Revistas
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN:
1661-6596
Año:
2024
Vol.:
25
N°:
2
Págs.:
799
Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disorder characterized by cognitive decline, memory loss, behavioral changes, and other neurological symptoms. Considering the urgent need for new AD therapeutics, in the present study we designed, synthesized, and evaluated multitarget compounds structurally inspired by sulfonylureas and pitolisant with the aim of obtaining multitarget ligands for AD treatment. Due to the diversity of chemical scaffolds, a novel strategy has been adopted by merging into one structure moieties displaying H3R antagonism and acetylcholinesterase inhibition. Eight compounds, selected by their binding activity on H3R, showed a moderate ability to inhibit acetylcholinesterase activity in vitro, and two of the compounds (derivatives 2 and 7) were also capable of increasing acetylcholine release in vitro. Among the tested compounds, derivative 2 was identified and selected for further in vivo studies. Compound 2 was able to reverse scopolamine-induced cognitive deficits with results comparable to those of galantamine, a drug used in clinics for treating AD. In addition to its efficacy, this compound showed moderate BBB permeation in vitro. Altogether, these results point out that the fragment-like character of compound 2 leads to an optimal starting point for a plausible medicinal chemistry approach for this novel strategy.
Revista:
BIOORGANIC AND MEDICINAL CHEMISTRY
ISSN:
0968-0896
Año:
2022
Vol.:
58
Págs.:
116577
Chagas disease (CD) is a centenarian neglected parasitosis caused by the protozoan Trypanosoma cruzi (T. cruzi). Despite the continuous efforts of many organizations and institutions, CD is still an important human health problem worldwide. A lack of a safe and affordable treatment has led drug discovery programmes to focus, for years, on the search for molecules enabling interference with enzymes that are essential for T. cruzi survival. In this work, the authors want to offer a brief overview of the different validated targets that are involved in diverse parasite pathways: glycolysis, sterol synthesis, the de novo biosynthesis of pyrimidine nucleotides, the degradative processing of peptides and proteins, oxidative stress damage and purine salvage and nucleotide synthesis and metabolism. Their structural aspects, function, active sites, etc. were studied and considered with the aim of defining molecular bases in the search for new effective treatments for CD. This review also compiles, as much as possible, all the inhibitors reported to date against these T. cruzi targets, serving as a reference for future research in this field.
Revista:
ACTA TROPICA
ISSN:
0001-706X
Año:
2022
Vol.:
233
Págs.:
106547
Current treatment for Chagas disease is based on only two drugs: benznidazole and nifurtimox. Compounds containing sulfur (S) in their structure have shown promising results in vitro and in vivo against Trypanosoma cruzi, the parasite causing Chagas disease. Notably, some reports show that the isosteric replacement of S by selenium (Se) could be an interesting strategy for the development of new compounds for the treatment of Chagas disease. To date, the activity against T. cruzi of three Se- containing groups has been compared with their S counterparts: selenosemicarbazones, selenoquinones, and selenocyanates. More studies are needed to confirm the positive results of Se compounds. Therefore, we have investigated S compounds described in the literature tested against T. cruzi. We focused on those tested in vivo that allowed isosteric replacement to propose their Se counterparts as promising compounds for the future development of new drugs against Chagas disease.
Revista:
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN:
0223-5234
Año:
2021
Vol.:
223
Págs.:
113646
The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, the most important parasitic infection in Latin America. The only treatments currently available are nitro-derivative drugs that are characterised by high toxicity and limited efficacy. Therefore, there is an urgent need for more effective, less toxic therapeutic agents. We have previously identified the potential for Mannich base derivatives as novel inhibitors of this parasite. To further explore this family of compounds, we synthesised a panel of 69 new analogues, based on multi-parametric structure-activity relationships, which allowed optimization of both anti-parasitic activity, physicochemical parameters and ADME properties. Additionally, we optimized our in vitro screening approaches against all three developmental forms of the parasite, allowing us to discard the least effective and trypanostatic derivatives at an early stage. We ultimately identified derivative 3c, which demonstrated excellent trypanocidal properties, and a synergistic mode of action against trypomastigotes in combination with the reference drug benznidazole. Both its druggability and low-cost production make this derivative a promising candidate for the preclinical, in vivo assays of the Chagas disease drug-discovery pipeline. (C) 2021 Elsevier Masson SAS. All rights reserved.
Revista:
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN:
0223-5234
Año:
2019
Vol.:
163
Págs.:
569 - 582
Chagas disease is a neglected chronical parasitosis caused by the parasite Trypanosoma cruzi (T. cruzi). Nine ferrocenyl Mannich base derivatives were synthetized and characterized to explore their in vitro activity on three T. cruzi strains of the parasite and their cytotoxicity on Vero cells to calculate the selectivity index (SI). Compound 2, 1-ferrocenyl-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one, stood out as the most promising derivative showing a half maximal inhibitory concentration (IC50) value around 5 mu M in both amastigote and trypomastigote forms of T. cruzi and SI values higher than 13, being the best value on the trypomastigote forms of the Arequipa strain (SI = 41.7). Moreover, 2 decreased the number of infected cells and was not genotoxic. Furthermore, its possible mechanism of action was studied through the alteration of the metabolites excreted by the parasite during glucose metabolism, the detection of mitochondrial alterations and the inhibition of superoxide dismutase (SOD). Finally, docking studies were executed to analyze the binding mode of the studied compounds to Fe-SOD enzyme.
Revista:
CHEMISTRYSELECT
ISSN:
2365-6549
Año:
2019
Vol.:
4
N°:
27
Págs.:
8112 - 8121
Chagas disease is a silent disease that continues to endanger millions of people and, due to its insufficient current chemotherapy, urgently requires the development of more effective drugs. With this objective, twenty-six Mannich base derivatives were synthesized, and their in vitro activity was evaluated against Trypanosoma cruzi. Three out of the twenty-six compounds showed interesting results, including IC50 valuesT. cruzi strains. In addition, these compounds showed similar infection rates in Vero cells compared to those of benznidazole at 50 mu M. Finally, some studies were performed to investigate the possible mechanism of action; moreover, computational studies proposed a binding mode of these derivatives to Fe-SOD. This new series of compounds has an encouraging antichagasic profile with a simplified structure and synthetic routes. Therefore, the most active compounds should be considered as leads for further optimization of the antichagasic activity.
Revista:
BIOORGANIC AND MEDICINAL CHEMISTRY
ISSN:
0968-0896
Año:
2019
Vol.:
27
N°:
17
Págs.:
3902 - 3917
The current chemotherapy against Chagas disease is inadequate and insufficient. A series of ten Mannich base-type derivatives have been synthesized to evaluate their in vitro antichagasic activity. After a preliminary screening, compounds 7 and 9 were subjected to in vivo assays in a murine model. Both compounds caused a substantial decrease in parasitemia in the chronic phase, which was an even better result than that of the reference drug benznidazole. In addition, compound 9 also showed better antichagasic activity during the acute phase. Moreover, metabolite excretion, effect on mitochondrial membrane potential and the inhibition of superoxide dismutase (SOD) studies were also performed to identify their possible mechanism of action. Finally, docking studies proposed a binding mode of the Fe-SOD enzyme similar to our previous series, which validated our design strategy. Therefore, the results suggest that these compounds should be considered for further preclinical evaluation as antichagasic agents.
Revista:
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN:
0223-5234
Año:
2018
Vol.:
155
Págs.:
459-482
The development of safe and affordable antiparasitic agents effective against neglected tropical diseases is a big challenge of the drug discovery. The drugs currently employed have limitations such as poor efficacy, drug resistance or side effects. Thus, the search for new promising drugs is more and more crucial. Metal complexes and, in particular, organometallic compounds may expand the list of the drug candidates due to the peculiar attributes that the presence of the metal core add to the organic fragment (e.g., redox and structural features, ability to interact with DNA or protein targets, etc.). To date, most organometallic compounds tested as anti-neglected tropical diseases are based on similarities or activity of the organic ligands against other diseases or parasites and/or consist in modification of existing drugs combining the features of the metal moiety and the organic ligands. This review focuses on recent studies (2012-2017) on organometallic compounds in treating kinetoplastid-caused diseases such as Human African trypanosomiasis, Chagas disease and leishmaniasis. This field of research, however, still lacks exhaustive studies to identify of parasitic targets and quantitative structure-activity relationships for a rational drug design.
Revista:
JOURNAL OF MEDICINAL CHEMISTRY
ISSN:
0022-2623
Año:
2018
Vol.:
61
N°:
13
Págs.:
5643 - 5663
Chagas disease is a potentially life-threatening and neglected tropical disease caused by Trypanosoma cruzi. One of the most important challenges related to Chagas disease is the search for new, safe, effective, and affordable drugs since the current therapeutic arsenal is inadequate and insufficient. Here, we report a simple and cost-effective synthesis and the biological evaluation of the second generation of Mannich base-type derivatives. Compounds 7, 9, and 10 showed improved in vitro efficiency and lower toxicity than benznidazole, in addition to no genotoxicity; thus, they were applied in in vivo assays to assess their activity in both acute and chronic phases of the disease. Compound 10 presented a similar profile to benznidazole from the parasitological perspective but also yielded encouraging data, as no toxicity was observed. Moreover, compound 9 showed lower parasitaemia and higher curative rates than benznidazole, also with lower toxicity in both acute and chronic phases. Therefore, further studies should be considered to optimize compound 9 to promote its further preclinical evaluation.
Revista:
JOURNAL OF HETEROCYCLIC CHEMISTRY
ISSN:
0022-152X
Año:
2017
Vol.:
54
N°:
4
Págs.:
2380 - 2388
Quinoxaline 1,4-di-N-oxide (QdNO) and N-acylhydrazone subunit are considered privileged scaffolds in medicinal chemistry because of its wide spectrum of biological activities, such as antibacterial, antitubercular, antiviral, anticancer, and antifungal. Beirut's reaction is the mostly commonly employed synthetic method to obtain QdNO; however, extended time, low yields, and byproduct formation are common features observed during the synthesis. Microwave-assisted organic synthesis (MW) has gained popularity as an effective way to speed up chemical reactions, increasing yields and selectivity of a variety of reactions. Therefore, in an effort to synthesize compounds with potential to tuberculosis treatment, we reported herein the use of MW as a tool to obtain new QdNO derivatives containing the N-acylhydrazone subunit. Four different synthetic routes were evaluated by using different benzofuroxan derivatives in the Beirut's reaction. The synthetic route D, which employed a dioxolan-benzofuroxan derivative, has shown to be the best condition to obtain the desired hybrid quinoxaline. MW drastically reduces the reaction time to obtain all compounds compared to conventional heating. For compound 13, for example, the use of MW instead of conventional heating was able to reduce the reaction time in 192-fold. In conclusion, the use of a benzofuroxan derivative without additional electrophilic sites besides N-oxide nitrogen and the employment of the microwave-assisted synthesis have proved to be the optimum condition to obtain quinoxaline 1,4-di-N-oxide N-acylhydrazone derivatives.
Autores:
Dos Santos Fernandes, G. F. (Autor de correspondencia); de Souza, P. C.; Moreno-Viguri, Elsa; et al.
Revista:
JOURNAL OF MEDICINAL CHEMISTRY
ISSN:
0022-2623
Año:
2017
Vol.:
60
N°:
20
Págs.:
8647 - 8660
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC(90)values of 1.10 and 6.62 mu M against active and nonreplicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective, leading to a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the, development of a novel chemical class of antitubercular drugs.
Revista:
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
ISSN:
1570-0232
Año:
2017
Vol.:
1061-1062
Págs.:
225 - 232
The development and validation of an analytical method for the simultaneous analysis of five neutral lipids in Trypanosoma cruzi epimastigotes by GC-MS is presented in this study. The validated method meets all validation parameters for all components and the chromatographic conditions have been optimized during its development. This analytical method has demonstrated good selectivity, accuracy, within-day precision, recovery and linearity in each of the established ranges. In addition, detection and quantification limits for squalene, cholesterol, ergosterol and lanosterol have been improved and it is worth highlighting the fact that this is the first time that squalene-2,3-epoxide validation data have been reported. The new validated method has been applied to epimastigotes treated with compounds with in vitro anti-T.cruzi activity. This new methodology is straightforward and constitutes a tool for screening possible sterol biosynthesis pathway inhibitors in Trypanosoma cruzi, one of the most studied targets in Chagas disease treatment. Therefore, it is an interesting and useful contribution to medicinal chemistry research.
Revista:
PARASITOLOGY
ISSN:
0031-1820
Año:
2017
Vol.:
144
N°:
13
Págs.:
1783 - 1790
Leishmaniasis is one of the world's most neglected diseases, and it has a worldwide prevalence of 12 million. There are no effective human vaccines for its prevention, and treatment is hampered by outdated drugs. Therefore, research aiming at the development of new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, we present 20 arylaminoketone derivatives with a very interesting in vitro and in vivo efficacy against Trypanosoma cruzi that have now been studied against promastigote and amastigote forms of Leishmania infantum, Leishmania donovani and Leishmania braziliensis strains. Six out of the 20 Mannich base-type derivatives showed Selectivity Index between 39 and 2337 times higher in the amastigote form than the reference drug glucantime. These six derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing a greater alteration in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy.
Autores:
Martín-Montes, A.; Plano, Daniel; Martín-Escolano, R.; et al.
Revista:
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN:
0066-4804
Año:
2017
Vol.:
61
N°:
6
Págs.:
e02546-16
The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents.
Revista:
BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS
ISSN:
0960-894X
Año:
2016
Vol.:
26
N°:
9
Págs.:
2188 - 2193
Twenty-four quinoxaline derivatives were evaluated for their antimycobacterial activity using BacTiter-Glo microbial cell viability assay. Five compounds showed MIC values < 3.1 mu M and IC50 values < 1.5 mu M in primary screening and therefore, they were moved on for further evaluation. Compounds 21 and 18 stand out, showing MIC values of 1.6 mu M and IC50 values of 0.5 and 1.0 mu M, respectively. Both compounds were the most potent against three evaluated drug-resistant strains. Moreover, they exhibited intracellular activity in infected macrophages, considering log-reduction and cellular viability. In addition, compounds 16 and 21 were potent against non-replicating Mycobacterium tuberculosis and compound 21 was bactericidal. Therefore, quinoxaline derivatives could be considered for making further advances in the future development of antimycobacterial agents.
Revista:
INTERNATIONAL JOURNAL FOR PARASITOLOGY, DRUGS AND DRUG RESISTANCE
ISSN:
2211-3207
Año:
2016
Vol.:
6
N°:
3
Págs.:
184 - 198
Synthesis of new 1-aryl-3-substituted propanol derivatives followed by structure-activity relationship, in silico drug-likeness, cytotoxicity, genotoxicity, in silico metabolism, in silico pharmacophore modeling, and in vivo studies led to the identification of compounds 22 and 23 with significant in vitro anti-plasmodial activity against drug sensitive (D6 IC50 <= 0.19 mu M) and multidrug resistant (FCR-3 IC50 <= 0.40 mu M and C235 IC50 <= 0.28 mu M) strains of Plasmodium falciparum. Adequate selectivity index and absence of genotoxicity was also observed. Notably, compound 22 displays excellent parasitemia reduction (98 +/- 1%), and complete cure with all treated mice surviving through the entire period with no signs of toxicity. One important factor is the agreement between in vitro potency and in vivo studies. Target exploration was performed; this chemotype series exhibits an alternative antimalarial mechanism. (C) 2016 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology.
Revista:
JOURNAL OF MEDICINAL CHEMISTRY
ISSN:
0022-2623
Año:
2016
Vol.:
59
N°:
24
Págs.:
10929 - 10945
Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide, and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity, and a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7, and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high antiparasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent.
Revista:
BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS
ISSN:
0960-894X
Año:
2016
Vol.:
26
N°:
3
Págs.:
903 - 906
We report the synthesis and in vitro activity against Trypanosoma cruzi epimastigotes of 15 novel quinoxaline derivatives. Ten of the derivatives presented IC50 values lower than the reference drugs Nfx and Bzn; four of them standed out with IC50 values lower than 1.5 ¿M. Moreover, unspecific cytotoxicity and genotoxicity studies are also reported. Compound 14 showed a SI higher than 24, whereas compound 10 was the only one that was negative in the genotoxicity screening.
Autores:
Alfonsino, G. E.; Santagati, A.; Basile, L.; et al.
Revista:
JOURNAL OF ADVANCES IN MEDICAL AND PHARMACEUTICAL SCIENCES
ISSN:
2394-1111
Año:
2015
Vol.:
4
N°:
1
Págs.:
1 - 12
Clinical depression encompasses a complex neurobiology involving multiple interacting systems. This intricate pathophysiology is, in part, correlated with dysfunction in serotonin (5HT) neurochemistry. The 5HT1a receptor (R) and SERT (serotonin transporter) components of this network are highly correlated to mood and anxiety regulation and difficulties in this regard in the realm of depression.
Aims: The current study was designed to develop a series of arylpiperazine derivatives ligands that are antagonists at both H5HT1aR and SERT.
Study Design: Development of new chemotype antagonists at H5HT1aR and SERT.
Place and Duration of Study: University of Catania (Italy) and University of Montana, Missoula, Montana, May 2008 to June 2013.
Methodology: Chinese Hamster Ovary cells transfected with the gene for the Human (H) 5HT1a Receptor were cultured, and membranes containing the receptor were prepared for competition assays between the test compounds and the agonist, [3H]8-OH-DPAT. For thermodynamics, Ki's were determined at a series of temperatures from 0-35 degrees C. Further, membranes from rat brain were utilized for competition assays between the test compounds and the SERT inhibitor, [3H] paroxetine.
Results: Many of these substances show nanomolar affinities at H5HT1aR, and a number of the compounds also have high efficacy in inhibiting SERT. It is of note that some members of this series also substantially discriminate between binding at H5HT1aR and H5HT7R, a receptor studied with these compounds in previous work. Thermodynamic properties for the compound 4-[4-(3-benzo [b] thiophen-3-yl-3-oxopropylamino) piperidin-1-yl] benzonitrile (BTPN; compound15) are also reported.
Conclusions: There are a few of these compounds that excel in all three categories of H5HT1aR affinity, SERT inhibitory activity, and discriminatory binding capacity between the two receptors. Implications in the context of clinical needs in depression and other nervous systems disorders are discussed.
Revista:
MOLECULES
ISSN:
1420-3049
Año:
2014
Vol.:
19
N°:
2
Págs.:
2166 - 2180
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.
Revista:
HELVETICA CHIMICA ACTA
ISSN:
0018-019X
Año:
2013
Vol.:
96
N°:
2
Págs.:
217 - 227
Revista:
MOLECULES
ISSN:
1420-3049
Año:
2013
Vol.:
18
N°:
4
Págs.:
4718 - 4727
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 mu M), while a cyclohexyl derivative (2.5 mu M) showed the best activity against L. amazonensis, and a 3-chloropropyl derivative (0.7 mu M) showed the best results against L. infantum. All these compounds also have a Cl substituent in the R-7 position.
Revista:
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN:
0223-5234
Año:
2013
Vol.:
66
Págs.:
324 - 334
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.
Revista:
MOLECULES
ISSN:
1420-3049
Año:
2012
Vol.:
17
N°:
8
Págs.:
9451 - 9461
Revista:
MOLECULES
ISSN:
1420-3049
Año:
2012
Vol.:
17
N°:
7
Págs.:
7737 - 7757
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.
Revista:
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN:
0223-5234
Año:
2012
Vol.:
52
Págs.:
1 - 13
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. (C)2012 Elsevier Masson SAS. All rights reserved.
Revista:
Electrochimica Acta
ISSN:
0013-4686
Año:
2011
Vol.:
56
N°:
9
Págs.:
3270 - 3275
Autores:
Benítez, Diego; Cabrera, Mauricio; Hernández, Paola; et al.
Revista:
JOURNAL OF MEDICINAL CHEMISTRY
ISSN:
0022-2623
Año:
2011
Vol.:
54
N°:
10
Págs.:
3624 - 3636
Revista:
Experimental Parasitology
ISSN:
0014-4894
Año:
2011
Vol.:
128
N°:
2
Págs.:
97 - 103
Revista:
Bioorganic & Medicinal Chemistry Letters
ISSN:
0960-894X
Año:
2011
Vol.:
21
N°:
12
Págs.:
3699 - 3703
Revista:
Bioorganic & Medicinal Chemistry Letters
ISSN:
0960-894X
Año:
2011
Vol.:
21
N°:
15
Págs.:
4498 - 4502
Revista:
J Med Chem
ISSN:
0022-2623
Año:
2011
Vol.:
54
N°:
8
Págs.:
3086 - 3090
Revista:
INFECTIOUS DISORDERS - DRUG TARGETS
ISSN:
1871-5265
Año:
2011
Vol.:
11
N°:
2
Págs.:
196 - 204
Revista:
Molecules
ISSN:
1420-3049
Año:
2011
Vol.:
16
N°:
9
Págs.:
7893 - 7908
Revista:
CHEMICAL BIOLOGY AND DRUG DESIGN
ISSN:
1747-0277
Año:
2011
Vol.:
77
N°:
4
Págs.:
255 - 267
Revista:
Experimental Parasitology
ISSN:
0014-4894
Año:
2011
Vol.:
127
N°:
4
Págs.:
745 - 751
Revista:
Bioorganic & Medicinal Chemistry
ISSN:
0968-0896
Año:
2010
Vol.:
18
N°:
21
Págs.:
7365 - 7379
Revista:
Bioorganic & Medicinal Chemistry
ISSN:
0968-0896
Año:
2010
Vol.:
18
N°:
7
Págs.:
2713 - 2719
Revista:
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN:
0223-5234
Año:
2010
Vol.:
45
N°:
10
Págs.:
4418 - 4426
