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1.
Bioorg Med Chem ; 101: 117638, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38394996

ABSTRACT

As a result of our continued efforts to pursue Gal-3 inhibitors that could be used to fully evaluate the potential of Gal-3 as a therapeutic target, two novel series of benzothiazole derived monosaccharides as potent (against both human and mouse Gal-3) and orally bioavailable Gal-3 inhibitors, represented by 4 and 5, respectively, were identified. These discoveries were made based on proposals that the benzothiazole sulfur atom could interact with the carbonyl oxygen of G182/G196 in h/mGal-3, and that the anomeric triazole moiety could be modified into an N-methyl carboxamide functionality. The interaction between the benzothiazole sulfur and the carbonyl oxygen of G196 in mGal-3 was confirmed by an X-ray co-crystal structure of early lead 9, providing a rare example of using a S···O binding interaction for drug design. It was found that for both the series, methylation of 3-OH in the monosaccharides caused no loss in h & mGal-3 potencies but significantly improved permeability of the molecules.


Subject(s)
Galectin 3 , Monosaccharides , Animals , Humans , Mice , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Drug Design , Galectin 3/antagonists & inhibitors , Galectins/antagonists & inhibitors , Monosaccharides/chemistry , Monosaccharides/pharmacology , Oxygen , Sulfur
2.
Glycobiology ; 31(10): 1390-1400, 2021 11 18.
Article in English | MEDLINE | ID: mdl-34228782

ABSTRACT

Galectin-3 (Gal-3), a ß-galactoside-binding lectin, has been implicated in a plethora of pathological disorders including fibrosis, inflammation, cancer and metabolic diseases. TD139-a thio-digalactoside inhibitor developed by Galecto Biotech as a potential therapeutic for idiopathic pulmonary fibrosis-is the most advanced small-molecule Gal-3 inhibitor in clinical studies. It binds to human Gal-3 with high affinity but has lower affinity towards mouse and rat homologs, which is also manifested in the differential inhibition of Gal-3 function. Using biophysical methods and high-resolution X-ray co-crystal structures of TD139 and Gal-3 proteins, we demonstrate that a single amino acid change corresponding to A146 in human Gal-3 is sufficient for the observed reduction in the binding affinity of TD139 in rodents. Site-directed mutagenesis of A146V (in human Gal-3) and V160A (in mouse Gal-3) was sufficient to interchange the affinities, mainly by affecting the off rates of the inhibitor binding. In addition, molecular dynamics simulations of both wild-type and mutant structures revealed the sustained favorable noncovalent interactions between the fluorophenyl ring and the active site A146 (human Gal-3 and mouse V160A) that corroborate the finding from biophysical studies. Current findings have ramifications in the context of optimization of drug candidates against Gal-3.


Subject(s)
Blood Proteins , Galectins , Thiogalactosides , Humans , Binding Sites/drug effects , Blood Proteins/antagonists & inhibitors , Blood Proteins/metabolism , Galectins/antagonists & inhibitors , Galectins/metabolism , Thiogalactosides/metabolism , Thiogalactosides/pharmacology
3.
J Chem Inf Model ; 57(3): 445-453, 2017 03 27.
Article in English | MEDLINE | ID: mdl-28257198

ABSTRACT

The development of new antimalarial therapies is essential, and lowering the barrier of entry for the screening and discovery of new lead compound classes can spur drug development at organizations that may not have large compound screening libraries or resources to conduct high-throughput screens. Machine learning models have been long established to be more robust and have a larger domain of applicability with larger training sets. Screens over multiple data sets to find compounds with potential malaria blood stage inhibitory activity have been used to generate multiple Bayesian models. Here we describe a method by which Bayesian quantitative structure-activity relationship models, which contain information on thousands to millions of proprietary compounds, can be shared between collaborators at both for-profit and not-for-profit institutions. This model-sharing paradigm allows for the development of consensus models that have increased predictive power over any single model and yet does not reveal the identity of any compounds in the training sets.


Subject(s)
Antimalarials/pharmacology , Machine Learning , Malaria/drug therapy , Models, Theoretical , Quantitative Structure-Activity Relationship , Antimalarials/therapeutic use , Bayes Theorem , Drug Discovery , Malaria/blood , ROC Curve , Temperature
4.
Antimicrob Agents Chemother ; 60(5): 3132-7, 2016 05.
Article in English | MEDLINE | ID: mdl-26883701

ABSTRACT

A library of compounds covering a broad chemical space was selected from a tuberculosis drug development program and was screened in a whole-cell assay against Mycobacterium ulcerans, the causative agent of the necrotizing skin disease Buruli ulcer. While a number of potent antitubercular agents were only weakly active or inactive against M. ulcerans, five compounds showed high activity (90% inhibitory concentration [IC90], ≤1 µM), making screening of focused antitubercular libraries a good starting point for lead generation against M. ulcerans.


Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Mycobacterium ulcerans/drug effects , Microbial Sensitivity Tests , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Quinolones/pharmacology , Thiazoles/pharmacology
5.
Bioorg Med Chem Lett ; 25(16): 3234-45, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-26087937

ABSTRACT

Whole cell based screens to identify hits against Mycobacterium tuberculosis (Mtb), carried out under replicating and non-replicating (NRP) conditions, resulted in the identification of multiple, novel but structurally related spiropiperidines with potent antitubercular properties. These compounds could be further classified into three classes namely 3-(3-aryl-1,2,4-oxadiazol-5-yl)-1'-alkylspiro[indene-1,4'-piperidine] (abbr. spiroindenes), 4-(3-aryl-1,2,4-oxadiazol-5-yl)-1'-alkylspiro[chromene-2,4'-piperidine] (abbr. spirochromenes) and 1'-benzylspiro[indole-1,4'-piperidin]-2(1H)-one (abbr. spiroindolones). Spiroindenes showed ⩾ 4 log10 kill (at 2-12 µM) on replicating Mtb, but were moderately active under non replicating conditions. Whole genome sequencing efforts of spiroindene resistant mutants resulted in the identification of I292L mutation in MmpL3 (Mycobacterial membrane protein Large), required for the assembly of mycolic acid into the cell wall core of Mtb. MIC modulation studies demonstrated that the mutants were cross-resistant to spirochromenes but not to spiroindolones. This Letter describes lead identification efforts to improve potency while reducing the lipophilicity and hERG liabilities of spiroindenes. Additionally, as deduced from the SAR studies, we provide insights regarding the new chemical opportunities that the spiroindolones can offer to the TB drug discovery initiatives.


Subject(s)
Antitubercular Agents/pharmacology , Piperidines/pharmacology , Spiro Compounds/pharmacology , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacokinetics , Bacteria/drug effects , Drug Resistance, Bacterial/genetics , Genome, Bacterial , High-Throughput Screening Assays , Hypoxia , Lipids/chemistry , Matrix Metalloproteinase 13/biosynthesis , Matrix Metalloproteinase 13/genetics , Mice , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/genetics , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacokinetics , Structure-Activity Relationship
6.
Bioorg Med Chem ; 23(24): 7694-710, 2015 Dec 15.
Article in English | MEDLINE | ID: mdl-26643218

ABSTRACT

We report the discovery of benzothiazoles, a novel anti-mycobacterial series, identified from a whole cell based screening campaign. Benzothiazoles exert their bactericidal activity against Mycobacterium tuberculosis (Mtb) through potent inhibition of decaprenylphosphoryl-ß-d-ribose 2'-oxidase (DprE1), the key enzyme involved in arabinogalactan synthesis. Specific target linkage and mode of binding were established using co-crystallization and protein mass spectrometry studies. Most importantly, the current study provides insights on the utilization of systematic medicinal chemistry approaches to mitigate safety liabilities while improving potency during progression from an initial genotoxic hit, the benzothiazole N-oxides (BTOs) to the lead-like AMES negative, crowded benzothiazoles (cBTs). These findings offer opportunities for development of safe clinical candidates against tuberculosis. The design strategy adopted could find potential application in discovery of safe drugs in other therapy areas too.


Subject(s)
Alcohol Oxidoreductases/metabolism , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Bacterial Proteins/metabolism , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/enzymology , Alcohol Oxidoreductases/antagonists & inhibitors , Bacterial Proteins/antagonists & inhibitors , Drug Design , Humans , Molecular Docking Simulation , Structure-Activity Relationship , Tuberculosis/drug therapy , Tuberculosis/microbiology
7.
J Med Chem ; 67(11): 9731-9744, 2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38807539

ABSTRACT

Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.


Subject(s)
Heart Failure , Potassium Channel Blockers , Animals , Heart Failure/drug therapy , Humans , Rats , Potassium Channel Blockers/therapeutic use , Potassium Channel Blockers/pharmacology , Potassium Channel Blockers/chemistry , Potassium Channel Blockers/pharmacokinetics , Potassium Channel Blockers/chemical synthesis , Structure-Activity Relationship , Potassium Channels, Inwardly Rectifying/antagonists & inhibitors , Potassium Channels, Inwardly Rectifying/metabolism , Drug Discovery , Diuresis/drug effects , Piperazines/pharmacology , Piperazines/chemistry , Piperazines/therapeutic use , Piperazines/chemical synthesis , Piperazines/pharmacokinetics , Male , Rats, Sprague-Dawley
8.
Bioorg Med Chem Lett ; 23(17): 4996-5001, 2013 Sep 01.
Article in English | MEDLINE | ID: mdl-23867166

ABSTRACT

Imidazo[1,2-a]pyridine-8-carboxamides as a novel antimycobacterial lead were generated by whole cell screening of a focused library against Mycobacterium tuberculosis. Herein, we describe the synthesis and structure activity relationship evaluation of this class of inhibitors and the optimization of physicochemical properties. These are selective inhibitors of Mycobacterium tuberculosis with no activity on either gram positive or gram negative pathogens.


Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Pyridines/chemistry , Pyridines/pharmacology , Amides/chemistry , Amides/pharmacology , Humans , Microbial Sensitivity Tests , Models, Molecular , Structure-Activity Relationship , Tuberculosis/drug therapy
9.
J Am Soc Mass Spectrom ; 34(5): 969-976, 2023 May 03.
Article in English | MEDLINE | ID: mdl-37018737

ABSTRACT

A mechanism of unusual tandem (MS/MS) fragmentation of protonated species of N-(triphenyl-λ5-phosphanylidene) derivatives, [M + H]+ to generate triphenylphosphine oxide (TPPO) within the mass spectrometer has been investigated and reported. Collision-induced dissociation of these molecules resulted in the generation of TPPO as a signature fragment. This fragment suggested the presence of a P-O bond in the structure which was contrary to the structure of the compound identified by nuclear magnetic resonance spectrometry (NMR) and single-crystal X-ray diffractometry (SXRD) techniques with a P═N bond rather than a P-O bond. In order to confirm the generation of the TPPO fragment within the mass spectrometer, 14 different N-(triphenyl-λ5-phosphanylidene) derivatives containing amide, 18O-labeled amide, thiamide, and nonacyl phosphazene derivatives were synthesized and their MS/MS behavior was studied by liquid chromatography-high-resolution mass spectrometry. Fragmentation of these amide derivatives generated TPPO/TPPS or their 18O-labeled analogues as the major fragment in almost all cases under similar MS conditions. Based on the outcome of these experiments, a plausible mechanism for such fragmentation, involving the intramolecular shifting of oxygen from carbon to phosphorus, has been proposed. DFT calculations for the protonated species at B3LYP-D3/6-31+G(d,p) further supported the proposed mechanism involving a four-membered ring, P-O-C-N, as the transition state. Details of this work are presented here.

10.
J Med Chem ; 65(16): 11084-11099, 2022 08 25.
Article in English | MEDLINE | ID: mdl-35969688

ABSTRACT

Galectin-3 (Gal-3), a member of the ß-galactoside-binding protein family, is implicated in a wide variety of human diseases. Identification of Gal-3 inhibitors with the right combination of potency (against both human and mouse Gal-3) and pharmacokinetic properties to fully evaluate the potential of Gal-3 for therapeutic intervention has been a major challenge due to the characteristics of its binding pocket: high hydrophilicity and key structural differences between human Gal-3 and the mouse ortholog. We report the discovery of a novel series of monosaccharide-based, highly potent, and orally bioavailable inhibitors of human and mouse Gal-3. The novel monosaccharide derivatives proved to be selective for Gal-3, the only member of the chimeric type of galectins, over Gal-1 and Gal-9, representative of the prototype and tandem-repeat type of galectins, respectively. The proposed binding mode for the newly identified ligands was confirmed by an X-ray cocrystal structure of a representative analogue bound to Gal-3 protein.


Subject(s)
Galectin 3 , Monosaccharides , Animals , Galectin 3/metabolism , Galectins , Humans , Ligands , Mice
11.
ACS Med Chem Lett ; 10(10): 1480-1485, 2019 Oct 10.
Article in English | MEDLINE | ID: mdl-31620237

ABSTRACT

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-ß-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.

12.
J Comput Chem ; 29(7): 1113-30, 2008 May.
Article in English | MEDLINE | ID: mdl-18074338

ABSTRACT

An explicit ion, implicit water solvent model for molecular dynamics was developed and tested with DNA and RNA simulations. The implicit water model uses the finite difference Poisson (FDP) model with the smooth permittivity method implemented in the OpenEye ZAP libraries. Explicit counter-ions, co-ions, and nucleic acid were treated with a Langevin dynamics molecular dynamics algorithm. Ion electrostatics is treated within the FDP model when close to the solute, and by the Coulombic model when far from the solute. The two zone model reduces computation time, but retains an accurate treatment of the ion atmosphere electrostatics near the solute. Ion compositions can be set to reproduce specific ionic strengths. The entire ion/water treatment is interfaced with the molecular dynamics package CHARMM. Using the CHARMM-ZAPI software combination, the implicit solvent model was tested on A and B form duplex DNA, and tetraloop RNA, producing stable simulations with structures remaining close to experiment. The model also reproduced the A to B duplex DNA transition. The effect of ionic strength, and the structure of the counterion atmosphere around B form duplex DNA were also examined.


Subject(s)
Computer Simulation , DNA/chemistry , Models, Chemical , RNA/chemistry , Water/chemistry , Algorithms , Software , Solubility , Solvents/chemistry , Static Electricity , Time Factors
13.
J Med Chem ; 60(4): 1379-1399, 2017 02 23.
Article in English | MEDLINE | ID: mdl-28075132

ABSTRACT

The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report the discovery of two diverse lead series imidazo[1,2-a]pyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial ATP synthesis. Through medicinal chemistry exploration, we established a robust structure-activity relationship of these two scaffolds, resulting in nanomolar potencies in an ATP synthesis inhibition assay. A biochemical deconvolution cascade suggested cytochrome c oxidase as the potential target of IPE class of molecules, whereas characterization of spontaneous resistant mutants of SQAs unambiguously identified ATP synthase as its molecular target. Absence of cross resistance against bedaquiline resistant mutants suggested a different binding site for SQAs on ATP synthase. Furthermore, SQAs were found to be noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis infection.


Subject(s)
Adenosine Triphosphate/metabolism , Antitubercular Agents/therapeutic use , Mycobacterium tuberculosis/drug effects , Pyridines/therapeutic use , Quinine/analogs & derivatives , Tuberculosis/drug therapy , Animals , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/pharmacology , Ethers/chemistry , Ethers/pharmacokinetics , Ethers/pharmacology , Ethers/therapeutic use , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Quinine/chemistry , Quinine/pharmacokinetics , Quinine/pharmacology , Quinine/therapeutic use , Tuberculosis/metabolism
14.
ChemMedChem ; 11(3): 331-9, 2016 Feb 04.
Article in English | MEDLINE | ID: mdl-26751718

ABSTRACT

Nitroarenes are less preferred in drug discovery due to their potential to be mutagenic. However, several nitroarenes were shown to be promising antitubercular agents with specific modes of action, namely, nitroimidazoles and benzothiazinones. The nitro group in these compounds is activated through different mechanisms, both enzymatic and non-enzymatic, in mycobacteria prior to binding to the target of interest. From a whole-cell screening program, we identified a novel lead nitrobenzothiazole (BT) series that acts by inhibition of decaprenylphosphoryl-ß-d-ribose 2'-epimerase (DprE1) of Mycobacterium tuberculosis (Mtb). The lead was found to be mutagenic to start with. Our efforts to mitigate mutagenicity resulted in the identification of 6-methyl-7-nitro-5-(trifluoromethyl)-1,3-benzothiazoles (cBTs), a novel class of antitubercular agents that are non-mutagenic and exhibit an improved safety profile. The methyl group ortho to the nitro group decreases the electron affinity of the series, and is hence responsible for the non-mutagenic nature of these compounds. Additionally, the co-crystal structure of cBT in complex with Mtb DprE1 established the mode of binding. This investigation led to a new non-mutagenic antitubercular agent and demonstrates that the mutagenic nature of nitroarenes can be solved by modulation of stereoelectronic properties.


Subject(s)
Antitubercular Agents/pharmacology , Benzothiazoles/pharmacology , Mutagens/chemistry , Mycobacterium tuberculosis/drug effects , Nitro Compounds/pharmacology , Antitubercular Agents/adverse effects , Antitubercular Agents/chemistry , Benzothiazoles/adverse effects , Benzothiazoles/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Nitro Compounds/adverse effects , Nitro Compounds/chemistry , Stereoisomerism , Structure-Activity Relationship
15.
J Med Chem ; 58(2): 753-66, 2015 Jan 22.
Article in English | MEDLINE | ID: mdl-25486447

ABSTRACT

M. tuberculosis thymidylate kinase (Mtb TMK) has been shown in vitro to be an essential enzyme in DNA synthesis. In order to identify novel leads for Mtb TMK, we performed a high throughput biochemical screen and an NMR based fragment screen through which we discovered two novel classes of inhibitors, 3-cyanopyridones and 1,6-naphthyridin-2-ones, respectively. We describe three cyanopyridone subseries that arose during our hit to lead campaign, along with cocrystal structures of representatives with Mtb TMK. Structure aided optimization of the cyanopyridones led to single digit nanomolar inhibitors of Mtb TMK. Fragment based lead generation, augmented by crystal structures and the SAR from the cyanopyridones, enabled us to drive the potency of our 1,6-naphthyridin-2-one fragment hit from 500 µM to 200 nM while simultaneously improving the ligand efficiency. Cyanopyridone derivatives containing sulfoxides and sulfones showed cellular activity against M. tuberculosis. To the best of our knowledge, these compounds are the first reports of non-thymidine-like inhibitors of Mtb TMK.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Mycobacterium tuberculosis/drug effects , Thymidylate Synthase/antagonists & inhibitors , Binding Sites , Drug Discovery , Enzyme Inhibitors/pharmacology , High-Throughput Screening Assays , Humans , Magnetic Resonance Spectroscopy , Mycobacterium tuberculosis/enzymology , Structure-Activity Relationship , Thymidylate Synthase/chemistry
16.
Chem Commun (Camb) ; (14): 1552-3, 2002 Jul 21.
Article in English | MEDLINE | ID: mdl-12189889

ABSTRACT

Calculated 13C NMR chemical shifts were key to assigning the structures of the conformational forms of complexed and uncomplexed bispidine derivatives.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Metals/chemistry , Chemical Phenomena , Chemistry, Physical , Magnetic Resonance Spectroscopy , Molecular Conformation
17.
J Mol Graph Model ; 20(5): 399-409, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11885961

ABSTRACT

The utility of database searching to identify chiral ligand motifs is outlined. The key elements of three known chiral ligands have been described as bond vectors. The CAVEAT program was then used to screen the Cambridge Structural Database (CSD), portions of the Chemical Abstracts Services three-dimensional database (CAS-3D), and the TRIAD tricyclic structure database for scaffolds containing these elements. Scaffolds corresponding to the known starting points were identified indicating that this method can be used to identify chiral ligand structural motifs. In addition, alternate structural motifs were found that suggested alternative possible ligands.


Subject(s)
Computer-Aided Design , Drug Design , Boranes , Databases, Factual , Ligands , Molecular Structure , Software , Stereoisomerism
18.
ACS Med Chem Lett ; 5(5): 491-5, 2014 May 08.
Article in English | MEDLINE | ID: mdl-24900867

ABSTRACT

A whole cell based screening effort on a focused library from corporate collection resulted in the identification of biarylmethoxy nicotinamides as novel inhibitors of M. tuberculosis (Mtu) H37Rv. The series exhibited tangible structure-activity relationships, and during hit to lead exploration, a cellular potency of 100 nM was achieved, which is an improvement of >200-fold from the starting point. The series is very specific to Mtu and noncytotoxic up to 250 µM as measured in the mammalian cell line THP-1 based cytotoxicity assay. This compound class retains its potency on several drug sensitive and single drug resistant clinical isolates, which indicate that the compounds could be acting through a novel mode of action.

19.
ACS Med Chem Lett ; 5(9): 1005-9, 2014 Sep 11.
Article in English | MEDLINE | ID: mdl-25221657

ABSTRACT

A cellular activity-based screen on Mycobacterium tuberculosis (Mtb) H37Rv using a focused library from the AstraZeneca corporate collection led to the identification of 2-phenylindoles and arylsulphonamides, novel antimycobacterial scaffolds. Both the series were bactericidal in vitro and in an intracellular macrophage infection model, active against drug sensitive and drug resistant Mtb clinical isolates, and specific to mycobacteria. The scaffolds showed promising structure-activity relationships; compounds with submicromolar cellular potency were identified during the hit to lead exploration. Furthermore, compounds from both scaffolds were tested for inhibition of known target enzymes or pathways of antimycobacterial drugs including InhA, RNA polymerase, DprE1, topoisomerases, protein synthesis, and oxidative-phosphorylation. Compounds did not inhibit any of the targets suggesting the potential of a possible novel mode of action(s). Hence, both scaffolds provide the opportunity to be developed further as leads and tool compounds to uncover novel mechanisms for tuberculosis drug discovery.

20.
J Med Chem ; 57(11): 4761-71, 2014 Jun 12.
Article in English | MEDLINE | ID: mdl-24818517

ABSTRACT

A novel pyrazolopyridone class of inhibitors was identified from whole cell screening against Mycobacterium tuberculosis (Mtb). The series exhibits excellent bactericidality in vitro, resulting in a 4 log reduction in colony forming units following compound exposure. The significant modulation of minimum inhibitory concentration (MIC) against a Mtb strain overexpressing the Rv3790 gene suggested the target of pyrazolopyridones to be decaprenylphosphoryl-ß-D-ribose-2'-epimerase (DprE1). Genetic mapping of resistance mutation coupled with potent enzyme inhibition activity confirmed the molecular target. Detailed biochemical characterization revealed the series to be a noncovalent inhibitor of DprE1. Docking studies at the active site suggest that the series can be further diversified to improve the physicochemical properties without compromising the antimycobacterial activity. The pyrazolopyridone class of inhibitors offers an attractive non-nitro lead series targeting the essential and vulnerable DprE1 enzyme for the discovery of novel antimycobacterial agents to treat both drug susceptible and drug resistant strains of Mtb.


Subject(s)
Antitubercular Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , Mycobacterium tuberculosis/drug effects , Oxidoreductases/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyridones/chemical synthesis , Alcohol Oxidoreductases , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Bacterial Proteins/genetics , Catalytic Domain , Drug Resistance, Bacterial , Microbial Sensitivity Tests , Molecular Docking Simulation , Mutation , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/isolation & purification , Oxidoreductases/genetics , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Structure-Activity Relationship
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