Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of Pyrazolo[1,5-a]pyridine-3-carboxamide Diaryl Derivatives as Drug Resistant Antituberculosis Agents.

ABSTRACT: A series of pyrazolo[1,5-a]pyridine-3-carboxamide (PPA) derivatives bearing diaryl side chain was designed and synthesized as new antituberculosis agents, aiming to improve the efficacy toward drug resistant Mycobacterium tuberculosis (Mtb) strains. Most of the substituted diphenyl and heterodiaryl PPAs exhibited excellent in vitro potency against the drug susceptive H37Rv strain (MIC < 0.002-0.381 ?g/mL) and drug resistant Mtb strains (INH-resistant (rINH), MIC < 0.002-0.465 ?g/mL; RMP-resistant (rRMP), MIC < 0.002-0.004 ?g/mL). Noticeably, some compounds also showed very low cytotoxicity against Vero cells. Further, compound 6j displayed good pharmacokinetic profiles with oral bioavailability (F) of 41% and significantly reduced the bacterial burden in an autoluminescent H37Ra infected mouse model.

SUBMITTER: Hu X

PROVIDER: S-EPMC6421536 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Identification of Pyrazolo[1,5-a]pyridine-3-carboxamide Diaryl Derivatives as Drug Resistant Antituberculosis Agents.

Hu Xianglong X Wan Baojie B Liu Yang Y Shen Jiayi J Franzblau Scott G SG Zhang Tianyu T Ding Ke K Lu Xiaoyun X

ACS medicinal chemistry letters 20190221 3

A series of pyrazolo[1,5-a]pyridine-3-carboxamide (PPA) derivatives bearing diaryl side chain was designed and synthesized as new antituberculosis agents, aiming to improve the efficacy toward drug resistant Mycobacterium tuberculosis (Mtb) strains. Most of the substituted diphenyl and heterodiaryl PPAs exhibited excellent in vitro potency against the drug susceptive H37Rv strain (MIC < 0.002-0.381 μg/mL) and drug resistant Mtb strains (INH-resistant (rINH), MI ...[more]

PMID: 30891129

Similar Datasets

2,3-Diaryl-3H-imidazo[4,5-b]pyridine derivatives as potential anticancer and anti-inflammatory agents.

Project description:In this study we examined the suitability of the 3H-imidazo[4,5-b]pyridine ring system in developing novel anticancer and anti-inflammatory agents incorporating a diaryl pharmacophore. Eight 2,3-diaryl-3H-imidazo[4,5-b]pyridine derivatives retrieved from our in-house database were evaluated for their cytotoxic activity against nine cancer cell lines. The results indicated that the compounds showed moderate cytotoxic activity against MCF-7, MDA-MB-468, K562 and SaOS2 cells, with K562 being the most sensitive among the four cancer cell lines. The eight 2,3-diaryl-3H-imidazo[4,5-b]pyridine derivatives were also evaluated for their COX-1 and COX-2 inhibitory activity in vitro. The results showed that compound 3f exhibited 2-fold selectivity with IC50 values of 9.2 and 21.8 µmol/L against COX-2 and COX-1, respectively. Molecular docking studies on the most active compound 3f revealed a binding mode similar to that of celecoxib in the active site of the COX-2 enzyme.

| S-EPMC5237703 | biostudies-literature

Design, Synthesis, and Biological Evaluation of Pyrazolo[1,5-a]pyridine-3-carboxamides as Novel Antitubercular Agents.

Project description:A series of pyrazolo[1,5-a]pyridine-3-carboxamide derivatives were designed and synthesized as new anti-Mycobacterium tuberculosis (Mtb) agents. The compounds exhibit promising in vitro potency with nanomolar MIC values against the drug susceptive H37Rv strain and a panel of clinically isolated multidrug-resistant Mtb (MDR-TB) strains. One of the representative compounds (5k) significantly reduces the bacterial burden in an autoluminescent H37Ra infected mouse model, suggesting its promising potential to be a lead compound for future antitubercular drug discovery.

| S-EPMC4499832 | biostudies-other

Ethyl 6-methyl-2-p-tolyl-pyrazolo[1,5-a]pyridine-5-carboxyl-ate.

Project description:In the title mol-ecule, C(18)H(18)N(2)O(2), the bicyclic ring system and the benzene ring form a dihedral angle of 13.45?(3)°. In the crystal structure, weak inter-molecular C-H?O hydrogen bonds link mol-ecules into chains propagated along [201].

| S-EPMC2970404 | biostudies-literature

Synthesis and evaluation of new 1,5-diaryl-3-[4-(methyl-sulfonyl)phenyl]-4,5-dihydro-1H-pyrazole derivatives as potential antidepressant agents.

Project description:In an effort to develop potent antidepressant agents, new pyrazoline derivatives 2a-s were synthesized and evaluated for their antidepressant-like activity by tail suspension test (TST) and modified forced swimming test (MFST). The effects of the compounds on spontaneous locomotor activity were also investigated using an activity cage apparatus. Among these derivatives, compounds 2b, 2d, 2f, 2o, and 2r decreased both horizontal and vertical activity number of the mice. On the other hand, compounds 2a, 2h, 2j, 2k, 2l, 2m, and 2n, which did not induce any significant change in the locomotor activity, significantly shortened the immobility time of mice in TST and MFST, representing the presence of the antidepressant-like effect. Additionally, the same compounds increased the swimming time of mice in MFST without any change in climbing duration, similar to the reference drug fluoxetine (10 mg/kg). In the light of previous papers examining the effects of pyrazolines on central nervous system, this study, once more, pointed out remarkable antidepressant activity potential of pyrazoline derivatives.

| S-EPMC6272793 | biostudies-literature

Targeting FtsZ for antituberculosis drug discovery: noncytotoxic taxanes as novel antituberculosis agents.

Project description:Screening of 120 taxanes identified a number of compounds that exhibited significant antituberculosis activity. Rational optimization of selected compounds led to the discovery that the C-seco-taxane-multidrug-resistance (MDR) reversal agents (C-seco-TRAs) are noncytotoxic at the upper limit of solubility and detection (>80 microM), while maintaining MIC(99) values of 1.25-2.5 microM against drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis (MTB). Treatment of MTB cells with TRA 3aa and 10a at the MIC caused filamentation and prolongation of the cells, a phenotypic response to FtsZ inactivation.

| S-EPMC2527599 | biostudies-literature

Discovery of Pyridazinone and Pyrazolo[1,5-a]pyridine Inhibitors of C-Terminal Src Kinase.

Project description:C-terminal Src kinase (CSK) functions as a negative regulator of T cell activation through inhibitory phosphorylation of LCK, so inhibitors of CSK are of interest as potential immuno-oncology agents. Screening of an internal kinase inhibitor collection identified pyridazinone lead 1, and a series of modifications led to optimized compound 13. Compound 13 showed potent activity in biochemical and cellular assays in vitro and demonstrated the ability to increase T cell proliferation induced by T cell receptor signaling. Compound 13 gave extended exposure in mice upon oral dosing and produced a functional response (decrease in LCK phosphorylation) in mouse spleens at 6 h post dose.

| S-EPMC6792176 | biostudies-literature

Advent of Imidazo[1,2-a]pyridine-3-carboxamides with Potent Multi- and Extended Drug Resistant Antituberculosis Activity.

Project description:A set of nine 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamides and one 2,6-dimethylimidazo[1,2-a]pyrimidine-3-carboxamide were synthesized. The compounds were evaluated for their in vitro anti-tuberculosis activity versus replicating, non-replicating, multi- and extensive drug resistant Mtb strains. The MIC(90) values of seven of these agents were ≤ 1 μM against the various tuberculosis strains tested. A representative compound of this class (1) was screened against seven non-tubercular strains as well as other non-mycobacteria organisms and demonstrated remarkable microbe selectivity. A transcriptional profiling experiment of Mtb treated with compound 1 was performed to give a preliminary indication of the mode of action. Lastly, the in vivo ADME properties of compounds 1, 3, 4, and 6 were assessed. The 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamides are a drug-like and synthetically accessible class of anti-TB agents that have excellent selective potency against multi- and extensive drug resistant TB and encouraging pharmacokinetics.

| S-EPMC3117668 | biostudies-literature

Structural Basis for PPAR? Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives.

Project description:Small-molecule agonism of peroxisome proliferator-activated receptor ? (PPAR?), a ligand-activated transcriptional factor involved in regulating fatty acid metabolism, is an important approach for treating dyslipidemia. Here, we determined the structures of the ligand-binding domain (LBD) of PPAR? in complex with 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives, which were recently identified as PPAR?-selective activators with markedly different structures from those of the well-known PPAR? agonists fibrates. The crystal structures of the complexes showed that they form a canonical hydrogen-bond network involving helix 12 in the LBD, which is thought to be essential for PPAR? activation, as also observed for fibrates. However, the phenyl side chain of the compounds occupies a small cavity between Ile272 and Ile354, which is rarely accessed by fibrates. This unique feature may be essential for subtype selectivity and combine with the well-characterized binding mode of fibrates to improve activity. These findings demonstrate the advantage of using 1H-pyrazolo-[3,4-b]pyridine as a skeleton of PPAR? agonists and provide insight into the design of molecules for treating dyslipidemia.

| S-EPMC7203124 | biostudies-literature

Four-component bicyclization approaches to skeletally diverse pyrazolo[3,4-b]pyridine derivatives.

Project description:A novel four-component bicyclization strategy has been established, allowing a flexible and practical approach to 37 examples of multicyclic pyrazolo[3,4-b]pyridines from low-cost and readily accessible arylglyoxals, pyrazol-5-amines, aromatic amines, 4-hydroxy-6-methyl-2H-pyran-2-one, and cyclohexane-1,3-diones. The polysubstituted cyclopenta[d]pyrazolo[3,4-b]pyridines were stereoselectively synthesized through a microwave-assisted special [3+2+1]/[3+2] bicyclization with good control of the spatial configuration of exocyclic double bonds. The novel [3+2+1]/[2+2+1] bicyclization resulted in 17 examples of unreported pyrazolo[3,4-b]pyrrolo[4,3,2-de]quinolones. Reasonable mechanisms for forming two new types of multicyclic pyrazolo[3,4-b]pyridines are also proposed.

| S-EPMC4242041 | biostudies-literature

Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4.

Project description:Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing.

| S-EPMC4468400 | biostudies-literature