ABSTRACT
Based on an (aminoaryl)benzothiazole quinazoline hit structure for kinase inhibition, a systematic optimization program resulted in a lead structure allowing for inhibitory activities in cellular phosphorylation assays in the low nanomolar range.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Aurora Kinases , Cell Line, Tumor , ErbB Receptors/chemistry , ErbB Receptors/metabolism , Humans , Models, Molecular , Molecular Structure , Phosphorylation/drug effects , Protein Binding , Protein Kinases/chemistry , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
Recent research has provided evidence that interference with bacterial cell-to-cell signaling is a promising strategy for the development of novel antimicrobial agents. Here we report on the computer-aided design of novel compounds that specifically inhibit an N-acyl-homoserine lactone-dependent communication system that is widespread among members of the genus Burkholderia. This genus comprises more than 30 species, many of which are important pathogens of animals and humans. Over the past few years, several Burkholderia species, most notably Burkholderia cenocepacia, have emerged as important opportunistic pathogens causing severe pulmonary deterioration in persons with cystic fibrosis. As efficient treatment of Burkholderia infections is hampered by the inherent resistance of the organisms to a large range of antibiotics, novel strategies for battling these pathogens need to be developed. Here we show that compounds targeting the B. cenocepacia signaling system efficiently inhibit the expression of virulence factors and attenuate the pathogenicity of the organism.
Subject(s)
Bacterial Proteins/antagonists & inhibitors , Burkholderia Infections/microbiology , Burkholderia cepacia/physiology , Drug Design , Signal Transduction/drug effects , Anti-Bacterial Agents/pharmacology , Burkholderia cepacia/genetics , Computer-Aided Design , Gene Expression Regulation, Bacterial , Signal Transduction/physiologyABSTRACT
A novel series of DHODH inhibitors was developed based on a lead which was obtained by a docking procedure and a medicinal chemistry exploration. The activity of the initial lead was improved by a QSAR method to yield low nanomolar inhibitors.
Subject(s)
Enzyme Inhibitors/chemistry , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Quantitative Structure-Activity Relationship , Binding Sites/drug effects , Binding Sites/physiology , Dihydroorotate Dehydrogenase , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Humans , Oxidoreductases Acting on CH-CH Group Donors/metabolismABSTRACT
A new naphthylisoquinoline alkaloid, ancistrolikokine D, and the likewise 5,8'-coupled alkaloid ancistroealaine A, as well as two further, biosynthetically related, but nitrogen-free natural products, ancistronaphthoic acid B and cis-isoshinanolone, have been isolated from Ancistrocladus likoko J. LEACUTE;ONARD (Ancistrocladaceae). The 5,8'-coupling of the new alkaloids and of the alkaloids isolated earlier hints at a close phylogenetic relationship of A. likoko to other Central African Ancistrocladus species. The compounds show moderate activities against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei rhodesiense.
Subject(s)
Alkaloids/isolation & purification , Anti-Infective Agents/isolation & purification , Caryophyllaceae/chemistry , Isoquinolines/chemistry , Isoquinolines/isolation & purification , Naphthalenes/chemistry , Naphthols/isolation & purification , Alkaloids/chemistry , Alkaloids/pharmacology , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Biological Products/chemistry , Biological Products/isolation & purification , Biological Products/pharmacology , Cell Line , Cell Survival/drug effects , Democratic Republic of the Congo , Inhibitory Concentration 50 , Isoquinolines/pharmacology , Leishmania donovani/drug effects , Magnetic Resonance Spectroscopy , Molecular Structure , Naphthols/chemistry , Naphthols/pharmacology , Plant Roots/chemistry , Plasmodium falciparum/drug effects , Rats , Structure-Activity Relationship , Trypanosoma/drug effectsABSTRACT
From the root bark of Triphyophyllum peltatum, the new naphthylisoquinoline alkaloid 5'-O-demethyldioncophylline A has been isolated. Its otherwise difficult separation from the largely dominating main alkaloid, dioncophylline A, was greatly facilitated by a bromination-benzylation procedure. From the resulting derivative, a crystal structure analysis with an anomalous X-ray diffraction was achieved, allowing confirmation of the full absolute stereostructure of the new alkaloid. The structure was further corroborated by a partial synthesis from dioncopeltine A. The natural product was shown to exhibit antimalarial activity against erythrocytic forms of Plasmodium falciparum.
