Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules.

ABSTRACT: We previously reported a series of coumestans-a naturally occurring tetracyclic scaffold containing a δ-lactone-that effectively target the thioesterase domain of polyketide synthase 13 (Pks13) in Mycobacterium tuberculosis (Mtb), resulting in superior anti-tuberculosis (TB) activity. Compared to the corresponding 'open-form' ethyl benzofuran-3-carboxylates, the enhanced anti-TB effects seen with the conformationally restricted coumestan series could be attributed to the extra π-π stacking interactions between the benzene ring of coumestans and the phenyl ring of F1670 residue located in the Pks13-TE binding domain. To further probe this binding feature, novel tetracyclic analogues were synthesized and evaluated for their anti-TB activity against the Mtb strain H₃₇Rv. Initial comparison of the 'open-form' analogueues against the tetracyclic counterparts again showed that the latter is superior in terms of anti-TB activity. In particular, the δ-lactam-containing 5H-benzofuro [3,2-c]quinolin-6-ones gave the most promising results. Compound 65 demonstrated potent activity against Mtb H₃₇Rv with MIC value between 0.0313 and 0.0625 μg/mL, with high selectivity to Vero cells (64-128 fold). The thermal stability analysis supports the notion that the tetracyclic compounds bind to the Pks13-TE domain as measured by nano DSF, consistent with the observed SAR trends. Compound 65 also showed excellent selectivity against actinobacteria and therefore unlikely to develop potential drug resistance to nonpathogenic bacteria.

SUBMITTER: Zhang W

PROVIDER: S-EPMC8689393 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Design, synthesis, and biological evaluation of conformationally constrained cis-amide Hsp90 inhibitors.

Project description:Conformationally constrained cis-amide chimeric inhibitors of Hsp90 have been synthesized and evaluated for their Hsp90 inhibitory activity. These new compounds exhibited Hsp90 ATPase inhibition and induced Hsp90-dependent client protein degradation in a dose-dependent manner. Biological data reported herein suggests that amide bond isomerization of geldanamycin derivatives plays an important role in affinity for the heteroprotein complex present in cancer cells.

| S-EPMC2697668 | biostudies-literature

Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting EGFR.

Project description:This letter describes the construction of conformationally constrained quinazoline analogues. Structure-activity relationship studies led to the identification of the lead compound 9n . Compound 9n exhibits effective in vitro activity against A431(WT,overexpression) and H1975([L858R/T790M]) cancer cell lines but is significantly less effective against EGFR negative cancer cell lines (SW620, A549, and K562). Compound 9n was also assessed for potency in enzymatic assays and in vivo antitumor studies. The results indicated that 9n is a potent kinase inhibitor against both wild-type and T790M mutant EGFR kinase. Meanwhile, an oral administration of 9n at a dose of 200 mg/kg produced a considerable antitumor effect in a A431 xenograft model, as compared to gefitinib. A preliminary pharmacokinetic study of 9n also indicates it has good pharmacokinetic properties, and therefore, it is a good starting point for further development.

| S-EPMC4027470 | biostudies-literature

Design, synthesis, and biological evaluation of conformationally constrained glycerol 3-phosphate acyltransferase inhibitors.

Project description:Glycerol 3-phosphate acyltransferase (GPAT) isozymes are central control points for fat synthesis in mammals. Development of inhibitors of these membrane-bound enzymes could lead to an effective treatment for obesity, but is thwarted by an absence of direct structural information. Based on a highly successful study involving conformationally constrained glycerol 3-phosphate analogs functioning as potent glycerol 3-phosphate dehydrogenase inhibitors, several series of cyclic bisubstrate and transition state analogs were designed, synthesized, and tested as GPAT inhibitors. The weaker in vitro inhibitory activity of these compounds compared to a previously described benzoic acid series was then examined in docking experiments with the soluble squash chloroplast GPAT crystal structure. These in silico experiments indicate that cyclopentyl and cyclohexyl scaffolds prepared in this study may be occluded from the enzyme active site by two protein loops that sterically guard the phosphate binding region. In view of these findings, future GPAT inhibitor design will be driven toward compounds based on planar frameworks able to slide between these loops and enter the active site, resulting in improved inhibitory activity.

| S-EPMC3184547 | biostudies-literature

A rigid bicyclic platform for the generation of conformationally locked neuraminidase inhibitors.

Project description:Rapid mutation of the influenza virus through genetic mixing raises the prospect of new strains that are both highly transmissible and highly lethal, and which have the ability to evade both immunization strategies (through mutation of hemagglutinin) and current therapies (through mutation of neuraminidase). Inspired by a need for next-generation therapeutics, a synthetic strategy for a new class of rigid, bicyclic inhibitors of influenza neuraminidase is reported.

| S-EPMC3516865 | biostudies-literature

Conformationally restricted quinazolone derivatives as PI3Kδ-selective inhibitors: the design, synthesis and biological evaluation.

Project description:A series of structurally novel quinazolone-based PI3Kδ-selective inhibitors were designed and synthesized via the approach of conformational restriction. The majority of them exhibited two-digit to single-digit nanomolar IC50 values against PI3Kδ, along with low micromolar to submicromolar GI50 values against human malignant B-cell line SU-DHL-6. The representative compound, with the most potent PI3Kδ inhibitory activity (IC50 = 6.3 nM) and anti-proliferative activity (GI50 = 0.21 μM) in this series, was further evaluated for its PI3Kδ selectivity, capability to down-regulate PI3K signaling in SU-DHL-6 cells, in vitro metabolic stability, and pharmacokinetic (PK) properties. The experimental results illustrated that this compound, as a promising lead, merits extensive structural optimization for exploring novel PI3Kδ-selective inhibitors as clinical candidates.

| S-EPMC6431952 | biostudies-literature

Design and synthesis of a library of tetracyclic hydroazulenoisoindoles.

Project description:Forty-four tetracyclic hydroazulenoisoindoles were synthesized via a tandem cyclopropanation/Cope rearrangement, followed by a Diels-Alder sequence from easily available five-membered cyclic cross-conjugated trienones. These trienones were obtained from two different routes depending upon whether R(1) and R(2) are alkyl or amino acid derived functional groups, via a rhodium(I)-catalyzed cycloisomerization reaction. To increase diversity, four maleimides and two 1,2,4-triazoline-3,5-diones were used as dienophiles in the Diels-Alder step. Several Diels-Alder adducts were further reacted under palladium-catalyzed hydrogenation conditions, leading to a diastereoselective reduction of the trisubstituted double bond. This library has demonstrated rapid access to a variety of structurally complex natural product-like compounds via stereochemical diversity and building block diversity approaches.

| S-EPMC3104412 | biostudies-literature

First Metal-Free Synthesis of Tetracyclic Pyrido and Pyrazino Thienopyrimidinone Molecules.

Project description:We report herein a new metal free synthetic pathway to generate tetracyclic compounds from 3-aminothieno[3,2-b]pyridine-2-carboxylate. To enlarge the molecular diversity, we studied the Suzuki coupling of 9-chloro-6H-pyrido[1,2-a]pyrido[2',3':4,5]thieno[3,2-d]pyrimidin-6-one and several boronic acids were easily introduced.

| S-EPMC6100531 | biostudies-literature

Structure-Based Design of Conformationally Constrained, Cell-Permeable STAT3 Inhibitors.

Project description:We report herein the structure-based design of a class of conformationally constrained, potent, cell-permeable small-molecule inhibitors to target the SH2 domain in STAT3. Compound 11 (CJ-1383) binds to STAT3 with a K(i) value of 0.95 µM, dose-dependently inhibits cellular STAT3 signaling and cancer cell growth, and induces apoptosis in the MDA-MB-468 cancer cell line with constitutively activated STAT3.

| S-EPMC2892918 | biostudies-literature

Design and synthesis of conformationally constraint Dyrk1A inhibitors by creating an intramolecular H-bond involving a benzothiazole core.

Project description:We present the development of conformationally pre-organised Dyrk1A inhibitors based on the hydroxybenzothiazole urea scaffold. The modifications introduced to the discovered hit (AHS-211) proved the crucial role of the urea linker to preserve the bioactive conformation and led to the development of compound b5 as a promising selective Dyrk1A inhibitor.

| S-EPMC6071757 | biostudies-literature

Structure and dynamics of the essential endogenous mycobacterial polyketide synthase Pks13

Project description: Not available

| EMPIAR-11608 | biostudies-other