Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

The combination of antagonism at histamine H3 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 H3 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 H3 antagonism affinity. However, since all these derivatives failed to block KATP channels, the link of these two related moieties should not be considered a good pharmacophore for obtaining new dual H3 antagonists with insulinotropic activity, suggesting the necessity to propose a new chemical hybrid prototype

New quinoxaline derivatives as potential MT₁ and MT₂ receptor ligands.

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 ligand

Antiplasmodial and leishmanicidal activities of 2-cyano-3-(4-phenylpiperazine-1-carboxamido) quinoxaline 1,4-dioxide derivatives.

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

New 1-aryl-3-substituted propanol derivatives as antimalarial agents

This paper describes the synthesis and in vitro antimalarial activity against a P. falciparum 3D7 strain of some new 1-aryl-3-substituted propanol derivatives. Twelve of the tested compounds showed an IC50 lower than 1 μM. These compounds were also tested for cytotoxicity in murine J774 macrophages. The most active compounds were evaluated for in vivo activity against P. berghei in a 4-day suppressive test. Compound 12 inhibited more than 50% of parasite growth at a dose of 50 mg/kg/day. In addition, an FBIT test was performed to measure the ability to inhibit ferriprotoporphyrin biocrystallization. This data indicates that 1-aryl-3-substituted propanol derivatives hold promise as a new therapeutic option for the treatment of malaria

New salicylamide and sulfonamide derivatives of quinoxaline 1,4-di-N-oxide with antileishmanial and antimalarial activities

Continuing with the efforts to identify new active compounds against malaria and leishmaniasis, fourteen 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 to analyze graphic SAR and ADME properties were undertaken. Results 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 foun

Novel quinoxaline 1,4-di-N-oxide derivatives as new potential antichagasic agents

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-Noxide 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 group

New quinoxaline and indole derivatives as MT1 and MT2 receptor agonists

There is a vast amount of studies which state that sleep is necessary for many functions, such as for encoding and consolidation of memory, for regulation of cognitive and emotional brain processes, for saving energy, for removing free radicals and for regulation of some neurotransmitters. Sleep disorders include a very frequent pathology of diverse origins. These disorders can appear alone or associated with each other, thereby making this pathology even more complex. In the second international classification of sleep disorders (ICSD-2), more than 90 sleep disorders are included divided in eight main categories. The most common sleep disorders include insomnia, sleep apnea, restless legs syndrome, and narcolepsy, with insomnia being the most prevalent among them. The treatment of insomnia for example, involves a great variety of treatments including psychological and behavioral therapies as well as pharmacological therapies. In many cases, combining the behavioral and pharmacological strategies results in the most efficacious treatment. In the past few years, melatonin receptors MT1 and MT2 have become one of the most interesting pharmacological targets for the treatment of many sleep disorders. Ever since the idea arose with regard to melatonin (MLT) acting as a hormonal photoperiodic messenger controlling the biological ¿clocks¿ of the individuals, the hypothesis that MLT administration might be a potential therapy to treat sleep disorders gained more acceptance. MLT exerts too many effects in the body including initiation and maintenance of sleep by the activation of MLT receptors MT1 and MT2. In the last few decades, a multitude of research groups have centered their efforts on the obtainment of new MT1 and MT2 receptor agonists in order to find a new drug for the treatment of diverse sleep disorders. All those compounds contain, without exception, an aliphatic chain substituted on a central aromatic ring and linked to an alkylamide or a derivative. Moreover, in the majority of these cases, the structures also possess an alkoxy group, generally a methoxy, joined to the central core. The principal aim of this work has been to synthesize new molecules as agonists of the melatonin receptors MT1 and MT2 with potential activity for the treatment of sleep disorders. In this sense, after having carried out an extensive bibliographical review, some initial compounds have been designed. Later, after obtaining the biological activity values, a SAR study has been performed and the starting hypothesis has been then redefined, followed by optimization of the initially designed structures. In addition, when enough data has been collected, alternative molecular modeling techniques have been included in this cycle that allows the discrimination of inactive molecules in stages previous to their synthesis. During this project forty-eight final compounds have been synthesized, for which four different synthetic routes have been optimized. Once the new derivatives have been chemically characterized, they have been sent to the ¿Institute de Recherches Servier¿ in France for being biologically evaluated in order to know their affinity for MT1/MT2 receptors first and their agonism/antagonism profile then. With this data a SAR study have been carried out which in combination with new bibliographic reviews performed have permit the redefinition of the starting hypothesis as well as of the initially designed structures. All these approaches have provided significantly promising results that open a new line of research for the development of future MT1/MT2 receptor agonists

Diseño, síntesis y evaluación biológica de nuevos derivados de piridazinoindol e indol como agonistas de los receptores MT1/MT2 de melatonina para el tratamiento de los trastornos del sueño

Since melatonin (MLT) was discovered, several physio-pathological functions have been associated with this hormone. One of the most important functions of this natural ligand is the regulation of sleep-wake cycles and its implication in insomnia and other sleep disorders. MLT exerts its actions through two GPCRs receptors, MT1 and MT2, which have been suggested as key targets in this area. Currently, numerous researches have focused their research on new melatoninergic ligands. We have reported design, synthesis and characterization of novel pyridazino[4,5-b]indole (PI) and indole (In) derivatives. In addition, these compounds have been evaluated biologically to melatonin receptors. Based on PI and In biological results, we designed a new pharmacophore to synthesize future leader ligands with potent affinity and activity to melatoninergic receptors with the following characteristics: an indole ring as central core, methoxy group substituted in the 6 position of indole ring, six-atom length distance between methoxy group and the first nitrogen atom of the side chain and two-methylene linker over the indole ring and attached to different nitrogenous chains such as N-acetamide, N-methylurea, N-ethylurea and N-methylsulfonamide