RESUMO
Corramycin 1 is a novel zwitterionic antibacterial peptide isolated from a culture of the myxobacterium Corallococcus coralloides. Though Corramycin displayed a narrow spectrum and modest MICs against sensitive bacteria, its ADMET and physchem profile as well as its high tolerability in mice along with an outstanding in vivo efficacy in an Escherichia coli septicemia mouse model were promising and prompted us to embark on an optimization program aiming at enlarging the spectrum and at increasing the antibacterial activities by modulating membrane permeability. Scanning the peptidic moiety by the Ala-scan strategy followed by key stabilization and introduction of groups such as a primary amine or siderophore allowed us to enlarge the spectrum and increase the overall developability profile. The optimized Corramycin 28 showed an improved mouse IV PK and a broader spectrum with high potency against key Gram-negative bacteria that translated into excellent efficacy in several in vivo mouse infection models.
Assuntos
Antibacterianos , Infecções por Escherichia coli , Camundongos , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/química , Bactérias Gram-Negativas , Bactérias , Testes de Sensibilidade MicrobianaRESUMO
Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.
Assuntos
Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Classe III de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Pirimidinonas/farmacologia , Sequência de Aminoácidos , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Área Sob a Curva , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Células CACO-2 , Linhagem Celular Tumoral , Classe III de Fosfatidilinositol 3-Quinases/química , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Células HeLa , Humanos , Masculino , Camundongos SCID , Modelos Químicos , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Neoplasias/patologia , Ligação Proteica , Estrutura Terciária de Proteína , Pirimidinonas/química , Pirimidinonas/farmacocinética , Ratos Sprague-Dawley , Homologia de Sequência de Aminoácidos , Termodinâmica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of 9-oxime-11,12-carbamate ketolides was synthesized for the first time through a key 11,12-hydrazonocarbamate intermediate that was first oximated and further deaminated to give the corresponding carbamate. The N-N bond cleavage was achieved through an original new reaction using glycoaldehyde dimer as deaminating reagent. The new compounds synthesized were shown to display improved antibacterial activities against Streptococcus pneumoniae and S. pyogenes resistant to erythromycin.
