RESUMEN
Pyrazolo[1,5-a]pyrimidines have been reported as potent inhibitors of mycobacterial ATP synthase for the treatment of Mycobacterium tuberculosis (M.tb). In this work, we report the design and synthesis of approximately 70 novel 3,5-diphenyl-N-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amines and their comprehensive structure-activity relationship studies. The most effective pyrazolo[1,5-a]pyrimidin-7-amine analogues contained a 3-(4-fluoro)phenyl group, together with a variety of 5-alkyl, 5-aryl and 5-heteroaryl substituents. A range of substituted 7-(2-pyridylmethylamine) derivatives were also active. Some of these compounds exhibited potent in vitro M.tb growth inhibition, low hERG liability and good mouse/human liver microsomal stabilities, highlighting their potential as inhibitors of M.tb.
RESUMEN
During our studies into preparing analogues of pyrazolopyrimidine as ATP synthesis inhibitors of Mycobacterium tuberculosis, a regiospecific condensation reaction between ethyl 4,4,4-trifluoroacetoacetate and 3-(4-fluorophenyl)-1H-pyrazol-5-amine was observed which was dependent on the specific reaction conditions employed. This work identifies optimized reaction conditions to access either the pyrazolo[3,4-ß]pyridine or the pyrazolo[1,5-α]pyrimidine scaffold. This has led to the structural confirmation of the previously reported pyrazolopyrimidine 17b which was reported as pyrazolo[1,5-α]pyrimidine structure 2 which was corrected to pyrazolo[3,4-ß]-pyrimidine 19.
RESUMEN
Drug resistant tuberculsosis (TB) is global health crisis that demands novel treatment strategies. Bacterial ATP synthase inhibitors such as bedaquiline and next-generation analogues (such as TBAJ-876) have shown promising efficacy in patient populations and preclinical studies, respectively, suggesting that selective targeting of this enzyme presents a validated therapeutic strategy for the treatment of TB. In this work, we report tetrahydronaphthalene amides (THNAs) as a new class of ATP synthase inhibitors that are effective in preventing the growth of Mycobacterium tuberculosis (M.tb) in culture. Design, synthesis and comprehensive structure-activity relationship studies for approximately 80 THNA analogues are described, with a small selection of compounds exhibiting potent (in some cases MIC90 <1 µg/mL) in vitro M.tb growth inhibition taken forward to pharmacokinetic and off-target profiling studies. Ultimately, we show that some of these THNAs possess reduced lipophilic properties, decreased hERG liability, faster mouse/human liver microsomal clearance rates and shorter plasma half-lives compared with bedaquiline, potentially addressing of the main concerns of persistence and phospholipidosis associated with bedaquiline.
Asunto(s)
Amidas/química , Antituberculosos/síntesis química , Mycobacterium tuberculosis/efectos de los fármacos , Tetrahidronaftalenos/síntesis química , Animales , Antituberculosos/efectos adversos , Antituberculosos/farmacocinética , Diarilquinolinas/farmacología , Diarilquinolinas/normas , Descubrimiento de Drogas , Humanos , Hígado , Ratones , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Tetrahidronaftalenos/efectos adversos , Tetrahidronaftalenos/farmacocinéticaRESUMEN
A series of 5,8-disubstituted tetrahydroisoquinolines were shown to be effective inhibitors of M. tb in culture and modest inhibitors of M. tb ATP synthase. There was a broad general trend of improved potency with higher lipophilicity. Large substituents (e.g., Bn) at the tetrahydroquinoline 5-position were well-tolerated, while N-methylpiperazine was the preferred 8-substituent. Structure-activity relationships for 7-linked side chains showed that the nature of the 7-linking group was important; -CO- and -COCH2- linkers were less effective than -CH2- or -CONH- ones. This suggests that the positioning of a terminal aromatic ring is important for target binding. Selected compounds showed much faster rates of microsomal clearance than did the clinical ATP synthase inhibitor bedaquiline, and modest inhibition of mycobacterial ATP synthase.
Asunto(s)
Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Tetrahidroisoquinolinas/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/químicaRESUMEN
Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia. To address these issues, we carried out a drug discovery programme to develop an improved second generation analogue of bedaquiline. From this medicinal chemistry program, a candidate (TBAJ-876) has been selected to undergo further preclinical evaluation. During this evaluation, three major metabolites arising from TBAJ-876 were observed in several preclinical animal models. We report here our synthetic efforts to unequivocally structurally characterize these three metabolites through their independent directed synthesis.
Asunto(s)
Diarilquinolinas/química , Diarilquinolinas/farmacología , Animales , Antituberculosos/química , Antituberculosos/farmacología , Fenómenos Químicos , Técnicas de Química Sintética , Diarilquinolinas/síntesis química , Desarrollo de Medicamentos , Humanos , Estructura Molecular , Análisis EspectralRESUMEN
Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.
Asunto(s)
Antituberculosos/farmacología , Diarilquinolinas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Animales , Antituberculosos/síntesis química , Antituberculosos/química , Diarilquinolinas/síntesis química , Diarilquinolinas/química , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium tuberculosis/crecimiento & desarrollo , Relación Estructura-ActividadRESUMEN
Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.
Asunto(s)
Antituberculosos/farmacología , Diarilquinolinas/farmacología , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Mycobacterium tuberculosis/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Piridinas/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Diarilquinolinas/síntesis química , Diarilquinolinas/química , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/química , Piridinas/síntesis química , Piridinas/química , Relación Estructura-ActividadRESUMEN
The ATP-synthase inhibitor bedaquiline is effective against drug-resistant tuberculosis but is extremely lipophilic (clogP 7.25) with a very long plasma half-life. Additionally, inhibition of potassium current through the cardiac hERG channel by bedaquiline, is associated with prolongation of the QT interval, necessitating cardiovascular monitoring. Analogues were prepared where the naphthalene C-unit was replaced with substituted pyridines to produce compounds with reduced lipophilicity, anticipating a reduction in half-life. While there was a direct correlation between in vitro inhibitory activity against M. tuberculosis (MIC90) and compound lipophilicity, potency only fell off sharply below a clogP of about 4.0, providing a useful lower bound for analogue design. The bulk of the compounds remained potent inhibitors of the hERG potassium channel, with notable exceptions where IC50 values were at least 5-fold higher than that of bedaquiline. Many of the compounds had desirably higher rates of clearance than bedaquiline, but this was associated with lower plasma exposures in mice, and similar or higher MICs resulted in lower AUC/MIC ratios than bedaquiline for most compounds. The two compounds with lower potency against hERG exhibited similar clearance to bedaquiline and excellent efficacy in vivo, suggesting further exploration of C-ring pyridyls is worthwhile.
Asunto(s)
Antituberculosos/farmacología , Diarilquinolinas/farmacología , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Mycobacterium tuberculosis/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Piridinas/farmacología , Animales , Antituberculosos/síntesis química , Antituberculosos/química , Diarilquinolinas/síntesis química , Diarilquinolinas/química , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/química , Piridinas/síntesis química , Piridinas/química , Relación Estructura-ActividadRESUMEN
Replacing the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of bicyclic heterocycles of widely differing lipophilicity gave analogs with a 4.5-fold range in clogP values. The biological results for these compounds indicate on average a lower clogP limit of about 5.0 in this series for retention of potent inhibitory activity (MIC90s) against M.tb in culture. Some of the compounds also showed a significant reduction in inhibition of hERG channel potassium current compared with bedaquiline, but there was no common structural feature that distinguished these.
Asunto(s)
Antituberculosos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Diarilquinolinas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Naftalenos/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Línea Celular Tumoral , Diarilquinolinas/química , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Naftalenos/química , Relación Estructura-ActividadRESUMEN
Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives appeared to have an additional contribution to antibacterial potency. The majority of the compounds were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability.
Asunto(s)
Antituberculosos/síntesis química , Diarilquinolinas/química , Compuestos Heterocíclicos/química , Administración Oral , Animales , Antituberculosos/farmacocinética , Antituberculosos/farmacología , Diarilquinolinas/farmacocinética , Diarilquinolinas/farmacología , Canal de Potasio ERG1/antagonistas & inhibidores , Canal de Potasio ERG1/metabolismo , Semivida , Humanos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Ratas , Relación Estructura-ActividadRESUMEN
Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6-substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.
RESUMEN
Novel extended side chain nitroimidazooxazine analogues featuring diverse linker groups between two aryl rings were studied as a potential strategy to improve solubility and oral activity against chronic infection by Mycobacterium tuberculosis. Both lipophilic and highly polar functionalities (e.g., carboxamide, alkylamine, piperazine, piperidine, but not sulfonamide) were well tolerated in vitro, and the hydrophilic linkers provided some solubility improvements, particularly in combination with pyridine rings. Most of the 18 compounds further assessed showed high microsomal stabilities, although in the acute infection mouse model, just one stilbene (6-fold) and two pyridine-containing acetylene derivatives (5-fold and >933-fold) gave in vivo efficacies notably superior to the clinical stage compound pretomanid (PA-824). The most efficacious analogue also displayed outstanding in vivo activity in the stringent chronic model (up to 24-fold better than the drug delamanid and 4-fold greater than our previous best phenylpyridine candidate), with favorable pharmacokinetics, including good oral bioavailability in the rat.
Asunto(s)
Antituberculosos/síntesis química , Antituberculosos/farmacología , Nitroimidazoles/química , Administración Oral , Animales , Antituberculosos/química , Antituberculosos/farmacocinética , Disponibilidad Biológica , Técnicas de Química Sintética , Enfermedad Crónica , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Nitroimidazoles/farmacología , Oxazoles/farmacología , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiologíaRESUMEN
PURPOSE: The human tumour suppressor protein p53 is mutated in nearly half of human tumours and most mutant proteins have single amino acid changes. Several drugs including the quinazoline derivative 1 (CP-31398) have been reported to restore p53 activity in mutant cells. The side chain of 1 contains a styryl linkage that compromises its stability and we wished to explore the activity of analogues containing more stable side chains. METHODS: Reactivation of p53 function was measured by flow cytometry as the ability to potentiate radiation-induced G(1)-phase cell cycle arrest and by western blotting to determine expression of p21(WAF1). DNA binding was measured by competition with ethidium and preliminary pharmacological and xenograft studies were carried out. RESULTS: Screening of analogues for potentiation of radiation-induced G(1)-phase cell cycle arrest using NZOV11, an ovarian tumour cell line containing a p53(R248Q) mutation, demonstrated that the (2-benzofuranyl)-quinazoline derivative 5 was among the most active of the analogues. Compound 5 showed similar effects in several other p53 mutant human tumour cell lines but not in a p53 null cell line. 5 also potentiated p21(WAF1) expression induced by radiation. DNA binding affinity was measured and found to correlate with p53 reactivation activity. Plasma concentrations of 5 in mice were sufficient to suggest in vivo activity and a small induced tumour growth delay (7 days) of NZM4 melanoma xenografts was observed. CONCLUSION: Compound 5 restores p53-like function to a human tumour cells lines expressing a variety of mutant p53 proteins, thus providing a basis for the design of further new drugs.
Asunto(s)
Mutación/efectos de los fármacos , Quinazolinas/farmacología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Animales , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , ADN-Topoisomerasas de Tipo II/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Ratones , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismoRESUMEN
Analogues of clinical tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824), in which the OCH(2) linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metabolism, reduce lipophilicity, and improve aqueous solubility. Several soluble monoaryl examples displayed moderately improved (â¼2- to 4-fold) potencies against replicating Mycobacterium tuberculosis but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivatives mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute M. tuberculosis infection but was poorly soluble. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a soluble, orally bioavailable carbamate analogue providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety.
Asunto(s)
Amidas/síntesis química , Antituberculosos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Carbamatos/síntesis química , Nitroimidazoles/síntesis química , Piperazinas/síntesis química , Urea/síntesis química , Enfermedad Aguda , Amidas/farmacocinética , Amidas/farmacología , Animales , Antituberculosos/farmacocinética , Antituberculosos/farmacología , Disponibilidad Biológica , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacocinética , Compuestos de Bifenilo/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Carbamatos/farmacocinética , Carbamatos/farmacología , Enfermedad Crónica , Perros , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Mycobacterium tuberculosis/efectos de los fármacos , Nitroimidazoles/farmacocinética , Nitroimidazoles/farmacología , Piperazinas/farmacocinética , Piperazinas/farmacología , Ratas , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Tuberculosis Pulmonar/tratamiento farmacológico , Urea/farmacocinética , Urea/farmacologíaRESUMEN
New analogues of antitubercular drug PA-824 were synthesized, featuring alternative side chain ether linkers of varying size and flexibility, seeking drug candidates with enhanced metabolic stability and high efficacy. Both α-methyl substitution and removal of the benzylic methylene were broadly tolerated in vitro, with a biaryl example of the latter class exhibiting an 8-fold better efficacy than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection and negligible fragmentation to an alcohol metabolite in liver microsomes. Extended linkers (notably propenyloxy, propynyloxy, and pentynyloxy) provided greater potencies against replicating M. tb (monoaryl analogues), with propynyl ethers being most effective under anaerobic (nonreplicating) conditions (mono/biaryl analogues). For benzyloxybenzyl and biaryl derivatives, aerobic activity was maximal with the original (OCH(2)) linker. One propynyloxy-linked compound displayed an 89-fold higher efficacy than the parent drug in the acute model, and it was slightly superior to antitubercular drug OPC-67683 in a chronic infection model.
Asunto(s)
Antituberculosos/síntesis química , Nitroimidazoles/síntesis química , Enfermedad Aguda , Animales , Antituberculosos/farmacocinética , Antituberculosos/farmacología , Enfermedad Crónica , Éteres , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Nitroimidazoles/farmacocinética , Nitroimidazoles/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiologíaRESUMEN
New heterocyclic analogues of the potent biphenyl class derived from antitubercular drug PA-824 were prepared, aiming to improve aqueous solubility but maintain high metabolic stability and efficacy. The strategy involved replacement of one or both phenyl groups by pyridine, pyridazine, pyrazine, or pyrimidine, in order to reduce lipophilicity. For para-linked biaryls, hydrophilicities (ClogP) correlated with measured solubilities, but highly soluble bipyridine analogues displayed weak antitubercular activities. A terminal pyridine or proximal heterocycle allowed retention of potency and provided solubility improvements, particularly at low pH, with examples from the latter classes displaying the better in vivo efficacies, high metabolic stabilities, and excellent pharmacokinetics. Five such compounds were >100-fold better than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection, and two orally bioavailable pyridine analogues (3-4-fold more soluble than the parent at low pH) were superior to antitubercular drug OPC-67683 in a chronic infection model.
Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Nitroimidazoles/química , Nitroimidazoles/farmacología , Oxazinas/química , Oxazinas/farmacología , Animales , Antituberculosos/síntesis química , Antituberculosos/uso terapéutico , Modelos Animales de Enfermedad , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos BALB C , Nitroimidazoles/síntesis química , Nitroimidazoles/uso terapéutico , Oxazinas/síntesis química , Oxazinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológicoRESUMEN
Recently described biphenyl analogues of the antituberculosis drug PA-824 displayed improved potencies against M. tuberculosis but were poorly soluble. Heterobiaryl analogues of these, in which the first phenyl ring was replaced with various 5-membered ring heterocycles, were prepared with the aim of identifying potent new candidates with improved aqueous solubility. The compounds were constructed by coupling the chiral 2-nitroimidazooxazine alcohol with various halomethyl-substituted arylheterocycles, by cycloadditions to a propargyl ether derivative of this alcohol, or by Suzuki couplings on haloheterocyclic methyl ether derivatives. The arylheterocyclic compounds were all more hydrophilic than their corresponding biphenyl analogues, and several showed solubility improvements. 1-Methylpyrazole, 1,3-linked-pyrazole, 2,4-linked-triazole, and tetrazole analogues had 3- to 7-fold higher MIC potencies against replicating M. tb than predicted by their lipophilicities. Two pyrazole analogues were >10-fold more efficacious than the parent drug in a mouse model of acute M. tb infection, and one displayed a 2-fold higher solubility.
Asunto(s)
Antituberculosos/síntesis química , Oxazinas/síntesis química , Animales , Antituberculosos/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Oxazinas/farmacología , Pirazoles , Solubilidad , Relación Estructura-ActividadRESUMEN
A series of biphenyl analogues of the new tuberculosis drug PA-824 was prepared, primarily by coupling the known (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol with iodobenzyl halides, followed by Suzuki coupling of these iodides with appropriate arylboronic acids or by assembly of the complete biaryl side chain prior to coupling with the above alcohol. Antitubercular activity was determined under both replicating (MABA) and nonreplicating (LORA) conditions. para-Linked biaryls were the most active, followed by meta-linked and then ortho-linked analogues. A more detailed study of a larger group of para-linked analogues showed a significant correlation between potency (MABA) and both lipophilicity (CLOGP) and the electron-withdrawing properties of terminal ring substituents ( summation operatorsigma). Selected compounds were evaluated for their efficacy in a mouse model of acute Mycobacterium tuberculosis infection. In vivo activity correlated well with the stability of compounds to microsomal metabolism. Three compounds bearing combinations of lipophilic, electron-withdrawing groups achieved >200-fold higher efficacies than the parent drug.
Asunto(s)
Antituberculosos/síntesis química , Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Nitroimidazoles/síntesis química , Nitroimidazoles/farmacología , Animales , Antituberculosos/química , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Nitroimidazoles/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Several enones are converted into their alpha-iodo derivatives in excellent yields and carbonylated with palladium catalysis in the presence of alcohol or amines to the alpha-carbonyl enones in satisfactory yields.