm Pheretima posthuma. In correlation to anthelmintic activity, the selected compounds were subjected for molecular docking studies and the compounds 3a and 5i have emerged as active anthelmintic agents with maximum binding affinity (?3.7 and ?5.4 kcal/mol).     

Antimycobacterial activities of novel 2-(sub)-3-fluoro/nitro-5,12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid

Various 2-(sub)-3-fluoro/nitro-5,12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid derivatives were synthesized from 2-aminothiophenol by a five-step reaction, evaluated for in-vitro and in-vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC2), and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the thirty-four synthesized compounds, 2-(3-(diethylcarbamoyl)piperidin-1-yl)-)-3-fluoro-5,12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid (7l) was found to be the most active compound in vitro with MIC of 0.18 and 0.08 microM against MTB and MTR-TB, respectively. Compound 7l was found to be 2 and 570 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in-vivo animal model 7l decreased the bacterial load in lung and spleen tissues with 2.78 and 3.12-log10 protections, respectively, at the dose of 50 mg/kg body weight.     

A novel oxazine ring closure reaction affording (Z)-((E)-2-styrylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylideno)acetaldehydes and their anti-osteoclastic bone resorption activity

A novel oxazine ring formation method was established using the reaction of 2-acetyl-(E)-3-styrylcarbonylaminobenzo[b]furans (4) with Vilsmeier-Haack-Arnold reagent to afford (E and Z)-((E)-2-styrylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylideno)acetaldehydes (5). (Z)-4-(8-Bromo-(E)-2-styrylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylideno)but-(E)-2-enoic acid ethyl ester (6b), derived from (Z)-5a, showed significantly potent anti-osteoclastic bone resorption activity comparable to 17beta-estradiol (E2).     

Synthesis and selective cyclooxygenase-2 (COX-2) inhibitory activity of a series of novel bicyclic pyrazoles

Novel series of pyrazolo[5,1-b]1,3-oxazolidines, pyrazolo[5,1-b]1,3-oxazines and imidazolidino[1,2-d]pyrazoles were synthesized. These compounds were evaluated in vitro for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in human whole blood (HWB). Several of the compounds were found to be novel and selective COX-2 inhibitors, the most potent and selective being 1-(5-cyclohexyl (2H,3H-pyrazolo[5,1-b]-1,3-oxazolidin-6-yl)-4-(methylsulfonyl)benzene, 7a (IC(5o) for COX-1>100 microM; for COX-2=1.3 microM).     

Synthesis of some new [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and [1,2,4]triazolo[3,4-b][1,3,4] thiadiazoles starting from 5-nitro-2-furoic acid and evaluation of their antimicrobial activity

New series of fused 1,2,4-triazoles such as, 6-(aryl)-3-(5-nitrofuran-2-yl)-5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 4-8, 6-(alkyl/aryl amino)-3-(5-nitrofuran-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 9-13 and 6-(4-substituted phenyl)-3-(5-nitrofuran-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 14-18 have been synthesized via the reaction of 4-amino-5-(5-nitrofuran-2-yl)-4H-1,2,4-triazole-3-thiol 3 with various reagents such as hetero aromatic aldehydes, alkyl/aryl isothiocyanates and 4-substituted phenacyl bromides, respectively. The structures of the newly synthesized compounds have been confirmed on the basis of elemental analysis and spectral studies. The newly synthesized triazolo derivatives have been investigated for their in vitro antibacterial activity. Most of the tested compounds showed interesting antibacterial activity against Staphylococcus aureus. Furthermore, the most potent antibacterial compounds 11-13 were evaluated for their in vitro cytotoxic activity against human cancer cell lines. It was found that compounds 11 and 13 showed higher cytotoxicity against Hep-G2 cell line as compared to standard.     

Synthesis and biological evaluation of L- and D-configuration 1,3-dioxolane 5-azacytosine and 6-azathymine nucleosides

Novel L- and D-configuration dioxolane 5-azacytosine and 6-azathymine nucleosides have been synthesized and evaluated for biological activity. (-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-5-azacytosine (6) showed significant activity against HBV, whereas the D-configuration analogue (14) has been found to exhibit potent anti-HIV activity.     

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.     

Design, synthesis and in vitro antitumor activity of new trans 2-[2-(heteroaryl)vinyl]-1,3-dimethylimidazolium iodides

The design, the synthesis, and the in vitro antitumor activities of trans 2-[2-(heteroaryl)vinyl]-1,3-dimethylimidazolium iodides versus MCF7 (human mammary carcinoma) and LNCap (prostate carcinoma) cell lines are reported. The design indicates trans 2-[2-[5-(2-chlorophenyl)furan-2-yl]vinyl]-1, 3-dimethylimidazolium iodide 5 and trans 2-[2-[5-(4-bromophenyl)furan-2-yl]vinyl]-1, 3-dimethylimidazolium iodide 6 as highly active compounds in the series. The synthesis of the above new derivatives and in vitro antitumor tests, confirm their significant antiproliferative and cytotoxic activities.     

Synthesis and antimicrobial activity of some new substituted pyrido[3′,2′:4,5]thieno[3,2-d]-pyrimidinone derivatives

A series of new 3-substituted-7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,4-dichlorophenyl)-2-methylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one derivatives were synthesized as antimicrobial agents using 7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,4-dichlorophenyl)-2-methyl-4H-pyrido[3′,2′:4,5]thieno[3,2-d]-[1,3]oxazin-4-one as a starting compound. Its condensation with substituted aniline derivatives or phenyl hydrazine gave the corresponding N-substituted derivatives. Treatment of the starting compound with hydrazine hydrate afforded the corresponding N-amino derivative, which was reacted with substituted phenylisocyanate and phenylisothiocyanate derivatives to give the corresponding semicarbazides and thiosemicarbazide derivatives. All the newly synthesized compounds were evaluated for their antimicrobial activities in comparison to streptomycin and fusidic acid as positive controls. The structure assignments of the new compounds are based on chemical and spectroscopic evidence.     

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.     

Identification and optimization of a novel series of [2.2.1]-oxabicyclo imide-based androgen receptor antagonists

A novel series of [2.2.1]-oxabicyclo imide-based compounds were identified as potent antagonists of the androgen receptor. Molecular modeling and iterative drug design were applied to optimize this series. The lead compound [3aS-(3aalpha,4beta,5beta,7beta,7aalpha)]-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile was shown to have potent in vivo efficacy after oral dosing in the CWR22 human prostate tumor xenograph model.     

A novel series of parenteral cephalosporins exhibiting potent activities against Pseudomonas aeruginosa and other Gram-negative pathogens: synthesis and structure-activity relationships

A series of 7beta-[2-(2-aminothiazol-4-yl)-2-(Z)-(carboxymethoxyimino)acetamido]cephalosporins bearing a 1-(substituted)-1H-pyrrolo[3,2-b]pyridinium group at C-3' position was synthesized and their in vitro antibacterial activities against Pseudomonas aeruginosa and other Gram-negative pathogens were evaluated. Among the cephalosporins prepared, 7beta-[2-(2-amino-5-chlorothiazol-4yl)-2(Z)-((S)-1-carboxyethoxyimino)acetamido]cephalosporins (42d) showed potent antibacterial activities against P. aeruginosa and other Gram-negative pathogens including the strains which produce class C beta-lactamase and extended spectrum beta-lactamase (ESBL). These results imply that both the Cl atom on the C-7 aminothiazole moiety and the alpha-substituent at the iminoether moiety are essential for the stability against beta-lactamase and the potent activity against Gram-negative bacteria including P. aeruginosa.     

Indolo[3,2-c]cinnolines with antiproliferative, antifungal, and antibacterial activity.

A series of indolo[3,2-c]cinnoline derivatives was prepared and tested to evaluate their biological activity. Most of them inhibited the proliferation of leukemia, lymphoma and solid tumor-derived cell lines at micromolar concentrations, whereas none of the compounds were active against HIV-1. With the exception of 7g, all title compounds showed antibacterial activity against gram-positive bacteria, being up to 200 times more potent than the reference drug streptomycin. Some of the indolo[3,2-c]cinnolines were also endowed with good antifungal activity, particularly against Criptococcus neoformans.     

Synthesis and biological evaluation of 1,3-oxathiolane 5-azapyrimidine, 6-azapyrimidine, and fluorosubstituted 3-deazapyrimidine nucleosides

(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]- 1,2,4-triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2,4-tr iazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,3, 5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]- 1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19-24) have been synthesized by the transglycosylation of (2R,5S)-1-[2-[[(tert-butyldiphenylsilyl) oxy]methyl]-1,3-oxathiolan-5-yl] cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B16F10, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.