ABSTRACT
Antibiotic resistance in bacteria has been an emerging public health problem, thus discovery of novel and effective antibiotics is urgent. A series of novel hybrids of N-aryl pyrrothine-base α-pyrone hybrids was designed, synthesized and evaluated as bacterial RNA polymerase (RNAP) inhibitors. Among them, compound 13c exhibited potent antibacterial activity against antibiotic-resistant S. aureus with the minimum inhibitory concentration (MIC) in the range of 1-4 µg/mL. Moreover, compound 13c exhibited strong inhibitory activity against E.coli RNAP with IC50 value of 16.06 µM, and cytotoxicity in HepG2 cells with IC50 value of 7.04 µM. The molecular docking study further suggested that compound 13c binds to the switch region of bacterial RNAP. In summary, compound 13c is a novel bacterial RNAP inhibitor, and a promising lead compound for further optimization.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , DNA-Directed RNA Polymerases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemistry , Escherichia coli/enzymology , Pyrones/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Binding Sites , Candida albicans/drug effects , Cell Survival/drug effects , DNA-Directed RNA Polymerases/metabolism , Enzyme Inhibitors/metabolism , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Hep G2 Cells , Humans , Microbial Sensitivity Tests , Molecular Docking Simulation , Pyrones/metabolism , Pyrones/pharmacology , Structure-Activity RelationshipABSTRACT
Most of reported steroidal FXR antagonists are restricted due to low potency. We described the design and synthesis of novel nonsteroidal scaffold SIPI-7623 derivatives as FXR antagonists. The most potent compound A-11 (IC50 = 7.8 ± 1.1 µM) showed better activity compared to SIPI-7623 (IC50 = 40.8 ± 1.7 µM) and guggulsterone (IC50 = 45.9 ± 1.1 µM). Docking of A-11 in FXR's ligand-binding domain was also studied.
Subject(s)
Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Valerates/chemistry , Valerates/pharmacology , Humans , Molecular Docking Simulation , Receptors, Cytoplasmic and Nuclear/metabolismABSTRACT
Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) α/ß were tested in vitro. Compound 26 had an IC50 value of 6.4 µM against LXRα and an IC50 value of 5.6 µM against LXRß. Docking studies and the results of structure-activity relationships support the further development of this chemical series as LXRα/ß antagonists.
Subject(s)
Fenofibrate/analogs & derivatives , Hypolipidemic Agents/chemistry , Orphan Nuclear Receptors/antagonists & inhibitors , Drug Discovery , Fenofibrate/pharmacology , Humans , Hypolipidemic Agents/pharmacology , Ligands , Liver X Receptors , Molecular Docking Simulation , Orphan Nuclear Receptors/metabolism , Structure-Activity RelationshipABSTRACT
A series of 5,7-dimethyl-oxazolo[5,4-d]pyrimidine-4,6(5H,7H)-dione derivatives, N5a-5l, was designed, synthesized and evaluated for their FGFR1-inhibition ability as well as cytotoxicity against three cancer cell lines (H460, B16F10 and A549) in vitro. Several compounds displayed good-to-excellent potency against these cancer cell lines compared to SU5402. Structure-activity relationship analyses indicated that compounds with a rigid structure and more heteroatoms at the side chain of the parent ring were more effective than those without these substitutions. The compound N5g (37.4% FGFR1 inhibition at 1.0 µM) was identified to have the most potent antitumor activities, with IC50 values of 5.472, 4.260 and 5.837 µM against H460, B16F10 and A549 cell lines, respectively. Together, our results suggest that 5,7-dimethyl-oxazolo[5,4-d]pyrimidine-4,6(5H,7H)-dione derivatives may serve as potential agents for the treatment of FGFR1-mediated cancers.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Oxazoles/pharmacology , Pyrimidines/pharmacology , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Oxazoles/chemical synthesis , Oxazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Structure-Activity RelationshipABSTRACT
In this study, a series of amide derivatives were synthesized and evaluated for their S-adenosyl-L-homocysteine hydrolase (SAHase) inhibitory activities. The results demonstrated that most of compounds displayed potent SAHase inhibitory activities. Interestingly, compounds 11 and 14 exhibited more potent inhibitory effects than the aristeromycin, one of the most potent SAHase inhibitors known so far. Compounds 12, 13, 15 and 17 exhibited a moderate effect (IC50<10.0 µM). The structure-activity relationship found that compounds with substituted indazole-5-yl group at Ar position and ethylamino group at the side chain showed better SAHase inhibitory activities.
Subject(s)
Amides/chemistry , Amides/pharmacology , Homocysteine/antagonists & inhibitors , Hydrolases/antagonists & inhibitors , Adenosine/analogs & derivatives , Adenosine/pharmacology , Structure-Activity RelationshipABSTRACT
The design and synthesis of a series of substituted 6-amino-4-(2,4-dimethoxyphenyl)-[1,2]dithiolo[4,3-b]pyrrol-5-ones are described. All the synthesized compounds were evaluated for raising leukocyte count activities in normal mice. Four compounds (8a, b, d, h) exhibited raising leukocyte count activities close or higher than positive control recombinant human granulocyte colony stimulating factor (rhG-CSF), and some (8e-g, k, p, r) had a moderate effect. Among them, the most potent compound 8a was evaluated for its antileukopenia activity in cyclophosphamide (CTX) treated mice. Interestingly, 8a exhibited significant antileukopenia activity as compared to rhG-CSF. The results suggest that this kind of compounds might be utilized for the development of new candidate for treatment of leukocytopenia.
Subject(s)
Leukocytes/drug effects , Leukopenia/drug therapy , Pyrroles/chemical synthesis , Animals , Cyclophosphamide/pharmacology , Granulocyte Colony-Stimulating Factor/metabolism , Leukocyte Count , Leukocytes/cytology , Leukocytes/metabolism , Leukopenia/blood , Mice , Mice, Inbred BALB C , Pyrroles/pharmacology , Recombinant Proteins/metabolismABSTRACT
The design and synthesis of two series of 8-(substituted styrol-formamido)phenyl-xanthine derivatives are described. Their in vitro monoamine oxidase B (MAO-B) inhibition were tested and the effect of substituents on the N-7, phenyl and the substituted positions are discussed. It was observed that compound 9b displayed significant MAO-B inhibition activity and selectivity, fluorine substitution plays a key role in the selectivity of MAO-B inhibition, and the styrol-formamido group at position-3' may enhance the activity and selectivity of 8-phenyl-xanthine analogues. These results suggest that such compounds may be utilized for the development of new candidate MAO-B inhibitors for treatment of Parkinson's disease.
Subject(s)
Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Xanthine/chemical synthesis , Xanthine/pharmacology , Fluorine/chemistry , Monoamine Oxidase Inhibitors/chemistry , Structure-Activity Relationship , Styrene/chemistry , Xanthine/chemistryABSTRACT
Monoamine oxidase-B (MAO-B) inhibitor has been used as neuroprotectants to treat the motor deficits of Parkinson's disease (PD). We designed and synthesized a class of 8-substituted benzamido-phenylxanthine derivatives as MAO-B inhibitors. The compounds have various inhibitory effects, with compound 6a having a K(i) value of 0.26 µM. Their promising activity in vitro suggests potential use in the treatment of PD.
