Novel anellated pyrazoloquinolin-3-ones: synthesis and in vitro BZR activity

A series of pyrazolo[4,3-c]pyrrolo[3,2-f]quinolin-3-one derivatives 6, 7a-c, 8a,b, 9a,b and 10-12 were synthesized as modified pyrazoloquinolinone analogs (PQs) and evaluated for their ability to inhibit radioligand to central and peripheral benzodiazepine receptors (BZRs) and their effect on GABA(A) alpha1beta2gamma2L receptors expressed in Xenopus laevis oocytes. Multistep synthesis starting from 5-nitroindole, via the Gould-Jacobs reaction to the quinoline nucleus, yielded key intermediates 9-chloro-3H-pyrrolo[3,2-f]quinoline-8-carboxylates. The reaction of the latter with methyl-hydrazine and various phenyl-hydrazines furnished the final compounds. In order to confirm the expected tetracyclic 2-substituted-2H-pyrazolopyrroloquinolin-3-one structure, IR spectrophotometric, mono-1H and 13C and bi-dimensional spectrometric and HRMS analyses were carried out: all compounds were found to be 2-substituted 3-keto tautomers; compound 6 only differed because it turned out to be 1-methyl-2H-pyrazolo[4,3-c]pyrrolo[3,2-f]quinolin-3-olo. The results of this work are consistent with those previously reported for PQs: 7-9 show high potency in displacing specific [3H]flunitrazepam from its receptor site; no compound was active in inhibiting the binding of [3H]PK 11195. They all act as antagonists at central BZR.     

Synthesis, antioxidant and toxicological study of novel pyrimido quinoline derivatives from 4-hydroxy-3-acyl quinolin-2-one

A series of novel pyrimido and other fused quinoline derivatives like 4-methyl pyrimido [5,4-c]quinoline-2,5(1H,6H)-dione (4a), 4-methyl-2-thioxo-1,2-dihydropyrimido [5,4-c]quinoline-5(6H)-one (4b), 2-amino-4-methyl-1,2-dihydropyrimido [5,4-c]quinolin-5(6H)-one (4c), 3-methylisoxazolo [4,5-c]quinolin-4(5H)-one (4d), 3-methyl-1H-pyrazolo [4,3-c]quinoline-4(5H)-one (5e), 5-methyl-1H-[1,2,4] triazepino [6,5-c]quinoline-2,6(3H,7H)-dione (5f), 5-methyl-2-thioxo-2,3-dihydro-1H-[1,2,4]triazepino [6,5-c]quinolin-6(7H)-one (5 g) were synthesized regioselectively from 4-hydroxy-3-acyl quinolin-2-one 3. They were screened for their in vitro antioxidant activities against radical scavenging capacity using DPPH(), Trolox equivalent antioxidant capacity (TEAC), total antioxidant activity by FRAP, superoxide radical (O(2)(°-)) scavenging activity, metal chelating activity and nitric oxide scavenging activity. Among the compounds screened, 4c and 5 g exhibited significant antioxidant activities.     

High affinity central benzodiazepine receptor ligands. Part 2: quantitative structure-activity relationships and comparative molecular field analysis of pyrazolo[4,3-c]quinolin-3-ones

A large series of 2-aryl(heteroaryl)-2,5-dihydropyrazolo[4,3-c]quinolin-3(3H)-ones (PQ, 106 compounds), carrying appropriate substituents at the quinoline and N2-phenyl rings, were designed, prepared and tested as central benzodiazepine receptor ligands. Compounds with an affinity significantly higher than the parent compound CGS-8216 were obtained, the most active ligand showing a pIC50 = 10.35. Hansch and comparative molecular field analyses gave coherent results suggesting the main structural requirements of high receptor binding affinity. The possible formation of a three-centred hydrogen bond (HB) at the HB donor site H2, as a key interaction for high receptor binding affinity, was assessed by the calculation and comparison of the molecular electrostatic potentials of a series of selected ligands.     

Structure-activity relationships of 2-Aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)-ones at the benzodiazepine receptor

A large series of 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)ones (PIs) carrying properly selected substituents at the indole and N₂-phenyl rings was prepared and tested as central benzodiazepine receptor (BZR) ligands and potential (anti)convulsant agents. Stereoelectronic requirements for high receptor affinity were detected by means of 2-D and 3-D QSAR analyses. BZR affinities and pharmacological profiles of the compounds were examined in comparison with some other pyridazinoindolones recently described by us and with pyrazoloquinoline (PQ) analogues. An anticonvulsant activity greater than PQs was generally observed for PIs. Notably, in the test of audiogenically induced seizures, one compound showed a potency comparable to that of diazepam.     

Synthesis and antiviral activities of new pyrazolo[4,3-c]quinolin-3-ones and their ribonucleoside derivatives

Several new pyrazolo[4,3-c]quinolin-3-one ribonucleosides (5a-g) and their corresponding heterocycle moieties (3a-g) were synthesized and evaluated against vaccinia virus (VV) and herpes simplex virus type 1 (HSV-1). The derivatives 3c and 3d showed modest inhibitory activity against vaccinia virus reaching 70% at a concentration of 100 microM. All heterocyclic compounds (3a-f) showed a modest inhibition against HSV-1, reaching the maximal inhibitory effect around 20-30%. The antiviral effects of most of the pyrazolo[4,3-c]quinolin-3-one ribonucleosides (5a-f) on VV and HSV were not impressive.     

Synthesis and pharmacological evaluation of pyrazolo[4,3-c]quinolinones as high affinity GABAA-R ligands and potential anxiolytics

The synthesis, in vitro ligand binding study and in vivo Elevated Plus Maze test (EPM) of a series of pyrazolo[4,3-c]quinolin-3-ones (PQs) are reported. Multistep synthesis of PQs started from anilines and diethyl 2-(ethoxymethylene)malonate to give the quinolin-4-one nucleus, via the Gould-Jacobs reaction. These quinolinones were transformed to 4-chloroquinolines, which react with aryl-hydrazines affording the final compounds. PQs exhibited different potency in displacing specific [³H]Flunitrazepam binding from the benzodiazepine binding site at the γ-aminobutyric acid receptor (GABA_A-R) depending on the substitution of the pyrazoloquinolone nucleus. PCA helped determine how different substituents contributed to the differential behavior of the PQs studied. Compounds with high affinity for the GABA_A-R were tested regarding their anxiolytic properties in Wistar adult male rats using the Elevated Plus Maze (EPM). Thus, PQs with a p-methoxy phenyl group at N-1 (7b-ii and 7c-ii) displayed a remarkable anxiolytic activity at low doses (0.5–1.0?mg/kg). Meanwhile, PQs featuring an unsubstituted phenyl (7b-i) or p-fluoro phenyl group (7b-iii) at the N-1 showed anxiogenic effects in the EPM test.     

Synthesis and biological evaluation of 2,5-dihydropyrazol

A novel series of 2,5-dihydropyrazolo[4,3-c]quinolin-3-ones has been prepared. These compounds showed good PDE 4 inhibitory activity and weak affinity for rolipram's binding site. They also exhibited a good anti-inflammatory profile without emetic side effects.     

Synthesis and positive inotropic activity of N-(4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(piperazin-1-yl)acetamide derivatives

A series of N-(4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(piperazin-1-yl)acetamide derivatives were synthesized and their positive inotropic activity was evaluated by measuring left atrium stroke volume on isolated rabbit heart preparations. Several compounds showed favorable activity compared with the standard drug, milrinone, among which N-(1-benzyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(4-benzylpiperazin-1-yl)acetamide 6j was found to be the most potent with the 13.2% increased stroke volume (milrinone 4.7%) at concentration of 3x10(-5) M in our in vitro study. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work.     

Synthesis and positive inotropic evaluation of N-(1-oxo-1,2,4,5-tetrahydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides bearing piperazine and 1,4-diazepane moieties

Two series of N-(1-oxo-1,2,4,5-tetrahydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides bearing piperazine and 1,4-diazepane moieties were synthesized and screened for their positive inotropic activity by measuring left atrium stroke volume on isolated rabbit heart preparations. Most of the derivatives exhibited better in vitro positive inotropic activity than the existing drug, milrinone, among which 2-(4-(4-chlorobenzyl)-1,4-diazepan-1-yl)-N-(1-oxo-1,2,4,5-tetrahydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 6c proved to be the most potent with 15.48 ± 0.27% increased stroke volume (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10(-5) M. The chronotropic effects of the compounds that exhibited inotropic effects were also evaluated.     

Optimization of a pyrazoloquinolinone class of Chk1 kinase inhibitors

The development of 2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-ones as inhibitors of Chk1 kinase is described. Introduction of a fused ring at the C7/C8 positions of the pyrazoloquinolinone provided an increase in potency while guidance from overlapping inhibitor bound Chk1 X-ray crystal structures contributed to the discovery of a potent and solubilizing propyl amine moiety in compound 52 (Chk1 IC(50)=3.1 nM).     

Antifungal properties of new series of quinoline derivatives

The series of quinoline derivatives were prepared. The synthetic approach, analytical, and spectroscopic data of all synthesized compounds are presented. All the prepared derivatives were analyzed using the reversed-phase high performance liquid chromatography (RP-HPLC) method for the lipophilicity measurement. In the present study, the correlation between RP-HPLC retention parameter log K (the logarithm of capacity factor K) and various calculated log P data is shown. The relationships between the lipophilicity and the chemical structure of the studied compounds are discussed as well. The prepared compounds were tested for their in vitro antifungal activity. 2-[(3-Hydroxyphenylimino)methyl]quinolin-8-ol (8), 2-[(4-hydroxyphenylimino)methyl]quinolin-8-ol (9) and 2-[(2,5-dichloro-4-nitrophenylamino)methoxymethyl]quinolin-8-ol (10) showed in vitro antifungal activity comparable to or higher than that of the standard fluconazole. Structure-activity relationships among the chemical structure, the physical properties, and the biological activities of the evaluated compounds are discussed in the article.     

Synthesis and structure-affinity relationships at the central benzodiazepine receptor of pyridazino[4,3-b]indoles and indeno[1,2-c]pyridazines.

A series of 2-aryl-3-chloro-2H-pyridazino[4,3-b]indoles, 2-aryl-3-methoxy-2H-pyridazino[4,3-b]indoles, and 2-aryl-2,5-dihydroindeno[1,2-c]pyridazino-3(3H)-ones has been prepared and tested for their ability to inhibit the [3H]flunitrazepam binding to the central benzodiazepine receptor. SAR are presented and discussed in comparison with existing pharmacophore models.     

Synthesis and biological activity of 2,5-diaryl-3-methylpyrimido[4,5-c]quinolin-1(2H)-one derivatives

A series of 2,5-diaryl-3-methylpyrimido[4,5-c]quinolin-1(2H)-ones (7-30), variously substituted at the 2- and 5-phenyl moieties, were synthesized and evaluated for their in vitro cytotoxic activity against a PC3 cancer cell line. Cytotoxicity data revealed that the type of substituent as well as substitution pattern have variable influence on cytotoxic activity. Among the compounds tested, compounds (9), (13), (18), (19), and (23) demonstrated appreciable cytotoxic activity with mean IC(50) values of 2.0, 1.4, 1.6, 2.2, and 1.9microM, respectively. Methyl substitution at the 2-phenyl ring was found to yield the least active compounds. Two of the most potent compounds (13) and (18) were further investigated for inhibition of tubulin polymerization and found to have no activity at the concentrations used in the assay.     

Synthesis and anti-inflammatory activities of N4,N5-disubstituted-3-methyl- H-pyrazolo[3,4-c]pyridazines

The synthesis and anti-inflammatory activity of 4,5-dihydroxy-3-methyl-1H-pyrazolo[3,4-c]pyridazine (4), 4,5-dichloro-3-methyl-1H-pyrazolo[3,4-c]pyridazine (5), 4,-benzoyloxy-3-methyl-1-benzoyl-1H-pyrazolo[3,4-c]pyridazin-5yl benzoate (6), 3-methyl-N4,N5-bis(4-methylphenyl)-1H-pyrazolo[3,4-c]pyridazine-4,5-diamine (7), 4[[5-(4-carboxyanilino)-3-methyl-1H-pyrazolo[3,4-c]pyridazin-4yl]amino]benzoic acid (8), N-[5-(benzoylamino)-3-methyl-1H-pyrazolo[3,4-c]pyridazin-4-yl]benzamide (9) and 3-methyl-N4,N5-bis[4-(1H-benzimidazol-2yl)phenyl]-1H-pyrazolo[3,4-c]pyridazine-4,5-diamine (10) are being reported.     

The effect of 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c]quinazoline on cell growth, cell cycle, induction of DNA fragmentation, and activity of caspase 3 in murine leukemia L1210 cells and fibroblast NIH-3T3 cells

Quinazolines are multitarget agents, which have broad spectrum of biological activity, and some of them are now in cancer clinical testing. 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c]quinazoline is a new synthetically prepared derivative, which in our previous study showed cytotoxic effects on cancer cell lines HeLa and B16. Quinazoline, at micromolar concentrations, induced morphological changes and necrosis of B16 cells, and at nanomolar concentrations it produced changes of F-actin cytoskeleton. It did not cause changes in the cell cycle, did not induce apoptotic cell death in B16 cells, did not have a mutagenic effect, and did not even behave as a typical intercalating agent. Little significant reduction of tumor volume in intramuscular transplanted B16 cells was observed. The aim of the present study was to examine the cytotoxic effect of 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c]quinazoline on murine leukemia L1210 cells and fibroblast NIH-3T3 cells. Induction of cell morphology and cell cycle changes, induction of apoptosis and caspase 3 activity were studied. Quinazoline acted cytotoxically on both cell lines. The sensitivity of leukemia L1210 cells to the quinazoline was higher than that of fibroblast NIH-3T3. The IC(100) was 12 microM for L1210 cells and 24 microM for NIH-3T3 cells. No effect of quinazoline on the cell cycle profile of L1210 and NIH-3T3 was detected, however, quinazoline induced an increase of the sub-G(0) cell fraction, apoptotic DNA fragmentation, and apoptotic morphological changes at a concentration of 12 microM. This quinazoline concentration induced caspase 3 activity. Our results demonstrated that induction of apoptotic cell death via activation of caspase 3 contributed to the cytotoxic effects of 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c]quinazoline in murine leukemia L1210 cells.     

3-Monoterpenyl-2,4-dioxygenated quinoline alkaloids from the aerial parts of Halfordia kendack

The aerial parts of Halfordia kendack (Rutaceae) have yielded the known alkaloid trans-erioaustralasine ([rel]-1-acetoxymethyl-4.8'-epoxy-3-(1'beta,2'beta-epoxy-3'beta,4'alpha-para-menthyl-3'-yl)quinolin-2-one) together with four new alkaloids. The latter were characterised by spectroscopic methods as trans-deacetoxyerioaustralasine ([rel]-1-methyl-4.8'-epoxy-3-(1'beta,2'beta-epoxy-3'beta,4'alpha-para-menthyl-3'-yl)quinolin-2-one), trans-deacetoxyerioaustralasine hydrate ([rel]-1-methyl-4.8'-epoxy-3-(1'alpha,2'alpha-dihydroxy-3'beta,4'alpha-para-;menthyl-3'-yl)quinolin-2-one), trans-erioaustralasine hydrate ([rel]-1-acetoxymethyl-4.8'-epoxy-3-(1'alpha,2'alpha-dihydroxy-3'beta,4'alpha-para-menthyl-3'-yl)quinolin-2-one) and trans-1-epi-deacetoxyerioaustralasine hydrate ([rel]-1-acetoxymethyl-4.8'-epoxy-3-(1'beta,2'alpha-dihydroxy-3'beta,4'alpha-para-menthyl-3'-yl)quinolin-2-one).     

Synthesis, structure-affinity relationships, and molecular modeling studies of novel pyrazolo[3,4-c]quinoline derivatives as adenosine receptor antagonists

This paper reports the study of new 2-phenyl- and 2-methylpyrazolo[3,4-c]quinolin-4-ones (series A) and 4-amines (series B), designed as adenosine receptor (AR) antagonists. The synthesized compounds bear at the 6-position various groups, with different lipophilicity and steric hindrance, that were thought to increase human A(1) and A(2A) AR affinities and selectivities, with respect to those of the parent 6-unsubstituted compounds. In series A, this modification was not tolerated since it reduced AR affinity, while in series B it shifted the binding towards the hA(1) subtype. To rationalize the observed structure-affinity relationships, molecular docking studies at A(2A)AR-based homology models of the A(1) and A(3) ARs and at the A(2A)AR crystal structure were carried out.     

Antimicrobial activity of some substituted triazoloquinazolines

Fifteen substituted 1,2,4-triazolo[4,3-c]quinazolines were tested for antibacterial and antifungal effects. The most effective derivatives had the triazoloquinazoline skeleton substituted with the pharmacologically active chromophores--morpholine, chlorine and nitro group. The broadest antimicrobial activity was found with 5-morpholin-4-yl-3-(5-nitrothien-2-yl)[1,2,4]triazolo[4,3-c]quinazoline in concentration of 10 mg/L for B. subtilis, 50 mg/L for S. aureus and 100 mg/L for C. tropicalis. The highest tested concentration of derivative caused 83% growth inhibition of R. nigricans.     

Ultrasound mediated catalyst free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones leading to novel quinoline derivatives: their evaluation as potential anti-cancer agents

A facile and catalyst free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones has been accomplished via the reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde with various aromatic amines in the presence of ultrasound. Some of these compounds were converted to the corresponding 2-(3-(hydroxymethyl)quinolin-2-yl)phenols and further structure elaboration of a representative quinoline derivative is presented. Molecular structure of two representative compounds was confirmed by single crystal X-ray diffraction study. Many of these compounds were evaluated for their anti-proliferative properties in vitro against four cancer cell lines and several compounds were found to be active. Further in vitro studies indicated that inhibition of sirtuins could be the possible mechanism of action of these molecules.     

Discovery and structure-activity relationship of N-phenyl-1H-pyrazolo[3,4-b]quinolin-4-amines as a new series of potent apoptosis inducers

We report the discovery and SAR study of a series of N-phenyl-1H-pyrazolo[3,4-b]quinolin-4-amines as potent inducers of apoptosis. N-(3-Acetylphenyl)-2,3-dihydro-1H-cyclopenta[b]quinolin-9-amine (2) was discovered through our cell- and caspase-based HTS assays as an inducer of apoptosis. Compound 2 is active against cancer cells derived from several human solid tumors, with EC(50) values ranging from 400 to 700 nM. SAR study of hit 2 led to the discovery of N-phenyl-1H-pyrazolo[3,4-b]quinolin-4-amines as a novel series of potent apoptosis inducers, with 1,3-dimethyl-N-(4-propionylphenyl)-1H-pyrazolo[3,4-b]quinolin-amine (6b) having EC(50) values ranging from 30 to 70 nM in cancer cells. These compounds also demonstrated potent activity in the cell growth inhibition assay, with GI(50) values of 16-42 nM for compound 6b.