RESUMO
Two novel compounds, pyridopyrimidines (1) and naphthyridines (2) were identified as potent inhibitors of bacterial NAD(+)-dependent DNA ligase (Lig) A in a fragment screening. SAR was guided by molecular modeling and X-ray crystallography. It was observed that the diaminonitrile pharmacophore made a key interaction with the ligase enzyme, specifically residues Glu114, Lys291, and Leu117. Synthetic challenges limited opportunities for diversification of the naphthyridine core, therefore most of the SAR was focused on a pyridopyrimidine scaffold. The initial diversification at R(1) improved both enzyme and cell potency. Further SAR developed at the R(2) position using the Negishi cross-coupling reaction provided several compounds, among these compounds 22g showed good enzyme potency and cellular potency.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , DNA Ligases/antagonistas & inibidores , NAD/metabolismo , Naftiridinas/farmacologia , Pirimidinas/farmacologia , Antibacterianos/síntese química , Proteínas de Bactérias/química , DNA Ligases/química , Haemophilus influenzae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Naftiridinas/síntese química , Pirimidinas/síntese química , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Type II bacterial topoisomerases are well validated targets for antimicrobial chemotherapy. Novel bacterial type II topoisomerase inhibitors (NBTIs) of these targets are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. We now disclose the optimization of a class of NBTIs towards Gram-negative pathogens, especially against drug-resistant Pseudomonas aeruginosa. Physicochemical properties (pKa and logD) were optimized for activity against P. aeruginosa and for reduced inhibition of the hERG channel. The optimized analogs 9g and 9i displayed potent antibacterial activity against P. aeruginosa, and a significantly improved hERG profile over previously reported analogs. Compound 9g showed an improved QT profile in in vivo models and lower clearance in rat over earlier compounds. The compounds show promise for the development of new antimicrobial agents against drug-resistant Pseudomonas aeruginosa.
Assuntos
DNA Topoisomerases Tipo II/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Animais , Físico-Química , Cães , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Cobaias , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/enzimologia , Pseudomonas aeruginosa/metabolismo , Ratos , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/químicaRESUMO
Structure-activity relationships are presented around a series of pyrazolopyrimidinediones that inhibit the growth of Helicobacter pylori by targeting glutamate racemase, an enzyme that provides d-glutamate for the construction of N-acetylglucosamine-N-acetylmuramic acid peptidoglycan subunits assimilated into the bacterial cell wall. Substituents on the inhibitor scaffold were varied to optimize target potency, antibacterial activity and in vivo pharmacokinetic stability. By incorporating an imidazole ring at the 7-position of scaffold, high target potency was achieved due to a hydrogen bonding network that occurs between the 3-position nitrogen atom, a bridging water molecule and the side chains Ser152 and Trp244 of the enzyme. The lipophilicity of the scaffold series proved important for expression of antibacterial activity. Clearances in vitro and in vivo were monitored to identify compounds with improved plasma stability. The basicity of the imidazole may contribute to increased aqueous solubility at lower pH allowing for improved oral bioavailability.
Assuntos
Isomerases de Aminoácido/antagonistas & inibidores , Antibacterianos/química , Antibacterianos/farmacologia , Helicobacter pylori/efeitos dos fármacos , Pirimidinonas/química , Pirimidinonas/farmacologia , Administração Oral , Isomerases de Aminoácido/metabolismo , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Disponibilidade Biológica , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Helicobacter pylori/enzimologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Camundongos , Modelos Moleculares , Pirazóis/administração & dosagem , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Selective inhibition of the angiotensin-converting enzyme C-domain (cACE) and neprilysin (NEP), leaving the ACE N-domain (nACE) free to degrade bradykinin and other peptides, has the potential to provide the potent antihypertensive and cardioprotective benefits observed for nonselective dual ACE/NEP inhibitors, such as omapatrilat, without the increased risk of adverse effects. We have synthesized three 1-carboxy-3-phenylpropyl dipeptide inhibitors with nanomolar potency based on the previously reported C-domain selective ACE inhibitor lisinopril-tryptophan (LisW) to probe the structural requirements for potent dual cACE/NEP inhibition. Here we report the synthesis, enzyme kinetic data, and high-resolution crystal structures of these inhibitors bound to nACE and cACE, providing valuable insight into the factors driving potency and selectivity. Overall, these results highlight the importance of the interplay between the S1' and S2' subsites for ACE domain selectivity, providing guidance for future chemistry efforts toward the development of dual cACE/NEP inhibitors.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Neprilisina/farmacologia , Peptidil Dipeptidase A/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/síntese química , Sítios de Ligação/efeitos dos fármacos , Bradicinina/metabolismo , Simulação por Computador , Cristalografia por Raios X , Humanos , Cinética , Lisinopril/farmacologia , Peptidil Dipeptidase A/química , Piridinas/farmacologia , Tiazepinas/farmacologiaRESUMO
New antibiotics with either a novel mode of action or novel mode of inhibition are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new spiropyrimidinetriones (SPTs), DNA gyrase inhibitors having activity against drug-resistant Mycobacterium tuberculosis (Mtb), the causative agent of TB. While the clinical candidate zoliflodacin has progressed to phase 3 trials for the treatment of gonorrhea, compounds herein demonstrated higher inhibitory potency against Mtb DNA gyrase (e.g., compound 42 with IC50 = 2.0) and lower Mtb minimum inhibitor concentrations (0.49 µM for 42). Notably, 42 and analogues showed selective Mtb activity relative to representative Gram-positive and Gram-negative bacteria. DNA gyrase inhibition was shown to involve stabilization of double-cleaved DNA, while on-target activity was supported by hypersensitivity against a gyrA hypomorph. Finally, a docking model for SPTs with Mtb DNA gyrase was developed, and a structural hypothesis was built for structure-activity relationship expansion.
Assuntos
Mycobacterium tuberculosis , Inibidores da Topoisomerase II , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , DNA Girase/genética , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Testes de Sensibilidade Microbiana , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/uso terapêuticoRESUMO
An SAR survey at the C-6 benzoxazinone position of a novel scaffold which inhibits bacterial type IIa topoisomerase demonstrates that a range of small electron donating groups (EDG) and electron withdrawing groups (EWG) are tolerated for antibacterial activity. Cyano was identified as a preferred substituent that affords good antibacterial potency while minimizing hERG cardiac channel activity.
Assuntos
Bactérias/enzimologia , Benzoxazinas/química , DNA Topoisomerases Tipo II/metabolismo , Inibidores Enzimáticos/farmacologia , Piperidinas/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The effectiveness of ß-lactam antibiotics is increasingly compromised by ß-lactamases. Boron-containing inhibitors are potent serine-ß-lactamase inhibitors, but the interactions of boron-based compounds with the penicillin-binding protein (PBP) ß-lactam targets have not been extensively studied. We used high-throughput X-ray crystallography to explore reactions of a boron-containing fragment set with the Pseudomonas aeruginosa PBP3 (PaPBP3). Multiple crystal structures reveal that boronic acids react with PBPs to give tricovalently linked complexes bonded to Ser294, Ser349, and Lys484 of PaPBP3; benzoxaboroles react with PaPBP3 via reaction with two nucleophilic serines (Ser294 and Ser349) to give dicovalently linked complexes; and vaborbactam reacts to give a monocovalently linked complex. Modifications of the benzoxaborole scaffold resulted in a moderately potent inhibition of PaPBP3, though no antibacterial activity was observed. Overall, the results further evidence the potential for the development of new classes of boron-based antibiotics, which are not compromised by ß-lactamase-driven resistance.
Assuntos
Antibacterianos/farmacologia , Compostos de Boro/farmacologia , Ensaios de Triagem em Larga Escala , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Pseudomonas aeruginosa/efeitos dos fármacos , Inibidores de beta-Lactamases/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Sítios de Ligação/efeitos dos fármacos , Compostos de Boro/síntese química , Compostos de Boro/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Proteínas de Ligação às Penicilinas/metabolismo , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/química , beta-LactamasesRESUMO
Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds 3-6. Compound 5 was further optimized via various structure-activity relationship (SAR) exploration methods to 29, a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound 5 led to the identification of a nonacid inhibitor of HAO1, 31, which has weaker potency and increased permeability.
Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , DNA/química , Bibliotecas de Moléculas Pequenas/química , Oxirredutases do Álcool/metabolismo , Animais , Sítios de Ligação , Cristalografia por Raios X , DNA/metabolismo , Desenho de Fármacos , Meia-Vida , Humanos , Hiperoxalúria Primária/metabolismo , Hiperoxalúria Primária/patologia , Indóis/química , Indóis/metabolismo , Masculino , Camundongos , Simulação de Acoplamento Molecular , Bibliotecas de Moléculas Pequenas/metabolismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/metabolismo , Transaminases/genética , Transaminases/metabolismoRESUMO
Phenotypic whole cell high-throughput screening of a â¼150,000 diverse set of compounds against Mycobacterium tuberculosis (Mtb) in cholesterol-containing media identified 1,3-diarylpyrazolyl-acylsulfonamide 1 as a moderately active hit. Structure-activity relationship (SAR) studies demonstrated a clear scope to improve whole cell potency to MIC values of <0.5 µM, and a plausible pharmacophore model was developed to describe the chemical space of active compounds. Compounds are bactericidal in vitro against replicating Mtb and retained activity against multidrug-resistant clinical isolates. Initial biology triage assays indicated cell wall biosynthesis as a plausible mode-of-action for the series. However, no cross-resistance with known cell wall targets such as MmpL3, DprE1, InhA, and EthA was detected, suggesting a potentially novel mode-of-action or inhibition. The in vitro and in vivo drug metabolism and pharmacokinetics profiles of several active compounds from the series were established leading to the identification of a compound for in vivo efficacy proof-of-concept studies.
Assuntos
Antituberculosos/farmacologia , Parede Celular/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Sulfonamidas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Descoberta de Drogas , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
Assuntos
Antituberculosos/química , Pirimidinonas/química , Animais , Antituberculosos/metabolismo , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Meia-Vida , Humanos , Ferro/metabolismo , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Microssomos/metabolismo , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Pirazóis/química , Pirimidinonas/metabolismo , Pirimidinonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Plasmodium falciparum phosphatidylinositol 4-kinase (PfPI4K) has emerged as a promising new drug target for novel antimalarial therapeutics. In the absence of a reliable high-resolution three-dimensional structure, a homology model of PfPI4K was built as a tool for structure-based drug design. This homology model has been validated against three distinct chemical series of potent inhibitors using docking and energy minimizations to elucidate the interactions crucial for PI4K inhibition and potent antiplasmodium activity. Despite its potential as an antimalarial target, the similarity between PfPI4K and structurally related human kinases poses a risk for human off-target kinase activity and associated toxicity. Comparative docking between PfPI4K and human phosphoinositide kinases (PIKs) presents compelling evidence for the origins of selectivity. This in-depth analysis of the PfPI4K homology model, the binding modes of the inhibitors, and the interactions responsible for selectivity over human kinases provides a powerful template for future optimization of Plasmodium PI4K inhibitors.
Assuntos
Antimaláricos , Plasmodium , 1-Fosfatidilinositol 4-Quinase , Antimaláricos/farmacologia , Desenho de Fármacos , Humanos , Plasmodium falciparumRESUMO
Herein, we report spiropyrimidinetriones (SPTs) incorporating N-linked azole substituents on a benzisoxazole scaffold with improved Gram-positive antibacterial activity relative to previously described analogues. SPTs have an unusual spirocyclic architecture and represent a new antibacterial class of bacterial DNA gyrase and topoisomerase IV inhibitors. They are not cross-resistant to fluoroquinolones and other DNA gyrase/topoisomerase IV inhibitors used clinically. The activity of the SPTs was assessed for DNA gyrase inhibition, and the antibacterial activity across Gram-positive and Gram-negative pathogens with N-linked 1,2,4-triazoles substituted on the 5-position provides the most worthwhile profile. Directed nucleophilic and electrophilic chemistry was developed to vary this 5-position with carbon, nitrogen, or oxygen substituents and explore structure-activity relationships including those around a target binding model. Compounds with favorable pharmacokinetic parameters were identified, and two compounds demonstrated cidality in a mouse model of Staphylococcus aureus infection.
Assuntos
Antibacterianos/farmacologia , DNA Girase/metabolismo , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Azóis/química , Azóis/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Isoxazóis/química , Isoxazóis/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinonas/síntese química , Pirimidinonas/química , Pirimidinonas/farmacologia , Ratos , Ratos Wistar , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus/metabolismo , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/químicaRESUMO
A phenotypic whole cell high-throughput screen against the asexual blood and liver stages of the malaria parasite identified a benzimidazole chemical series. Among the hits were the antiemetic benzimidazole drug Lerisetron 1 (IC50 NF54 = 0.81 µM) and its methyl-substituted analogue 2 (IC50 NF54 = 0.098 µM). A medicinal chemistry hit to lead effort led to the identification of chloro-substituted analogue 3 with high potency against the drug-sensitive NF54 (IC50 NF54 = 0.062 µM) and multidrug-resistant K1 (IC50 K1 = 0.054 µM) strains of the human malaria parasite Plasmodium falciparum. Compounds 2 and 3 gratifyingly showed in vivo efficacy in both Plasmodium berghei and P. falciparum mouse models of malaria. Cardiotoxicity risk as expressed in strong inhibition of the human ether-a-go-go-related gene (hERG) potassium channel was identified as a major liability to address. This led to the synthesis and biological assessment of around 60 analogues from which several compounds with improved antiplasmodial potency, relative to the lead compound 3, were identified.
RESUMO
Cajal recognized that the elaborate shape of neurons is fundamental to their function in the brain. However, there are no simple and generalizable genetic methods to study neuronal or glial cell morphology in the mammalian brain. Here, we describe four mouse lines conferring Cre-dependent sparse cell labeling based on mononucleotide repeat frameshift (MORF) as a stochastic translational switch. Notably, the optimized MORF3 mice, with a membrane-bound multivalent immunoreporter, confer Cre-dependent sparse and bright labeling of thousands of neurons, astrocytes, or microglia in each brain, revealing their intricate morphologies. MORF3 mice are compatible with imaging in tissue-cleared thick brain sections and with immuno-EM. An analysis of 151 MORF3-labeled developing retinal horizontal cells reveals novel morphological cell clusters and axonal maturation patterns. Our study demonstrates a conceptually novel, simple, generalizable, and scalable mouse genetic solution to sparsely label and illuminate the morphology of genetically defined neurons and glia in the mammalian brain.
Assuntos
Astrócitos/ultraestrutura , Encéfalo/ultraestrutura , Microglia/ultraestrutura , Neurônios/ultraestrutura , Células Horizontais da Retina/ultraestrutura , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Mutação da Fase de Leitura/genética , Proteínas de Fluorescência Verde/genética , Integrases , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Microglia/patologia , Repetições de Microssatélites/genética , Neurônios/metabolismo , Neurônios/patologia , Células Horizontais da Retina/metabolismo , Células Horizontais da Retina/patologiaRESUMO
An SAR study of an HTS screening hit generated a series of pyridodiazepine amines as potent inhibitors of Helicobacter pylori glutamate racemase (MurI) showing highly selective anti-H. pylori activity, marked improved solubility, and reduced plasma protein binding. X-ray co-crystal E-I structures were obtained. These uncompetitive inhibitors bind at the MurI dimer interface.
Assuntos
Aminas/química , Isomerases de Aminoácido/química , Química Farmacêutica/métodos , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/enzimologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Ligação Competitiva , Dimerização , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
An early SAR study of a screening hit series has generated a series of 9-benzyl purines as inhibitors of bacterial glutamate racemase (MurI) with micromolar enzyme potency and improved physical properties. X-ray co-crystal EI structures were obtained.
Assuntos
Isomerases de Aminoácido/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias Gram-Positivas/enzimologia , Purinas/síntese química , Purinas/farmacologia , Antibacterianos/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/genética , Enterococcus faecium/efeitos dos fármacos , Enterococcus faecium/genética , Bactérias Gram-Positivas/genética , Conformação Molecular , Estrutura Molecular , Purinas/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Relação Estrutura-AtividadeRESUMO
A successful scaffold-hopping approach gave a novel series of inhibitors of bacterial glutamate racemase (MurI). Early SAR studies of the 8-benzyl pteridine-6,7-diones led to compounds with micromolar enzyme potency and antibacterial activity.
Assuntos
Isomerases de Aminoácido/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias Gram-Positivas/enzimologia , Pteridinas/síntese química , Pteridinas/farmacologia , Antibacterianos/química , Técnicas de Química Combinatória , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pteridinas/química , Relação Estrutura-AtividadeRESUMO
Advances in the genetics, function, and stage-specificity of Plasmodium kinases has driven robust efforts to identify targets for the design of antimalarial therapies. Reverse genomics following phenotypic screening against Plasmodia or related parasites has uncovered vulnerable kinase targets including PI4K, PKG, and GSK-3, an approach bolstered by access to human disease-directed kinase libraries. Alternatively, screening compound libraries against Plasmodium kinases has successfully led to inhibitors with antiplasmodial activity. As with other therapeutic areas, optimizing compound ADMET and PK properties in parallel with target inhibitory potency and whole cell activity becomes paramount toward advancing compounds as clinical candidates. These and other considerations will be discussed in the context of progress achieved toward deriving important, novel mode-of-action kinase-inhibiting antimalarial medicines.
Assuntos
Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Plasmodium/efeitos dos fármacos , Plasmodium/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/química , Humanos , Malária/enzimologia , Malária/parasitologiaRESUMO
A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure-activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite Plasmodium falciparum. In the humanized P. falciparum mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg-1. In vitro mode-of-action studies revealed Plasmodium falciparum phosphatidylinositol-4-kinase as the target.
Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Malária/tratamento farmacológico , Naftiridinas/química , Naftiridinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , 1-Fosfatidilinositol 4-Quinase/química , Animais , Antimaláricos/química , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Modelos Animais de Doenças , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Camundongos , Modelos Moleculares , Naftiridinas/farmacocinética , Naftiridinas/uso terapêutico , Plasmodium falciparum/fisiologia , Conformação Proteica , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
A lead-optimization program around a 2,6-imidazopyridine scaffold was initiated based on the two early lead compounds, 1 and 2, that were shown to be efficacious in an in vivo humanized Plasmodium falciparum NODscidIL2Rγnull mouse malaria infection model. The observation of atypical dose-response curves when some compounds were tested against multidrug resistant malaria parasite strains guided the optimization process to define a chemical space that led to typical sigmoidal dose-response and complete kill of multidrug resistant parasites. After a structure and property analysis identified such a chemical space, compounds were prepared that displayed suitable activity, ADME, and safety profiles with respect to cytotoxicity and hERG inhibition.