Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Discovery of Novel Thiophene-arylamide Derivatives as DprE1 Inhibitors with Potent Antimycobacterial Activities.

ABSTRACT: In this study, we report the design and synthesis of a series of novel thiophene-arylamide compounds derived from the noncovalent decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) inhibitor TCA1 through a structure-based scaffold hopping strategy. Systematic optimization of the two side chains flanking the thiophene core led to new lead compounds bearing a thiophene-arylamide scaffold with potent antimycobacterial activity and low cytotoxicity. Compounds 23j, 24f, 25a, and 25b exhibited potent in vitro activity against both drug-susceptible (minimum inhibitory concentration (MIC) = 0.02-0.12 μg/mL) and drug-resistant (MIC = 0.031-0.24 μg/mL) tuberculosis strains while retaining potent DprE1 inhibition (half maximal inhibitory concentration (IC₅₀) = 0.2-0.9 μg/mL) and good intracellular antimycobacterial activity. In addition, these compounds showed good hepatocyte stability and low inhibition of the human ether-à-go-go related gene (hERG) channel. The representative compound 25a with acceptable pharmacokinetic property demonstrated significant bactericidal activity in an acute mouse model of tuberculosis. Moreover, the molecular docking study of template compound 23j provides new insight into the discovery of novel antitubercular agents targeting DprE1.

SUBMITTER: Wang P

PROVIDER: S-EPMC8154581 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Scaffold Morphing To Identify Novel DprE1 Inhibitors with Antimycobacterial Activity.

Project description:We report a novel benzimidazole (BI) based DprE1 inhibitor that resulted from scaffold morphing of a 1,4-azaindole series. The clinical progression of the 1,4-azaindole series from our previous work validates the potential of exploring newer chemical entities with antimycobacterial activity driven via a noncovalent inhibition of the decaprenylphosphoryl-?-d-ribose-2'-epimerase (DprE1). The representative compounds from the new scaffold reported in this study exhibited an improved solubility and higher free plasma fraction, while retaining potent DprE1 inhibition and antimycobacterial activity. A representative compound from the benzimidazole series demonstrated good efficacy in a murine model of tuberculosis. Furthermore, molecular modeling of the BI scaffold suggests plausible modes of binding in the active site of DprE1 enzyme from Mycobacterium tuberculosis that can be used for further exploration of the series.

| S-EPMC6792157 | biostudies-literature

Discovery of novel arylamide derivatives containing piperazine moiety as inhibitors of tubulin polymerisation with potent liver cancer inhibitory activity.

Project description:In this work, a series of novel arylamide derivatives containing piperazine moiety were designed and synthesised as tubulin polymerisation inhibitors. Among 25 target compounds, compound 16f (MY-1121) exhibited low nanomolar IC50 values ranging from 0.089 to 0.238 μM against nine human cancer cells. Its inhibitory effects on liver cancer cells were particularly evident with IC50 values of 89.42 and 91.62 nM for SMMC-7721 and HuH-7 cells, respectively. Further mechanism studies demonstrated that compound 16f (MY-1121) could bind to the colchicine binding site of β-tubulin and directly act on β-tubulin, thus inhibiting tubulin polymerisation. Additionally, compound 16f (MY-1121) could inhibit colony forming ability, cause morphological changes, block cell cycle arrest at the G2 phase, induce cell apoptosis, and regulate the expression of cell cycle and cell apoptosis related proteins in liver cancer cells. Overall, the promising bioactivities of compound 16f (MY-1121) make the novel arylamide derivatives have the value for further development as tubulin polymerisation inhibitors with potent anticancer activities.

| S-EPMC10392279 | biostudies-literature

Novel 2-Carbonylbenzo[b]thiophene 1,1-Dioxide Derivatives as Potent Inhibitors of STAT3 Signaling Pathway.

Project description:Signal transducer and activator of transcription 3 (STAT3) is considered to be an attractive therapeutic target for cancer therapy. In this study, a series of 2-carbonylbenzo[b]thiophene 1,1-dioxide derivatives (CBT) were designed to inhibit the STAT3 SH2 domain phosphorylation site Try 705. We demonstrated that incorporation of basic flexible groups through amide bond linkage to benzo[b]thiophene 1,1-dioxide (BTP) achieved compounds with higher antiproliferative potency than BTP itself. The most potent compound 6o, as indicated from luciferase reporter gene assay, inhibited the STAT3 pathway by decreasing the phosphorylation level of STAT3 Tyr705, while the phosphorylation level of other upstream tyrosine kinases in this pathway was not significantly inhibited. Compound 6o was also shown to trigger ROS generation and accumulation, thus consequently attributed partially to the observed cell apoptosis. This study provided important structural information for the development of inhibitors targeting the STAT3 pathway.

| S-EPMC4569881 | biostudies-literature

Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors.

Project description:Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) is the most common mutation in patients with acute myeloid leukemia (AML). FLT3-ITD+ induces constitutive activation of FLT3, causing an abnormally rapid proliferation of cancer cells. In this study, we identified novel FLT3 inhibitors and investigated 5-(4-fluorophenyl)-N-phenyloxazol-2-amine (compound 7; 7c) as candidates for the treatment of AML. The results showed that 7c inhibited the activities of FLT3 and mutated FLT3 in a cell-free kinase assay and Molm-13 and MV4-11 cells, as well as the proliferation of FLT3-ITD+ AML cells, increasing apoptosis. The anti-leukemic activity of 7c was confirmed by in vivo tumor growth inhibition in MV4-11 xenograft mice. Besides, 7c suppressed the expression of DNA damage repair genes. Combination treatment with 7c and olaparib (a poly (ADP-ribose) polymerase [PARP] inhibitor) synergistically inhibited cell proliferation in Molm-13 and MV4-11 cells. Our findings demonstrated that 7c is a therapeutic candidate targeting FLT3 for AML treatment and suggested that combination treatment with 7c and a PARP inhibitor may be an effective therapy regimen for FLT3-mutated AML.

| S-EPMC7663913 | biostudies-literature

Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors.

Project description:Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with oral bioavailability and brain penetrant capability were developed. Inhibitor 17 was a potent and isoform selective JNK3 inhibitor (IC50 = 35 nM), had significant inhibition to only JNK3 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in human liver microsome (t 1/2 = 66 min) and a clean CYP-450 inhibition profile, and was orally bioavailable and brain penetrant. Moreover, cocrystal structures of compounds 17 and 27 in human JNK3 were solved at 1.84 Å, which showed that these JNK3 isoform selective inhibitors bound to the ATP pocket, had interactions in both hydrophobic pocket-I and hydrophobic pocket-II.

| S-EPMC7812606 | biostudies-literature

Discovery of novel quinazoline derivatives bearing semicarbazone moiety as potent EGFR kinase inhibitors.

Project description:Aimed at discovering effective EGFR inhibitors, six series of quinazoline derivatives bearing a semicarbazone moiety were designed, synthesized and evaluated in different cancer cell lines (A549, HepG2, MCF-7 and PC-3). Most of the selected compounds showed remarkable cytotoxicity with IC50 values reaching the nanomole range. Further, the inhibition efficacy of 11 compounds against EGFR kinases was tested, which demonstrated excellent IC50 values in nanomolar level. Importantly, 2 compounds exhibited IC50 values of 0.05?nM and 0.1?nM against wild type EGFR respectively, suggesting more potent activities than that of the positive control, Afatinib (4.0?nM). Excitingly, 2 compounds showed excellent enzyme inhibitory activity with 8.6?nM and 5.6?nM for double T790?M/L858R mutant EGFRs, which is almost the same as Afatinib (3.8?nM). Structure-activity relationships (SARs) analysis indicated that the type of small molecule amine in pyrrole moiety or the chain length of pyrrolamine moiety had no obvious impact on the inhibition efficacy of our synthesized compounds against cancer cells. In addition, results of cell cycle analysis indicated that the G2/M phase of A549 cells was efficiently arrested by the selected compounds. These preliminary results demonstrate that 2 compounds may be promising lead compound-targeting EGFR.

| S-EPMC6232652 | biostudies-literature

Peptide deformylase inhibitors as potent antimycobacterial agents.

Project description:Peptide deformylase (PDF) catalyzes the hydrolytic removal of the N-terminal formyl group from nascent proteins. This is an essential step in bacterial protein synthesis, making PDF an attractive target for antibacterial drug development. Essentiality of the def gene, encoding PDF from Mycobacterium tuberculosis, was demonstrated through genetic knockout experiments with Mycobacterium bovis BCG. PDF from M. tuberculosis strain H37Rv was cloned, expressed, and purified as an N-terminal histidine-tagged recombinant protein in Escherichia coli. A novel class of PDF inhibitors (PDF-I), the N-alkyl urea hydroxamic acids, were synthesized and evaluated for their activities against the M. tuberculosis PDF enzyme as well as their antimycobacterial effects. Several compounds from the new class had 50% inhibitory concentration (IC50) values of <100 nM. Some of the PDF-I displayed antibacterial activity against M. tuberculosis, including MDR strains with MIC90 values of <1 microM. Pharmacokinetic studies of potential leads showed that the compounds were orally bioavailable. Spontaneous resistance towards these inhibitors arose at a frequency of < or =5 x 10(-7) in M. bovis BCG. DNA sequence analysis of several spontaneous PDF-I-resistant mutants revealed that half of the mutants had acquired point mutations in their formyl methyltransferase gene (fmt), which formylated Met-tRNA. The results from this study validate M. tuberculosis PDF as a drug target and suggest that this class of compounds have the potential to be developed as novel antimycobacterial agents.

| S-EPMC1635232 | biostudies-literature

Discovery of benzothiazole amides as potent antimycobacterial agents.

Project description:From a high throughput screening of commercially available libraries against nontuberculous mycobacteria and Mycobacterium tuberculosis, numerous hits were identified with moderate activity. Extensive medicinal chemistry optimization has led to a series of potent benzothiazole amide antimycobacterial agents. Replacement of the adamantyl group with cyclohexyl derivatives and further development of this series resulted in an advanced lead compound, CRS400393, which demonstrated excellent potency and a mycobacteria-specific spectrum of activity. MIC values ranged from 0.03 to 0.12??g/mL against Mycobacterium abscessus and other rapid-grower NTM, and 1-2??g/mL against Mycobacterium avium complex. The preliminary mechanism of action studies suggested these agents may target MmpL3, a mycobacterial mycolic acid transporter. The series has demonstrated in vivo efficacy in a proof of concept mouse model of M. abscessus infection.

| S-EPMC6263154 | biostudies-literature

Substituted 2-(3',4',5'-trimethoxybenzoyl)-benzo[b]thiophene derivatives as potent tubulin polymerization inhibitors.

Project description:The central role of microtubules in cell division and mitosis makes them a particularly important target for anticancer agents. On our early publication, we found that a series of 2-(3',4',5'-trimethoxybenzoyl)-3-aminobenzo[b]thiophenes exhibited strong antiproliferative activity in the submicromolar range and significantly arrested cells in the G2-M phase of the cell cycle and induced apoptosis. In order to investigate the importance of the amino group at the 3-position of the benzo[b]thiophene skeleton, the corresponding 3-unsubstituted and methyl derivatives were prepared. A novel series of inhibitors of tubulin polymerization, based on the 2-(3,4,5-trimethoxybenzoyl)-benzo[b]thiophene molecular skeleton with a methoxy substituent at the C-4, C-5, C-6 or C-7 position on the benzene ring, was evaluated for antiproliferative activity against a panel of five cancer cell lines, for inhibition of tubulin polymerization and for cell cycle effects. Replacing the methyl group at the C-3 position resulted in increased activity compared with the corresponding 3-unsubstituted counterpart. The structure-activity relationship established that the best activities were obtained with the methoxy group placed at the C-4, C-6 or C-7 position. Most of these compounds exhibited good growth inhibition activity and arrest K562 cells in the G2-M phase via microtubule depolymerization.

| S-EPMC2922916 | biostudies-literature

Discovery of Metal Ions Chelator Quercetin Derivatives with Potent Anti-HCV Activities.

Project description:Analogues or isosteres of α,γ-diketoacid (DKA) 1a show potent inhibition of hepatitis C virus (HCV) NS5B polymerase through chelation of the two magnesium ions at the active site. The anti-HCV activity of the flavonoid quercetin (2) could partly be attributed to it being a structural mimic of DKAs. In order to delineate the structural features required for the inhibitory effect and improve the anti-HCV potency, two novel types of quercetin analogues, 7-O-arylmethylquercetins and quercetin-3-O-benzoic acid esters, were designed, synthesized and evaluated for their anti-HCV properties in cell-based assays. Among the 38 newly synthesized compounds, 7-O-substituted derivative 3i and 3-O-substituted derivative 4f were found to be the most active in the corresponding series (EC50 = 3.8 μM and 9.0 μΜ, respectively). Docking studies suggested that the quercetin analogues are capable of establishing key coordination with the two magnesium ions as well as interactions with residues at the active site of HCV NS5B.

| S-EPMC6272327 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data