RESUMEN
1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) catalyzes the second step of the non-mevalonate (or MEP) pathway that functions in several organisms and plants for the synthesis of isoprenoids. DXR is essential for the survival of multiple pathogenic bacteria/parasites, including those that cause tuberculosis and malaria in humans. DXR function is inhibited by fosmidomycin (1), a natural product, which forms a chelate with the active site divalent metal (Mg2+/Mn2+) through its hydroxamate metal-binding group (MBG). Most of the potent DXR inhibitors are structurally similar to 1 and retain hydroxamate despite the unfavourable pharmacokinetic and toxicity profile of the latter. We provide our perspective on the lack of non-hydroxamate DXR inhibitors. We also highlight the fundamental flaws in the design of MBG in these molecules, primarily responsible for their failure to inhibit DXR. We also suggest that for designing next-generation non-hydroxamate DXR inhibitors, approaches followed for other metalloenzymes targets may be exploited.
Asunto(s)
Isomerasas Aldosa-Cetosa/metabolismo , Amidas/química , Antimaláricos/química , Antituberculosos/química , Ácidos Borónicos/química , Inhibidores Enzimáticos/química , Amidas/farmacología , Antimaláricos/farmacología , Antituberculosos/farmacología , Ácidos Borónicos/farmacología , Dominio Catalítico , Cationes Bivalentes/química , Inhibidores Enzimáticos/farmacología , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Magnesio/química , Manganeso/química , Modelos Moleculares , Mycobacterium tuberculosis/efectos de los fármacos , Unión Proteica , Relación Estructura-Actividad , Terpenos/químicaRESUMEN
Numerous metal-containing enzymes (metalloenzymes) have been considered as drug targets related to diseases such as cancers, diabetes, anemia, AIDS, malaria, bacterial infection, fibrosis, and neurodegenerative diseases. Inhibitors of the metalloenzymes have been developed independently, most of which are mimics of substrates of the corresponding enzymes. However, little attention has been paid to the interactions between inhibitors and active site metal ions. This review is focused on different metal binding fragments and their chelating properties in the metal-containing active binding pockets of metalloenzymes. We have enumerated over one hundred of inhibitors targeting various metalloenzymes and identified over ten kinds of fragments with different binding patterns. Furthermore, we have investigated the inhibitors that are undergoing clinical evaluation in order to help looking for more potential scaffolds bearing metal binding fragments. This review will provide deep insights for the rational design of novel inhibitors targeting the metal-containing binding sites of specific proteins.
Asunto(s)
Quelantes/uso terapéutico , Química Farmacéutica/métodos , Metaloproteínas/antagonistas & inhibidores , Animales , Dominio Catalítico , Diseño de Fármacos , HumanosRESUMEN
The synthesis of saccharin (1,2-benzisothiazol-3-one-1,1-dioxide) derivatives substituted on the benzene ring has seen limited development despite the longevity of this compound's use as an artificial sweetener. This type of saccharin derivative would however present attractive properties for the development of new bioactive, drug-like small molecule compounds. Here we report the derivatisation of the benzene ring of saccharin using Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC) to synthesise a diverse library of novel saccharin-1,2,3-triazole conjugates. All library compounds retain the capability for interactions with biomolecules via the unmodified sulfonamide and lactam groups of the parent saccharin core heterocycle. The compounds also encompass alternate orientations of the 1,2,3-triazole heterocycle, thus further adding diversity to the potential hydrogen bonding interactions of these compounds with biomolecules of therapeutic interest. Our findings demonstrate that specifically functionalized derivatives of saccharin may be prepared from either saccharin azide or saccharin alkyne building blocks in high yield using CuAAC.
Asunto(s)
Sacarina/análogos & derivados , Bibliotecas de Moléculas Pequeñas/síntesis química , Catálisis , Química Clic , Reacción de Cicloadición , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
New peptide molecules with metal binding abilities proved to be active against multidrug resistant clinical isolates. One of them labeled with a dansylated lysine has been imaged inside single-multidrug resistant bacteria cells by deep ultraviolet fluorescence, showing a heterogeneous subcellular localization. The fluorescence intensity is clearly related to the accumulation of the drug inside the bacteria, being dependent both on its concentration and on the incubation time with cells.