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1.
Acta Pharm ; 71(3): 485-495, 2021 Sep 01.
Article in English | MEDLINE | ID: mdl-36654088

ABSTRACT

Trichomoniasis is a public health problem worldwide. Trichomoniasis treatment consists of the use of nitroimidazole derivatives; however, therapeutic ineffectiveness occurs in 5 to 20 % of the cases. Therefore, it is essential to propose new pharmacological agents against this disease. In this work, esters of quinoxaline-7-carboxylate-1,4-di-N-oxide (EQX-NO) were evaluated in in vitro assays as novel trichomonicidal agents. Additionally, an in vitro enzyme assay and molecular docking analysis against triosephosphate isomerase of Trichomonas vaginalis to confirm their mechanism of action were performed. Ethyl (compound 12) and n-propyl (compound 37) esters of quinoxaline-7-carboxy-late-1,4-di-N-oxide derivatives showed trichomonicidal activity comparable to nitazoxanide, whereas five methyl (compounds 5, 15, 19, 20 and 22), four isopropyl (compounds 28, 29, 30 and 34), three ethyl (compounds 4, 13 and 23) and one npropyl (compound 35) ester derivatives displayed activity comparable to albendazole. Compounds 6 and 20 decreased 100 % of the enzyme activity of recombinant protein triosephosphate isomerase.

2.
Molecules ; 23(6)2018 06 15.
Article in English | MEDLINE | ID: mdl-29914062

ABSTRACT

Tuberculosis continues to be a public health problem in the world, and drug resistance has been a major obstacle in its treatment. Quinoxaline 1,4-di-N-oxide has been proposed as a scaffold to design new drugs to combat this disease. To examine the efficacy of this compound, this study evaluates methyl, ethyl, isopropyl, and n-propyl esters of quinoxaline 1,4-di-N-oxide derivatives in vitro against Mycobacterium tuberculosis (pansusceptible and monoresistant strains). Additionally, the inhibitory effect of esters of quinoxaline 1,4-di-N-oxide on M. tuberculosis gyrase supercoiling was examined, and a stability analysis by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was also carried out. Results showed that eight compounds (T-007, T-018, T-011, T-069, T-070, T-072, T-085 and T-088) had an activity similar to that of the reference drug isoniazid (minimum inhibitory concentration (MIC) = 0.12 µg/mL) with an effect on nonreplicative cells and drug monoresistant strains. Structural activity relationship analysis showed that the steric effect of an ester group at 7-position is key to enhancing its biological effects. Additionally, T-069 showed a high stability after 24 h in human plasma at 37 °C.


Subject(s)
Antitubercular Agents/chemical synthesis , Mycobacterium tuberculosis/drug effects , Quinoxalines/chemical synthesis , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Chromatography, Liquid , Drug Resistance, Bacterial/drug effects , Drug Stability , Esters/chemical synthesis , Esters/chemistry , Esters/pharmacology , Humans , Microbial Sensitivity Tests , Molecular Structure , Quinoxalines/chemistry , Quinoxalines/pharmacology , Structure-Activity Relationship , Tandem Mass Spectrometry
3.
Parasitol Res ; 117(1): 45-58, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29159705

ABSTRACT

Leishmaniasis is a neglected tropical disease caused by the parasite of the genus Leishmania. About 13 million people are infected worldwide, and it is estimated that 350 million are at risk of infection. Clinical manifestations depend on the parasite species and factors related to the host such as the immune system, nutrition, housing, and financial resources. Available treatments have severe side effects; therefore, research currently focuses on finding more active and less toxic compounds. Quinoxalines have been described as promising alternatives. In this context, 17 isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives were evaluated as potential leishmanicidal agents. Their effect on the cell metabolism of Leishmania mexicana promastigotes and their cytotoxic effects on the J774.A1 cell line and on erythrocytes were evaluated, and their selectivity index was calculated. Compounds T-069 (IC50 = 1.49 µg/mL), T-070 (IC50 = 1.71 µg/mL), T-072 (IC50 = 6.62 µg/mL), T-073 (IC50 = 1.25 µg/mL), T-085 (IC50 = 0.74 µg/mL), and T-116 (IC50 = 0.88 µg/mL) were the most active against L. mexicana promastigotes and their mechanism of action was characterized by flow cytometry and microscopy. Compound T-073, the most selective quinoxaline derivative, induced cell membrane damage, phosphatidylserine exposition, reactive oxygen species production, disruption of the mitochondrion membrane potential, and DNA fragmentation, all in a dose-dependent manner, indicating the induction of regulated necrosis. Light and transmission electron microscopy showed the drastic morphological changes induced and the mitochondrion as the most sensitive organelle in response to T-073. This study describes the mechanism by which active isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide quinoxalines affect the parasite.


Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania mexicana/drug effects , Quinoxalines/pharmacology , Animals , Cell Death/drug effects , Cell Line , Membrane Potential, Mitochondrial/drug effects , Mice , Quinoxalines/chemistry , Reactive Oxygen Species
4.
Molecules ; 22(2)2017 Feb 01.
Article in English | MEDLINE | ID: mdl-28157150

ABSTRACT

Chagas disease or American trypanosomiasis is a worldwide public health problem. In this work, we evaluated 26 new propyl and isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives as potential trypanocidal agents. Additionally, molecular docking and enzymatic assays on trypanothione reductase (TR) were performed to provide a basis for their potential mechanism of action. Seven compounds showed better trypanocidal activity on epimastigotes than the reference drugs, and only four displayed activity on trypomastigotes; T-085 was the lead compound with an IC50 = 59.9 and 73.02 µM on NINOA and INC-5 strain, respectively. An in silico analysis proposed compound T-085 as a potential TR inhibitor with better affinity than the natural substrate. Enzymatic analysis revealed that T-085 inhibits parasite TR non-competitively. Compound T-085 carries a carbonyl, a CF3, and an isopropyl carboxylate group at 2-, 3- and 7-position, respectively. These results suggest the chemical structure of this compound as a good starting point for the design and synthesis of novel trypanocidal derivatives with higher TR inhibitory potency and lower toxicity.


Subject(s)
NADH, NADPH Oxidoreductases/antagonists & inhibitors , Quinoxalines/chemistry , Quinoxalines/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Binding Sites , Inhibitory Concentration 50 , Molecular Conformation , Molecular Docking Simulation , Molecular Dynamics Simulation , NADH, NADPH Oxidoreductases/chemistry , Parasitic Sensitivity Tests , Protein Binding , Structure-Activity Relationship , Trypanosoma cruzi/drug effects
5.
Anticancer Agents Med Chem ; 17(5): 682-691, 2017.
Article in English | MEDLINE | ID: mdl-27396382

ABSTRACT

BACKGROUND: Quinoxalines have shown a wide variety of biological activities including as antitumor agents. The aims of this study were to evaluate the activity of quinoxaline 1,4-di-N-oxide derivatives on K562 cells, the establishment of the mechanism of induced cell death, and the construction of predictive QSAR models. MATERIAL AND METHODS: Sixteen esters of quinoxaline-7-carboxylate 1,4-di-N-oxide were evaluated for antitumor activity on K562 chronic myelogenous leukemia cells and their IC50 values were determined. The mechanism of induced cell death by the most active molecule was assessed by flow cytometry and an in silico study was conducted to optimize and calculate theoretical descriptors of all quinoxaline 1,4-di-N-oxide derivatives. QSAR and QPAR models were created using genetic algorithms. RESULTS & CONCLUSIONS: Our results show that compounds C5, C7, C10, C12 and C15 had the lowest IC50 of the series. C15 was the most active compound (IC50= 3.02 µg/mL), inducing caspase-dependent apoptotic cell death via the intrinsic pathway. QSAR and QPAR studies are discussed.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cyclic N-Oxides/pharmacology , Quantitative Structure-Activity Relationship , Quantum Theory , Quinoxalines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cyclic N-Oxides/chemical synthesis , Cyclic N-Oxides/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , K562 Cells , Molecular Structure , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Tumor Cells, Cultured
6.
Parasitol Res ; 113(6): 2027-35, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24691716

ABSTRACT

In this work, a novel series of ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives were evaluated in vitro on Trypanosoma cruzi trypomastigotes and Leishmania mexicana promastigotes, and cytotoxicity activity in murine macrophages was tested. In silico molecular docking simulations of trypanothione reductase were also done. Three compounds of 33 quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives showed better anti-T. cruzi activity than nifurtimox and beznidazole; two compounds had better anti-leishmanial activity that amphotericin-B, and two compounds showed better activity against both parasites than reference drugs. Compounds M2, M7, M8 and E5, showed low cytotoxic activity on the host cell. The in silico studies suggest that compound M2 is a potential trypanothione reductase inhibitor.


Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania mexicana/drug effects , Quinoxalines/pharmacology , Trypanosoma cruzi/drug effects , Animals , Antiprotozoal Agents/chemistry , Macrophages , Mice , Quinoxalines/chemistry , Structure-Activity Relationship
7.
Molecules ; 19(2): 2166-80, 2014 Feb 18.
Article in English | MEDLINE | ID: mdl-24552985

ABSTRACT

We report the synthesis and antimalarial activities of eighteen quinoxaline and quinoxaline 1,4-di-N-oxide derivatives, eight of which are completely novel. Compounds 1a and 2a were the most active against Plasmodium falciparum strains. Structure-activity relationships demonstrated the importance of an enone moiety linked to the quinoxaline ring.


Subject(s)
Antimalarials/chemistry , Plasmodium falciparum/drug effects , Quinoxalines/chemistry , Structure-Activity Relationship , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Cell Line , Humans , Molecular Structure , Parasitic Sensitivity Tests , Plasmodium falciparum/pathogenicity , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology
8.
Eur J Med Chem ; 66: 324-34, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23811257

ABSTRACT

As a continuation of our research and with the aim of obtaining new agents against Chagas disease, an extremely neglected disease which threatens 100 million people, eighteen new quinoxaline 1,4-di-N-oxide derivatives have been synthesized following the Beirut reaction. The synthesis of the new derivatives was optimized through the use of a new and more efficient microwave-assisted organic synthetic method. The new derivatives showed excellent in vitro biological activity against Trypanosoma cruzi. Compound 17, which was substituted with fluoro groups at the 6- and 7-positions of the quinoxaline ring, was the most active and selective in the cytotoxicity assay. The electrochemical study showed that the most active compounds, which were substituted by electron-withdrawing groups, possessed a greater ease of reduction of the N-oxide groups.


Subject(s)
Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Chagas Disease/drug therapy , Oxides/chemistry , Quinoxalines/chemistry , Quinoxalines/pharmacology , Trypanosoma cruzi/drug effects , Animals , Antiprotozoal Agents/therapeutic use , Antiprotozoal Agents/toxicity , Cell Line , Electrochemistry , Mice , Mutagenesis/drug effects , Quinoxalines/therapeutic use , Quinoxalines/toxicity
9.
Bioorg Med Chem ; 21(15): 4550-8, 2013 Aug 01.
Article in English | MEDLINE | ID: mdl-23787289

ABSTRACT

In our search for new antiamoebic agents, a new series of ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives have been synthesized using the Beirut reaction. All compounds were characterized by spectroscopic techniques and elemental analysis. Antiamoebic activity was evaluated in vitro against Entamoeba histolytica strain HM1:IMSS by the microdilution method, and the structure-activity relationship was analyzed. We found that eleven quinoxaline derivatives showed greater activity than metronidazole and nitazoxanide with IC50 values in the range 1.99-0.35 µM. Compounds T-001 and T-016 shows IC50 values of 1.41 and 1.47 µM, respectively, with a value of selectivity index >60.


Subject(s)
Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Entamoeba histolytica/drug effects , Quinoxalines/chemistry , Quinoxalines/pharmacology , Antiprotozoal Agents/chemical synthesis , Cyclic N-Oxides/chemical synthesis , Cyclic N-Oxides/chemistry , Cyclic N-Oxides/pharmacology , Models, Molecular , Molecular Structure , Quinoxalines/chemical synthesis , Spectrum Analysis , Structure-Activity Relationship
10.
Molecules ; 18(4): 4718-27, 2013 Apr 22.
Article in English | MEDLINE | ID: mdl-23609622

ABSTRACT

Malaria and leishmaniasis are two of the World's most important tropical parasitic diseases. Continuing with our efforts to identify new compounds active against malaria and leishmaniasis, twelve new 1,4-di-N-oxide quinoxaline derivatives were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against Plasmodium falciparum FCR-3 strain, Leishmania infantum and Leishmania amazonensis. Their toxicity against VERO cells (normal monkey kidney cells) was also assessed. The results obtained indicate that a cyclopentyl derivative had the best antiplasmodial activity (2.9 µM), while a cyclohexyl derivative (2.5 µM) showed the best activity against L. amazonensis, and a 3-chloropropyl derivative (0.7 µM) showed the best results against L. infantum. All these compounds also have a Cl substituent in the R7 position.


Subject(s)
Antiparasitic Agents/pharmacology , Leishmania/drug effects , Plasmodium/drug effects , Quinoxalines/pharmacology , Amides/chemistry , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Antimalarials/toxicity , Antiparasitic Agents/chemistry , Antiparasitic Agents/toxicity , Chlorocebus aethiops , Humans , Inhibitory Concentration 50 , Leishmania infantum/drug effects , Oxides/chemistry , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Quinoxalines/chemistry , Quinoxalines/toxicity , Structure-Activity Relationship , Vero Cells
11.
Molecules ; 17(8): 9451-61, 2012 Aug 07.
Article in English | MEDLINE | ID: mdl-22871647

ABSTRACT

Malaria and leishmaniasis are two of the World's most important tropical parasitic diseases. Thirteen new 2-cyano-3-(4-phenylpiperazine-1-carboxamido) quinoxaline 1,4-dioxide derivatives (CPCQs) were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against erythrocytic forms of Plasmodium falciparum and axenic forms of Leishmania infantum. Their toxicity against VERO cells (normal monkey kidney cells) was also assessed. None of the tested compounds was efficient against Plasmodium, but two of them showed good activity against Leishmania. Toxicity on VERO was correlated with leishmanicidal properties.


Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania infantum/drug effects , Piperazines/pharmacology , Plasmodium falciparum/drug effects , Quinoxalines/pharmacology , Animals , Antiprotozoal Agents/chemical synthesis , Catalysis , Chlorocebus aethiops , Dimethylformamide/chemistry , Drug Evaluation, Preclinical , Ethylamines/chemistry , Inhibitory Concentration 50 , Piperazines/chemical synthesis , Quinoxalines/chemical synthesis , Solvents/chemistry , Structure-Activity Relationship , Vero Cells
12.
Molecules ; 17(7): 7737-57, 2012 Jun 25.
Article in English | MEDLINE | ID: mdl-22732886

ABSTRACT

Ever since the idea arose that melatonin might promote sleep and resynchronize circadian rhythms, many research groups have centered their efforts on obtaining new melatonin receptor ligands whose pharmacophores include an aliphatic chain of variable length united to an N-alkylamide and a methoxy group (or a bioisostere), linked to a central ring. Substitution of the indole ring found in melatonin with a naphthalene or quinoline ring leads to compounds of similar affinity. The next step in this structural approximation is to introduce a quinoxaline ring (a bioisostere of the quinoline and naphthalene rings) as the central nucleus of future melatoninergic ligands.


Subject(s)
Quinoxalines/chemistry , Receptor, Melatonin, MT1/metabolism , Receptor, Melatonin, MT2/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , Indoles/chemistry , Ligands , Naphthalenes/chemistry , Quinolines/chemistry , Quinoxalines/chemical synthesis , Receptor, Melatonin, MT1/agonists , Receptor, Melatonin, MT2/agonists , Structure-Activity Relationship
13.
Eur J Med Chem ; 52: 1-13, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22444026

ABSTRACT

The combination of antagonism at histamine H(3) receptor and the stimulation of insulin secretion have been proposed as an approach to new dual therapeutic agents for the treatment of type 2 diabetes mellitus associated with obesity. We have designed and synthesized a new series of non-imidazole derivatives, based on a basic amine ring connected through an alkyl spacer of variable length to a phenoxysulfonylurea moiety. These compounds were initially evaluated for histamine H(3) receptor binding affinities, suggesting that a propoxy chain linker between the amine and the core ring could be essential for optimal binding affinity. Compound 56, 1-(naphthalen-1-yl)-3-[(p-(3-pyrrolidin-1-ylpropoxy)benzene)]sulfonylurea exhibited the best H(3) antagonism affinity. However, since all these derivatives failed to block K(ATP) channels, the link of these two related moieties should not be considered a good pharmacophore for obtaining new dual H(3) antagonists with insulinotropic activity, suggesting the necessity to propose a new chemical hybrid prototype.


Subject(s)
Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Potassium Channel Blockers/chemistry , Potassium Channel Blockers/pharmacology , Receptors, Histamine H3/metabolism , Sulfonylurea Compounds/chemistry , Sulfonylurea Compounds/pharmacology , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , HEK293 Cells , Humans , Structure-Activity Relationship
14.
Molecules ; 16(9): 7893-908, 2011 Sep 13.
Article in English | MEDLINE | ID: mdl-22143549

ABSTRACT

As reported in our previous papers, a series of quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives were synthesized and studied as anti-tuberculosis agents. Here, the capability of the shake-flask method was studied and the retention time (expressed as log K) of 20 compounds were determined by RP-HPLC analysis. We found that the prediction of log P by the RP-HPLC analysis can result in a high accuracy and can replace the shake-flask method avoiding the experimental problems presented by quinoxaline di-N-oxides. The studied compounds were subjected to the ALOGPS module with the aim of comparing experimental log P(o/w) values and predicted data. Moreover, a preliminary in silico screening of the QSAR relationship was made confirming the influence of reduction peak potential, lipophilicity, H-bond donor capacity and molecular dimension descriptors on anti-tuberculosis activity.


Subject(s)
Cyclic N-Oxides/analysis , Cyclic N-Oxides/pharmacology , Mycobacterium tuberculosis/drug effects , Quinolines/analysis , Quinolines/pharmacology , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology , Chromatography, High Pressure Liquid , Cyclic N-Oxides/chemical synthesis , Microbial Sensitivity Tests , Quantitative Structure-Activity Relationship , Quinolines/chemical synthesis , Quinoxalines/chemistry , Tuberculosis
15.
ISRN Pharmacol ; 2011: 314209, 2011.
Article in English | MEDLINE | ID: mdl-22084710

ABSTRACT

Phenazine 5,10-dioxides (PDOs) are a new class of bioreductive cytotoxins, which could act towards tumours containing hypoxic regions. The PDOs selective-hypoxic bioreduction was probed in vitro; however, the mechanism of action has not been completely explained. Besides, PDOs in vivo antitumour activities have not been demonstrated hitherto. We study the mechanism of hypoxic/normoxic cytotoxicity of PDO representative members. Electron spin resonance is used to confirm (•)OH production, alkaline comet assay to determine genotoxicity, and gel electrophoresis and flow cytometry to analyze DNA fragmentation and cell cycle distribution. Chemically induced rat breast tumours are employed to evaluate in vivo activities. For the most selective cytotoxin, 7(8)-bromo-2-hydroxyphenazine 5,10-dioxide (PDO1), exclusive hypoxic (•)OH production is evidenced, while for the unselective ones, (•)OH is produced in both conditions (normoxia and simulated hypoxia). In normoxia (Caco-2 cells), PDO1 induces cell-cycle arrest and DNA fragmentation but does not significantly induce apoptosis neither at IC(50) nor IC(80). No difference in the comet-assay scores are observed in normoxia and simulated hypoxia being the unselective 2-amino-7(8)-bromophenazine 5,10-dioxide (PDO2) the most genotoxic. The in vivo efficacy with the absence of systemic toxicity of PDO1 and PDO2 is checked out. Results from this study highlight the potential of PDOs as new therapeutics for cancer.

16.
Bioorg Med Chem Lett ; 21(15): 4498-502, 2011 Aug 01.
Article in English | MEDLINE | ID: mdl-21724395

ABSTRACT

Continuing with our efforts to identify new active compounds against malaria and leishmaniasis, 14 new 3-amino-1,4-di-N-oxide quinoxaline-2-carbonitrile derivatives were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against Plasmodium falciparum Colombian FCR-3 strain and Leishmania amazonensis strain MHOM/BR/76/LTB-012A. Further computational studies were carried out in order to analyze graphic SAR and ADME properties. The results obtained indicate that compounds with one halogenous group substituted in position 6 and 7 provide an efficient approach for further development of antimalarial and antileishmanial agents. In addition, interesting ADME properties were found.


Subject(s)
Antimalarials/chemistry , Leishmania mexicana/drug effects , Quinoxalines/chemistry , Salicylamides/chemistry , Sulfonamides/chemistry , Trypanocidal Agents/chemistry , Animals , Antimalarials/pharmacokinetics , Antimalarials/toxicity , Macrophages/drug effects , Macrophages/immunology , Mice , Plasmodium falciparum/drug effects , Salicylamides/pharmacokinetics , Salicylamides/toxicity , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/toxicity , Trypanocidal Agents/pharmacokinetics , Trypanocidal Agents/toxicity
17.
Drug Chem Toxicol ; 34(3): 285-93, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21649483

ABSTRACT

Nitric oxide donor tocopherol analogs were found to be incorporated in low-density lipoprotein to release nitric oxide into the hydrophobic core of the lipoprotein, thus inhibiting lipid oxidation processes associated with atheroma plaque formation. Previously, we studied their cytotoxicity against human and murine macrophages as first selection for in vivo studies. Herein, we examined both the in vitro mutagenic and DNA-damage effects of selected compounds to further evaluate drug potential. While the compounds of interest were nongenotoxics in both experimental tests (Ames and alkaline comet), one of the potential blood metabolites exhibited genotoxicity (alkaline comet test), and the furazan derivative was mutagenic (Ames test). Two selected (nitrooxy and furoxan) compounds were studied in long- and short-term in vivo treatment, and in these conditions, animal toxicity was not evidenced, suggesting the possibility of these compounds as potential antiatherogenic drugs.


Subject(s)
Atherosclerosis/drug therapy , Mutagens/toxicity , Nitric Oxide Donors/toxicity , Tocopherols/toxicity , Animals , Cell Line , Comet Assay , Dose-Response Relationship, Drug , Humans , Injections, Intramuscular , Male , Mice , Mice, Inbred Strains , Microsomes, Liver/metabolism , Molecular Structure , Mutagens/chemistry , Nitric Oxide Donors/chemistry , Nitric Oxide Donors/therapeutic use , Rats , Rats, Sprague-Dawley , Salmonella typhimurium/drug effects , Salmonella typhimurium/genetics , Structure-Activity Relationship , Tocopherols/chemistry , Tocopherols/therapeutic use
18.
Bioorg Med Chem Lett ; 21(12): 3699-703, 2011 Jun 15.
Article in English | MEDLINE | ID: mdl-21570839

ABSTRACT

The increase in the prevalence of drug-resistant tuberculosis cases demonstrates the need of discovering new and promising compounds with antimycobacterial activity. As a continuation of our research and with the aim of identifying new antitubercular drugs candidates, a new series of quinoxaline 1,4-di-N-oxide derivatives containing isoniazid was synthesized and evaluated for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Moreover, various drug-like properties of new compounds were predicted. Taking into account the biological results and the promising drug-likeness profile of these compounds, make them valid leads for further experimental research.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Hydrazines/chemical synthesis , Hydrazines/pharmacology , Mycobacterium tuberculosis/drug effects , Animals , Anti-Bacterial Agents/chemistry , Cells, Cultured , Chlorocebus aethiops , Hydrazines/chemistry , Inhibitory Concentration 50 , Isonicotinic Acids/chemical synthesis , Isonicotinic Acids/chemistry , Isonicotinic Acids/pharmacology , Molecular Structure , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Quinoxalines/pharmacology , Vero Cells
19.
J Med Chem ; 54(8): 3086-90, 2011 Apr 28.
Article in English | MEDLINE | ID: mdl-21469694

ABSTRACT

We report benzo[b]thiophene derivatives synthesized according to a dual strategy. 8j, 9c, and 9e with affinity values toward 5-HT(7)R and 5-HTT were selected to probe their antidepressant activity in vivo using the forced swimming text (FST). The results showed significant antidepressant activity after chronic treatment. 9c was effective in reducing the immobility time in FST even after acute treatment. These findings identify these compounds as a new class of antidepressants with a rapid onset of action.


Subject(s)
Antidepressive Agents/therapeutic use , Thiophenes/therapeutic use , Magnetic Resonance Spectroscopy , Spectrophotometry, Infrared
20.
J Med Chem ; 54(10): 3624-36, 2011 May 26.
Article in English | MEDLINE | ID: mdl-21506600

ABSTRACT

For a fourth approach of quinoxaline N,N'-dioxides as anti-trypanosomatid agents against T. cruzi and Leishmania, we found extremely active derivatives. The present study allows us to state the correct requirements for obtaining optimal in vitro anti-T. cruzi activity. Derivatives possessing electron-withdrawing substituents in the 2-, 3-, 6-, and 7-positions were the most active compounds. With regard to these features and taking into account their mammal cytotoxicity, some trifluoromethylquinoxaline N,N'-dioxides have been proposed as candidates for further clinical studies. Consequently, mutagenicity and in vivo analyses were performed with the most promising derivatives. In addition, with regard to the mechanism of action studies, it was demonstrated that mitochondrial dehydrogenases are involved in the anti-T. cruzi activity of the most active derivatives.


Subject(s)
Cyclic N-Oxides/chemistry , Quinoxalines/chemistry , Quinoxalines/chemical synthesis , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Electrons , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Mutagenicity Tests , Parasitemia/drug therapy , Quinoxalines/pharmacology , Toxicity Tests , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/metabolism
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