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1.
ACS Med Chem Lett ; 10(10): 1480-1485, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31620237

RESUMO

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.

2.
Acta Trop ; 185: 212-218, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29802846

RESUMO

Parasitic worms are receiving much attention as a potential new therapeutic approach to treating autoimmune and allergic conditions but concerns remain regarding their safety. As an alternative strategy, we have focused on the use of defined parasitic worm products and recently taken this one step further by designing drug-like small molecule analogues of one such product, ES-62, which is anti-inflammatory by virtue of covalently attached phosphorylcholine moieties. Previously, we have shown that ES-62 mimics are efficacious in protecting against disease in mouse models of rheumatoid arthritis, systemic lupus erythematosus and skin and lung allergy. Given the potential role of chronic inflammation in fibrosis, in the present study we have focused our attention on lung fibrosis, a debilitating condition for which there is no cure and which in spite of treatment slowly gets worse over time. Two mouse models of fibrosis - bleomycin-induced and LPS-induced - in which roles for inflammation have been implicated were adopted. Four ES-62 analogues were tested - 11a and 12b, previously shown to be active in mouse models of allergic and autoimmune disease and 16b and AIK-29/62 both of which are structurally related to 11a. All four compounds were found to significantly reduce disease development in both fibrosis models, as shown by histopathological analysis of lung tissue, indicating their potential as treatments for this condition.


Assuntos
Anti-Inflamatórios/uso terapêutico , Proteínas de Helminto/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL
3.
J Med Chem ; 60(4): 1379-1399, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28075132

RESUMO

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.


Assuntos
Trifosfato de Adenosina/metabolismo , Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Piridinas/uso terapêutico , Quinina/análogos & derivados , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/química , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Éteres/química , Éteres/farmacocinética , Éteres/farmacologia , Éteres/uso terapêutico , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Quinina/química , Quinina/farmacocinética , Quinina/farmacologia , Quinina/uso terapêutico , Tuberculose/metabolismo
4.
Bioorg Med Chem Lett ; 25(16): 3234-45, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-26087937

RESUMO

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.


Assuntos
Antituberculosos/farmacologia , Piperidinas/farmacologia , Compostos de Espiro/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/farmacocinética , Bactérias/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Genoma Bacteriano , Ensaios de Triagem em Larga Escala , Hipóxia , Lipídeos/química , Metaloproteinase 13 da Matriz/biossíntese , Metaloproteinase 13 da Matriz/genética , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Piperidinas/síntese química , Piperidinas/farmacocinética , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Relação Estrutura-Atividade
5.
ACS Med Chem Lett ; 5(9): 1005-9, 2014 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-25221657

RESUMO

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.

6.
Antimicrob Agents Chemother ; 58(10): 6165-71, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25114134

RESUMO

The Mur ligases play an essential role in the biosynthesis of bacterial peptidoglycan and hence are attractive antibacterial targets. A screen of the AstraZeneca compound library led to the identification of compound A, a pyrazolopyrimidine, as a potent inhibitor of Escherichia coli and Pseudomonas aeruginosa MurC. However, cellular activity against E. coli or P. aeruginosa was not observed. Compound A was active against efflux pump mutants of both strains. Experiments using an E. coli tolC mutant revealed accumulation of the MurC substrate and a decrease in the level of product upon treatment with compound A ,: indicating inhibition of MurC enzyme in these cells. Such a modulation was not observed in the E. coli wild-type cells. Further, overexpression of MurC in the E. coli tolC mutant led to an increase in the compound A MIC by ≥16-fold, establishing a correlation between MurC inhibition and cellular activity. In addition, estimation of the intracellular compound A level showed an accumulation of the compound over time in the tolC mutant strain. A significant compound A level was not detected in the wild-type E. coli strain even upon treatment with high concentrations of the compound. Therefore, the lack of MIC and absence of MurC inhibition in wild-type E. coli were possibly due to suboptimal compound concentration as a consequence of a high efflux level and/or poor permeativity of compound A.


Assuntos
Proteínas de Escherichia coli/metabolismo , Escherichia coli/citologia , Escherichia coli/enzimologia , Peptídeo Sintases/metabolismo , Alanina/metabolismo , Proteínas da Membrana Bacteriana Externa/genética , Proteínas da Membrana Bacteriana Externa/metabolismo , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Mutação , Peptídeo Sintases/genética , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Uridina Difosfato Ácido N-Acetilmurâmico/metabolismo
7.
J Med Chem ; 57(15): 6572-82, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-24967731

RESUMO

Diarylthiazole (DAT), a hit from diversity screening, was found to have potent antimycobacterial activity against Mycobacterium tuberculosis (Mtb). In a systematic medicinal chemistry exploration, we demonstrated chemical opportunities to optimize the potency and physicochemical properties. The effort led to more than 10 compounds with submicromolar MICs and desirable physicochemical properties. The potent antimycobacterial activity, in conjunction with low molecular weight, made the series an attractive lead (antibacterial ligand efficiency (ALE)>0.4). The series exhibited excellent bactericidal activity and was active against drug-sensitive and resistant Mtb. Mutational analysis showed that mutations in prrB impart resistance to DAT compounds but not to reference drugs tested. The sensor kinase PrrB belongs to the PrrBA two component system and is potentially the target for DAT. PrrBA is a conserved, essential regulatory mechanism in Mtb and has been shown to have a role in virulence and metabolic adaptation to stress. Hence, DATs provide an opportunity to understand a completely new target system for antimycobacterial drug discovery.


Assuntos
Antituberculosos/química , Proteínas de Bactérias/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Proteínas Quinases/metabolismo , Tiazóis/química , Animais , Antituberculosos/síntese química , Antituberculosos/farmacologia , Proteínas de Bactérias/genética , Farmacorresistência Bacteriana , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Polimorfismo de Nucleotídeo Único , Proteínas Quinases/genética , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia
8.
J Med Chem ; 57(11): 4761-71, 2014 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-24818517

RESUMO

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.


Assuntos
Antituberculosos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Pirazóis/síntese química , Piridonas/síntese química , Oxirredutases do Álcool , Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/genética , Domínio Catalítico , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mutação , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/isolamento & purificação , Oxirredutases/genética , Pirazóis/química , Pirazóis/farmacologia , Piridonas/química , Piridonas/farmacologia , Relação Estrutura-Atividade
9.
J Med Chem ; 57(12): 5419-34, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24871036

RESUMO

4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by whole genome sequencing of mutants raised against AQs, identified decaprenylphosphoryl-ß-d-ribose 2'-epimerase (DprE1) as the primary target responsible for the antitubercular activity. Mass spectrometry and enzyme kinetic studies indicated that AQs are noncovalent, reversible inhibitors of DprE1 with slow on rates and long residence times of ∼100 min on the enzyme. In general, AQs have excellent leadlike properties and good in vitro secondary pharmacology profile. Although the scaffold started off as a single active compound with moderate potency from the whole cell screen, structure-activity relationship optimization of the scaffold led to compounds with potent DprE1 inhibition (IC50 < 10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb.


Assuntos
Amidas/química , Antituberculosos/química , Proteínas de Bactérias/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Piperidinas/química , Quinolonas/química , Oxirredutases do Álcool , Amidas/farmacocinética , Amidas/farmacologia , Animais , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Farmacorresistência Bacteriana , Genoma Bacteriano , Humanos , Cinética , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mutação , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/genética , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ligação Proteica , Quinolonas/farmacocinética , Quinolonas/farmacologia , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade
10.
J Med Chem ; 56(23): 9701-8, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24215368

RESUMO

We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis in vitro and demonstrates efficacy in mouse tuberculosis models. The series emerged from scaffold morphing efforts and was demonstrated to noncovalently inhibit decaprenylphosphoryl-ß-D-ribose2'-epimerase (DprE1). With "drug-like" properties and no expectation of pre-existing resistance in the clinic, this chemical class has the potential to be developed as a therapy for drug-sensitive and drug-resistant tuberculosis.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Indóis/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Oxirredutases do Álcool , Animais , Antituberculosos/farmacocinética , Antituberculosos/uso terapêutico , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Indóis/farmacocinética , Indóis/farmacologia , Indóis/uso terapêutico , Camundongos , Ratos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
11.
J Microbiol Methods ; 94(2): 152-158, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23747411

RESUMO

Dihydrofolate reductase (DHFR) plays a central role in maintaining cellular pool of tetrahydrofolic acid, a cofactor necessary for DNA, RNA and protein synthesis. The clinical validation of DHFR as antibacterial target was established by the success of trimethoprim (TMP). DHFR is also an attractive target for identifying anti-tuberculosis molecules however, due to observed weak cellular potency, no DHFR inhibitors have been developed as drugs so far. TMP and its analogs have poor cellular potency on Mycobacterium tuberculosis and Mycobacterium smegmatis cells. We found a mutant strain of M. smegmatis, mc²155 to be sensitive to TMP whereas wild type strain was not inhibited by TMP. We utilized this system to probe if poor or lack of activity of TMP is a consequence of poor intracellular compound levels. An LC-MS based method was developed for measuring TMP and rifampicin (RIF) in M. smegmatis. Using the assay, equivalent RIF levels were observed in both strains however, TMP was detected only in mc²155 cells, hence proving a positive correlation between potency and compound levels. To the best of our knowledge this is the first time LC-MS method has been used to measure compound levels in mycobacterial cells. We propose it to be a valuable tool to understand the lack of potency or resistance mechanisms in antimycobacterial drug development.


Assuntos
Antibióticos Antituberculose/análise , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Mycobacterium smegmatis/química , Mycobacterium smegmatis/efeitos dos fármacos , Antibióticos Antituberculose/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Antagonistas do Ácido Fólico/análise , Antagonistas do Ácido Fólico/farmacologia , Mycobacterium smegmatis/enzimologia , Mycobacterium smegmatis/genética , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/genética , Rifampina/análise , Rifampina/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Trimetoprima/análise , Trimetoprima/farmacologia
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