RESUMO
Plasmodium falciparum subtilisin-like protease 1 (PfSUB1) is a serine protease that plays key roles in the egress of the parasite from red blood cells and in preparing the released merozoites for the subsequent invasion of new erythrocytes. The development of potent and selective PfSUB1 inhibitors could pave the way to the discovery of potential antimalarial drugs endowed with an innovative mode of action and consequently able to overcome the current problems of resistance to established chemotherapies. Through the screening of a proprietary library of compounds against PfSUB1, we identified hydrazone 2 as a hit compound. Here we report a preliminary investigation of the structure-activity relationships for a class of PfSUB1 inhibitors related to our identified hit.
Assuntos
Antimaláricos/química , Hidrazonas/química , Plasmodium falciparum/enzimologia , Proteínas de Protozoários/antagonistas & inibidores , Quinolinas/química , Inibidores de Serina Proteinase/química , Subtilisinas/antagonistas & inibidores , Antimaláricos/síntese química , Antimaláricos/farmacologia , Hidrazonas/síntese química , Hidrazonas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/metabolismo , Quinolinas/síntese química , Quinolinas/farmacologia , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Subtilisinas/metabolismoRESUMO
We investigated some pyrrolobenzoxazepinone (PBOs, 3e-i) analogues of early described effective non-nucleoside inhibitors of HIV-1 reverse transcriptase (RT). Enzymological studies of 3e-i enantiomers, with wild type (wt) RT and some drug-resistant mutants, revealed a stereoselective mode of action and selectivity for RT ternary complex. Unexpectedly (+)-3g was found more potent towards the L100I mutant than towards the wt RT, whereas (+)-3h inhibited the K103N mutant and RT wt with comparable potency.
Assuntos
Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/química , HIV-1 , Oxazepinas/química , Inibidores da Transcriptase Reversa/química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/genética , HIV-1/metabolismo , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Mutação , Oxazepinas/metabolismo , Oxazepinas/farmacologia , Pirróis/química , Pirróis/metabolismo , Pirróis/farmacologia , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Among the enzymes involved in the life cycle of HCV, the non-structural protein NS3, with its double function of protease and NTPase/helicase, is essential for the virus replication. Exploiting our previous knowledge in the development of nucleotide-mimicking NS3 helicase (NS3h) inhibitors endowed with key structural and electronic features necessary for an optimal ligand-enzyme interaction, we developed the tetrahydroacridinyl derivative 3a as the most potent NS3h competitive inhibitor reported to date (HCV NS3h K(i)=20 nM).
Assuntos
Descoberta de Drogas , Hepacivirus/enzimologia , Hidrazinas/química , Hidrazinas/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Ligação Competitiva/efeitos dos fármacos , Hidrazinas/síntese química , Ligação Proteica , Pirazinas/síntese química , Quinolinas/síntese químicaRESUMO
Here we describe the identification and preliminary characterization of a new class of pyrrolo(imidazo)quinoxaline hydrazones as florescent probes for Aß(1-42) fibrils. All the newly developed compounds were able to bind amyloid fibrils formed in vitro and some of them displayed an increase of their fluorescence upon binding. When tested on brain tissue preparations presenting Aß deposits, the described hydrazones selectively stained amyloid structures and did not display aspecific binding. The hydrazones did not show antifibrillogenic activity and electron microscopy analysis revealed that they do not interfere with fibrils structure. The described pyrrolo(imidazo)quinoxalines could be useful for studying amyloid structures in vitro. Moreover, their experimentally proven ability to cross the blood-brain barrier in mouse opens the possibility of developing these compounds as potential amyloid imaging agents for in vivo applications.
Assuntos
Peptídeos beta-Amiloides/química , Corantes Fluorescentes/química , Hidrazonas/química , Fragmentos de Peptídeos/química , Quinoxalinas/química , Peptídeos beta-Amiloides/síntese química , Animais , Encéfalo/metabolismo , Cristalografia por Raios X , Corantes Fluorescentes/farmacocinética , Hidrazonas/sangue , Hidrazonas/farmacocinética , Masculino , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Fragmentos de Peptídeos/síntese química , Quinoxalinas/sangue , Quinoxalinas/farmacocinética , Espectrometria de Fluorescência , Estereoisomerismo , Distribuição TecidualRESUMO
Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase (hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.
Assuntos
Acetilcolinesterase/química , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Modelos Moleculares , Tacrina/análogos & derivados , Tacrina/síntese química , Sítios de Ligação , Biologia Computacional , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Conformação Proteica , Relação Estrutura-Atividade , Tacrina/químicaRESUMO
We describe herein the design, synthesis, biological evaluation, and structure-activity relationship (SAR) studies of an innovative class of antimalarial agents based on a polyaromatic pharmacophore structurally related to clotrimazole and easy to synthesize by low-cost synthetic procedures. SAR studies delineated a number of structural features able to modulate the in vitro and in vivo antimalarial activity. A selected set of antimalarials was further biologically investigated and displayed low in vitro toxicity on a panel of human and murine cell lines. In vitro, the novel compounds proved to be selective for free heme, as demonstrated in the beta-hematin inhibitory activity assay, and did not show inhibitory activity against 14-alpha-lanosterol demethylase (a fungal P450 cytochrome). Compounds 2, 4e, and 4n exhibited in vivo activity against P. chabaudi after oral administration and thus represent promising antimalarial agents for further preclinical development.
Assuntos
Antimaláricos/síntese química , Clotrimazol/análogos & derivados , Clotrimazol/síntese química , Animais , Antifúngicos/síntese química , Antifúngicos/farmacologia , Antifúngicos/toxicidade , Antimaláricos/farmacologia , Antimaláricos/toxicidade , Linhagem Celular , Clotrimazol/farmacologia , Clotrimazol/toxicidade , Inibidores das Enzimas do Citocromo P-450 , Desenho de Fármacos , Feminino , Compostos Férricos/química , Heme/química , Humanos , Técnicas In Vitro , Camundongos , Modelos Moleculares , Oxirredutases/antagonistas & inibidores , Testes de Sensibilidade Parasitária , Plasmodium berghei/efeitos dos fármacos , Plasmodium chabaudi/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Protoporfirinas/química , Estereoisomerismo , Esterol 14-Desmetilase , Relação Estrutura-AtividadeRESUMO
A promising way to interfere with biological processes is through the modulation of protein-protein interactions by means of small molecules acting as peptidomimetics. The 1,4-benzodiazepine scaffold has been widely reported as a peptide-mimicking, pharmacogenic system. While several synthetic pathways to C6-8 substituted benzodiazepines have been disclosed, few 1,4-benzodiazepines substituted at C9 have been reported. Herein, we describe a versatile approach to introduce cyclic, protonatable functionality at C8/C9. Introduction of the piperazine system at C8 and C9 gave access to a unique functionalization of the versatile benzodiazepine skeleton, broadening tailoring options on the benzofused side of the molecule, and the possibility of discovering novel peptidomimetics potentially able to modulate protein-protein interactions. Coupling of activated amino acids with poorly reactive anilines under mild conditions, while avoiding racemization, gave easy access to these compounds. Efficient amino acid activation was obtained by exploiting the rapid formation of acid chlorides under low temperature and acid/base free conditions, using triphenylphosphine and hexachloroacetone. This procedure successfully resulted in high reaction yields, did not produce racemization (ee > 98%, as demonstrated by using chiral solvating agents), and was compatible with the acid sensitive protecting groups present in the substrates.
Assuntos
Benzodiazepinas/síntese química , Mimetismo Molecular , Peptídeos/química , Benzodiazepinas/química , Piperazina , Piperazinas/química , Ligação Proteica , EstereoisomerismoRESUMO
Tacrine based reversible inhibitors of cholinesterases (ChEIs) containing peptidic tethers were synthesized to interact with specific regions at the gorge level, and their potency was determined with human (h) acetylcholinesterase and butyrylcholinesterase. Analogues 3i,j and 3l,m were identified as promising hits and may pave the way for the development of a new series of tacrine based enzyme selective hChEIs.
Assuntos
Inibidores da Colinesterase , Peptídeos/síntese química , Peptídeos/farmacologia , Tacrina , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Estrutura Molecular , Peptídeos/química , Relação Estrutura-Atividade , Tacrina/análogos & derivados , Tacrina/síntese química , Tacrina/química , Tacrina/farmacologiaRESUMO
We have recently developed five novel pyrrolo-1,5-benzoxazepines as proapoptotic agents. Their JNK-dependent induction of apoptosis in tumor cells suggested their potential as novel anticancer agents. The core structure of the apoptotic agent 6 was investigated, and the SARs were expanded with the design and synthesis of several analogues. To define the apoptotic mechanism of the new compounds and the localization of their drug target, two analogues of 6 were designed and synthesized to delineate events leading to JNK activation. The cell-penetrating compound 16 induced apoptosis in tumor cells, while its nonpenetrating analogue, 17, was incapable of inducing apoptosis or activating JNK. Plasma membrane permeabilization of tumor cells resulted in 17-induced JNK activation, suggesting that the pyrrolo-1,5-benzoxazepine molecular target is intracellular. Interestingly, compound 6 displayed cytotoxic activity against a panel of human tumor cell lines but demonstrated negligible toxicity in vivo with no effect on the animals' hematology parameters.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzoxazinas/síntese química , Benzoxazinas/farmacologia , Tiazepinas/síntese química , Tiazepinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Benzoxazinas/química , Benzoxazinas/farmacocinética , Transporte Biológico , Linhagem Celular Tumoral , Desenho de Fármacos , Células HL-60 , Humanos , Células K562 , Modelos Moleculares , Estrutura Molecular , Tiazepinas/química , Tiazepinas/farmacocinéticaRESUMO
Using rational drug design to develop atypical antipsychotic drug candidates, we generated novel and metabolically stable pyrrolobenzazepines with an optimized pK(i) 5-HT(2A)/D(2) ratio. 5a, obtained by a new palladium-catalyzed three-step synthesis, was selected for further pharmacological and biochemical investigations and showed atypical antipsychotic properties in vivo. 5a was active on conditioned avoidance response at 0.56 mg/kg, it had low cataleptic potential and proved to be better than ST1899, clozapine, and olanzapine, representing a new clinical candidate.
Assuntos
Antipsicóticos/síntese química , Benzazepinas/síntese química , Paládio , Pirróis/síntese química , Animais , Antipsicóticos/química , Antipsicóticos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Benzazepinas/química , Benzazepinas/farmacologia , Sítios de Ligação , Catalepsia/induzido quimicamente , Catálise , Linhagem Celular , Cristalografia por Raios X , Antagonistas dos Receptores de Dopamina D2 , Desenho de Fármacos , Técnicas In Vitro , Camundongos , Modelos Moleculares , Conformação Molecular , Pirróis/química , Pirróis/farmacologia , Ensaio Radioligante , Ratos , Receptor 5-HT2A de Serotonina/química , Receptores de Dopamina D2/química , Antagonistas do Receptor 5-HT2 de Serotonina , Relação Estrutura-AtividadeRESUMO
Pyrrolobenzoxazepinones (PBOs) represent a new class of human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is 5. Molecular modeling studies based on the X-ray structures of HIV-1 RT prompted the synthesis of novel analogues which were tested as anti-HIV agents. The PBO derivatives specifically designed to target the highly conserved amino acid residues within the beta12-beta13 hairpin, namely primer grip, proved to be very potent against the most common mutant enzymes, including the highly resistant K103N mutant strain. Structure-activity relationships (SARs) are discussed in terms of a possible interaction with the RT binding site, depending on the nature of the substituents at C-6. Among the pyrrolobenzoxazepines investigated, 15c appeared to be the most promising NNRTI of the series characterized by potent antiviral activity, broad spectrum, and low cytotoxicity. 15c showed synergistic antiviral activity with AZT.
Assuntos
Fármacos Anti-HIV/síntese química , Transcriptase Reversa do HIV/química , HIV-1/efeitos dos fármacos , Oxazepinas/síntese química , Pirróis/síntese química , Inibidores da Transcriptase Reversa/síntese química , Sequência de Aminoácidos , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Células Cultivadas , Sequência Conservada , Desenho de Fármacos , Farmacorresistência Viral , Sinergismo Farmacológico , HIV-1/genética , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/virologia , Camundongos , Modelos Moleculares , Mutação , Oxazepinas/química , Oxazepinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos , Zidovudina/farmacologiaRESUMO
L-Glutamate is the major excitatory neurotransmitter in mammalian central nervous system, and excitatory amino acid transporters (EAATs) are essential for terminating synaptic excitation and for maintaining extracellular glutamate concentration below toxic levels. Although the structure of these channel-like proteins has not been yet reported, their membrane topology has been hypothesised based on biochemical and protein sequence analyses. In the case of an inadequate clearance from synaptic cleft and from the extrasynaptic space, glutamate behaves as a potent neurotoxin, and it may be related to several neurodegenerative pathologies including epilepsy, ischemia, amyotrophic lateral sclerosis, and Alzheimer disease. The recent boom of glutamate is demonstrated by the enormous amount of publications dealing with the function of glutamate, with its role on modulation of synaptic transmission throughout the brain, mainly focusing: i). on the structure of its receptors, ii). on molecular biology and pharmacology of Glu transporters, and iii). on the role of glutamate uptake and reversal uptake in several neuropathologies. This review will deal with the recent and most interesting published results on Glu transporters membrane topology, Glu transporters physiopathological role and Glu transporters medicinal chemistry, highlighting the guidelines for the development of potential neuroprotective agents targeting neuronal high-affinity sodium-dependent glutamate transporters.
Assuntos
Sistema X-AG de Transporte de Aminoácidos/fisiologia , Ácido Glutâmico/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Sódio/metabolismo , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Animais , Membrana Celular/metabolismo , Desenho de Fármacos , Humanos , Ligantes , Conformação Molecular , Estrutura Molecular , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Receptores de Glutamato/metabolismoRESUMO
In the present study, we have synthesized and tested novel pyridopyrrolo- and pyrrolobenzoxazepine derivatives, as novel and selective peripheral type benzodiazepine receptor (PBR) ligands, and their ability to modulate steroid biosynthesis has been investigated. A subset of new ligands bind the PBR (rat brain and testis) with picomolar affinity, representing the most potent ligands that have been identified to date, and elicited effects on endogenous rate of steroidogenesis in MA10 Leydig cells, having similar potency and effect as PK11195. Several compounds, differently substituted at C-7, were used as molecular yardsticks to probe the spatial dimension of the lipophilic pocket L4 in the receptor binding site.
Assuntos
Azepinas/síntese química , Sondas Moleculares/síntese química , Receptores de GABA-A/efeitos dos fármacos , Esteroides/biossíntese , Animais , Azepinas/química , Azepinas/farmacologia , Sítios de Ligação , Ligação Competitiva , Linhagem Celular , Córtex Cerebral/metabolismo , Ligação de Hidrogênio , Técnicas In Vitro , Ligantes , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Sondas Moleculares/química , Sondas Moleculares/farmacologia , Oxazepinas/síntese química , Oxazepinas/química , Oxazepinas/farmacologia , Progesterona/biossíntese , Ratos , Relação Estrutura-Atividade , Testículo/citologia , Testículo/ultraestruturaRESUMO
The intramolecular hydrogen bond formed between a protonated amine and a neighboring H-bond acceptor group in the side chain of amodiaquine and isoquine is thought to play an important role in their antimalarial activities. Here we describe isoquine-based compounds in which the intramolecular H-bond is mimicked by a methylene linker. The antimalarial activities of the resulting benzoxazines, their isosteric tetrahydroquinazoline derivatives, and febrifugine-based 1,3-quinazolin-4-ones were examined in vitro (against Plasmodium falciparum ) and in vivo (against Plasmodium berghei ). Compounds 6b,c caused modest inhibition of chloroquine transport via the parasite's "chloroquine resistance transporter" (PfCRT) in a Xenopus laevis oocyte expression system. In silico predictions and experimental evaluation of selected drug-like properties were also performed on compounds 6b,c. Compound 6c emerged from this work as the most promising analogue of the series; it possessed low toxicity and good antimalarial activity when administered orally to P. berghei -infected mice.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Benzoxazinas/química , Benzoxazinas/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Animais , Linhagem Celular , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Mimetismo Molecular , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Adenosine kinase (AK) catalyzes the phosphorylation of adenosine (Ado) to AMP by means of a kinetic mechanism in which the two substrates Ado and ATP bind the enzyme in a binary and/or ternary complex, with distinct protein conformations. Most of the described inhibitors have Ado-like structural motifs and are nonselective, and some of them (e.g., the tubercidine-like ligands) are characterized by a toxic profile. We have cloned and expressed human AK (hAK) and searched for novel non-substrate-like inhibitors. Our efforts to widen the structural diversity of AK inhibitors led to the identification of novel non-nucleoside, noncompetitive allosteric modulators characterized by a unique molecular scaffold. Among the pyrrolobenzoxa(thia)zepinones (4a-qq) developed, 4a was identified as a non-nucleoside prototype hAK inhibitor. 4a has proapoptotic efficacy, slight inhibition of short-term RNA synthesis, and cytostatic activity on tumor cell lines while showing low cytotoxicity and no significant adverse effects on short-term DNA synthesis in cells.
Assuntos
Adenosina Quinase/antagonistas & inibidores , Antineoplásicos/síntese química , Modelos Moleculares , Oxazepinas/síntese química , Pirróis/síntese química , Adenosina Quinase/química , Regulação Alostérica , Sítio Alostérico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/biossíntese , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Oxazepinas/química , Oxazepinas/farmacologia , Pirróis/química , Pirróis/farmacologia , RNA/biossíntese , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
As a continuation of our efforts to develop innovative ligands for D(3), 5-HT(1A), and 5-HT(2A) receptors with low propensity to block hERG channels, we propose a series bishetero(homo)arylpiperazines 5a-m as novel and potent multifunctional ligands characterized by low occupancy at D(2) and 5-HT(2C) receptors.
Assuntos
Antipsicóticos/síntese química , Piperazinas/síntese química , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D3/metabolismo , Animais , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Ligantes , Camundongos , Modelos Moleculares , Piperazinas/farmacocinética , Piperazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
We investigated the pharmacological profile of a novel series of quinoxaline-based 5-HT(3) receptor ligands bearing an extra basic moiety on the piperazine N-4. High affinity and selectivity were dependent on the electronic properties of the substituents, and at cardiac level 3a and 3c modulated chronotropy but not inotropy. In von Bezold-Jarisch reflex test 3a-c were partial agonists while 3i was a full agonist. Preliminary pharmacokinetic studies indicated that 3a is a brain penetrating agent.
Assuntos
Pirróis/síntese química , Quinoxalinas/síntese química , Agonistas do Receptor 5-HT3 de Serotonina , Animais , Barreira Hematoencefálica/metabolismo , Agonismo Parcial de Drogas , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Ligantes , Contração Miocárdica/efeitos dos fármacos , Pirróis/química , Pirróis/farmacologia , Quinoxalinas/farmacocinética , Quinoxalinas/farmacologia , Ratos , Reflexo/efeitos dos fármacos , Antagonistas do Receptor 5-HT3 de Serotonina , Relação Estrutura-AtividadeRESUMO
The synthesis and the biological characterization of novel highly selective pyrroloquinoxaline 5-HT(3) receptor (5-HT(3)R) ligands are described. In functional and in vivo biological studies the novel quinoxalines modulated cardiac parameters by direct interaction with myocardial 5-HT(3)Rs. The potent 5-HT(3)R ligands 4h and 4n modulate chronotropy (right atrium) but not inotropy (left atrium) at the cardiac level, being antagonist and partial agonist, respectively. Preliminary pharmacokinetic studies indicate that (S)-4n and 4a, representatives of the novel 5-HT(3)R ligands, possess poor blood-brain barrier permeability, being the prototypes of peripherally acting 5-HT(3)R modulators endowed with a clear-cut pharmacological activity at the cardiac level. The unique properties of 4h and 4n, compared to their previously described centrally active N-methyl analogue 5a, are mainly due to the hydrophilic groups at the distal piperazine nitrogen. These analogues represent novel pharmacological tools for investigating the role of peripheral 5-HT(3)R in the modulation of cardiac parameters.
Assuntos
Coração/efeitos dos fármacos , Miocárdio/metabolismo , Pirróis/síntese química , Pirróis/farmacologia , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Receptores 5-HT3 de Serotonina/metabolismo , Animais , Barorreflexo/efeitos dos fármacos , Fenômenos Químicos , Feminino , Cobaias , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Masculino , Camundongos , Modelos Moleculares , Pirróis/farmacocinética , Quinoxalinas/farmacocinética , Quipazina/análogos & derivados , Quipazina/síntese química , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Agonistas do Receptor 5-HT3 de Serotonina , Relação Estrutura-AtividadeRESUMO
Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.
Assuntos
Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Desenho de Fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D3/metabolismo , Animais , Antipsicóticos/química , Antipsicóticos/classificação , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Camundongos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Antimalarial agents structurally based on novel pharmacophores, synthesized by low-cost synthetic procedures and characterized by low potential for developing resistance are urgently needed. Recently, we developed an innovative class of antimalarials based on a polyaromatic pharmacophore. Hybridizing the 4-aminoquinoline or the 9-aminoacridine system of known antimalarials with the clotrimazole-like pharmacophore, characterized by a polyarylmethyl group, we describe herein the development of a unique class (4a-l and 5a-c) of antimalarials selectively interacting with free heme and interfering with Plasmodium falciparum (Pf) heme metabolism. Combination of the polyarylmethyl system, able to form and stabilize radical intermediates, with the iron-complexing and conjugation-mediated electron transfer properties of the 4(9)-aminoquinoline(acridine) system led to potent antimalarials in vitro against chloroquine sensitive and resistant Pf strains. Among the compounds synthesized, 4g was active in vivo against P. chabaudi and P. berghei after oral administration and, possessing promising pharmacokinetic properties, it is a candidate for further preclinical development.