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1.
J Med Chem ; 65(8): 6273-6286, 2022 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-35417155

RESUMEN

The muscarinic acetylcholine receptor (mAChR) subtype 5 (M5) represents a novel potential target for the treatment of multiple addictive disorders, including opioid use disorder. Through chemical optimization of several functional high-throughput screening hits, VU6019650 (27b) was identified as a novel M5 orthosteric antagonist with high potency (human M5 IC50 = 36 nM), M5 subtype selectivity (>100-fold selectivity against human M1-4) and favorable physicochemical properties for systemic dosing in preclinical addiction models. In acute brain slice electrophysiology studies, 27b blocked the nonselective muscarinic agonist oxotremorine-M-induced increases in neuronal firing rates of midbrain dopamine neurons in the ventral tegmental area, a part of the mesolimbic dopaminergic reward circuitry. Moreover, 27b also inhibited oxycodone self-administration in male Sprague-Dawley rats within a dose range that did not impair general motor output.


Asunto(s)
Trastornos Relacionados con Opioides , Receptor Muscarínico M5 , Animales , Neuronas Dopaminérgicas , Masculino , Ratas , Ratas Sprague-Dawley , Receptor Muscarínico M1 , Receptores Muscarínicos
2.
Molecules ; 27(3)2022 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-35164376

RESUMEN

There are numerous pyrazine and phenazine compounds that demonstrate biological activities relevant to the treatment of disease. In this review, we discuss pyrazine and phenazine agents that have shown potential therapeutic value, including several clinically used agents. In addition, we cover some basic science related to pyrazine and phenazine heterocycles, which possess interesting reactivity profiles that have been on display in numerous cases of innovative total synthesis approaches, synthetic methodologies, drug discovery efforts, and medicinal chemistry programs. The majority of this review is focused on presenting instructive total synthesis and medicinal chemistry efforts of select pyrazine and phenazine compounds, and we believe these incredible heterocycles offer promise in medicine.


Asunto(s)
Química Farmacéutica , Descubrimiento de Drogas/métodos , Compuestos Heterocíclicos/síntesis química , Fenazinas/química , Pirazinas/química , Humanos
3.
Chem Commun (Camb) ; 58(6): 827-830, 2022 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-34931645

RESUMEN

The use of Pd(OAc)2 as the catalyst and AgOAc as the oxidant enabled the direct regioselective oxidative C-H/C-H cross-coupling of pyrazolo[1,5-a]pyrimidines or pyrazolo[1,5-a]pyridines with various five-membered heteroarenes without the need of pre-activation and/or directing groups. Successful coupling partners include thiophenes, benzothiophenes, thiazoles, furans, oxazoles, indoles and imidazo[1,2-a]pyridines.

4.
ACS Chem Neurosci ; 10(8): 3740-3750, 2019 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-31268669

RESUMEN

Opioid use disorder (OUD) is a debilitating neuropsychiatric condition characterized by compulsive opioid use, dependence, and repeated relapse after periods of abstinence. Given the high risk of developing OUD following prescription opioid use, the continued need for opioid-induced analgesia, and the limitations of current OUD treatments, it is necessary to develop novel, non-opioid-based treatments for OUD and decrease abuse potential of prescription opioids. Recent evidence suggests that negative allosteric modulation (NAM) of the M5 muscarinic acetylcholine receptor (M5 mAChR) may provide an alternative therapeutic approach for the treatment of OUD. Previous studies demonstrated localization of M5 mAChR expression within the mesocorticolimbic reward circuitry and that the selective M5 NAM ML375 attenuates both cocaine and alcohol self-administration in rats. In the present study, the effects of ML375 were evaluated in rats self-administering the µ-opioid agonists oxycodone or remifentanil on a progressive ratio (PR) schedule or on cue reactivity (a rodent model of relapse) in the absence of oxycodone following 72 h of abstinence. ML375 reduced the PR break point for oxycodone and remifentanil self-administration and attenuated cue-elicited responding. Importantly, ML375 did not affect sucrose pellet-maintained responding on a PR schedule or opioid-induced antinociception using the hot-plate and tail-flick assays. We also confirm expression of M5 mAChR mRNA in the ventral tegmental area and show that this is primarily on dopamine (tyrosine hydroxylase mRNA-positive) neurons. Taken together, these findings suggest that selective functional antagonism of the M5 mAChR may represent a novel, non-opioid-based treatment for OUD.


Asunto(s)
Regulación Alostérica/efectos de los fármacos , Narcóticos/administración & dosificación , Nocicepción/efectos de los fármacos , Oxicodona/administración & dosificación , Receptor Muscarínico M5/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Señales (Psicología) , Masculino , Ratas , Ratas Sprague-Dawley , Remifentanilo/administración & dosificación , Recompensa , Autoadministración
5.
J Org Chem ; 84(10): 6459-6464, 2019 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-31039303

RESUMEN

Here, we report the first total synthesis of hinduchelins A-D, a family of nontoxic catechol derivatives from Streptoalloteichus hindustanus, possessing a druglike chemotype and modest iron-chelating ability. A concise synthesis was developed employing methyl 5-methyloxazole-4-carboxylate as a single starting material to provide hinduchelins A-D (and unnatural analogues) in only four steps and 5-15% overall yields; moreover, the stereochemistry of hinduchelin A was reassigned from ( S) to ( R). Biological evaluation confirmed that natural and unnatural hinduchelins are weak iron chelators (siderophores).


Asunto(s)
Catecoles/química , Catecoles/síntesis química , Quelantes del Hierro/química , Quelantes del Hierro/síntesis química , Actinobacteria/química , Técnicas de Química Sintética , Estereoisomerismo
6.
J Med Chem ; 62(17): 7618-7642, 2019 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-30951303

RESUMEN

Bacteria utilize multiple mechanisms that enable them to gain or acquire resistance to antibiotic therapies during the treatment of infections. In addition, bacteria form biofilms which are surface-attached communities of enriched populations containing persister cells encased within a protective extracellular matrix of biomolecules, leading to chronic and recurring antibiotic-tolerant infections. Antibiotic resistance and tolerance are major global problems that require innovative therapeutic strategies to address the challenges associated with pathogenic bacteria. Historically, natural products have played a critical role in bringing new therapies to the clinic to treat life-threatening bacterial infections. This Perspective provides an overview of antibiotic resistance and tolerance and highlights recent advances (chemistry, biology, drug discovery, and development) from various research programs involved in the discovery of new antibacterial agents inspired by a diverse series of natural product antibiotics.


Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Productos Biológicos/farmacología , Farmacorresistencia Microbiana/efectos de los fármacos , Antibacterianos/química , Productos Biológicos/química , Tolerancia a Medicamentos , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular
7.
J Org Chem ; 84(9): 5855-5862, 2019 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-30807155

RESUMEN

Here we report the first synthesis of a family of novel heterocyclic compounds based on a 5-dihydropyrazolo[3',4':5,6]pyrano[3,4- b]pyridine core. In the course of our drug discovery programs, we had need to access the previously unknown 5-dihydropyrazolo[3',4':5,6]pyrano[3,4- b]pyridine core. Initial attempts required long reaction times, which led to degradation and side products. Reaction optimization identified a Pd-catalyzed, microwave-assisted C-H heteroarylation protocol for the rapid, general, and high yielding synthesis of this tricyclic core (as well as related analogs) suitable to drive optimization efforts.

8.
ACS Chem Neurosci ; 10(3): 1025-1034, 2019 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-30280567

RESUMEN

The muscarinic acetylcholine receptor (mAChR) subtype 5 (M5) was the most recent mAChR to be cloned and has since emerged as a potential therapeutic target for a number of indications. Early studies with knockout animals have provided clues to the receptor's role in physiological processes related to Alzheimer's disease, schizophrenia, and addiction, and until recently, useful subtype-selective tools to further probe the pharmacology of M5 have remained elusive. Small-molecule allosteric modulators have since gained traction as a means by which to selectively examine muscarinic pharmacology. This review highlights the discovery and optimization of M5 positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs).


Asunto(s)
Descubrimiento de Drogas/tendencias , Agonistas Muscarínicos/uso terapéutico , Antagonistas Muscarínicos/uso terapéutico , Receptor Muscarínico M5/agonistas , Receptor Muscarínico M5/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/fisiología , Animales , Descubrimiento de Drogas/métodos , Humanos , Agonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/farmacología , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Receptor Muscarínico M5/fisiología , Trastornos Relacionados con Sustancias/tratamiento farmacológico
9.
J Med Chem ; 61(9): 3962-3983, 2018 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-29638121

RESUMEN

Bacterial biofilms are surface-attached communities comprised of nonreplicating persister cells housed within a protective extracellular matrix. Biofilms display tolerance toward conventional antibiotics, occur in ∼80% of infections, and lead to >500000 deaths annually. We recently identified halogenated phenazine (HP) analogues which demonstrate biofilm-eradicating activities against priority pathogens; however, the synthesis of phenazines presents limitations. Herein, we report a refined HP synthesis which expedited the identification of improved biofilm-eradicating agents. 1-Methoxyphenazine scaffolds were generated through a Buchwald-Hartwig cross-coupling (70% average yield) and subsequent reductive cyclization (68% average yield), expediting the discovery of potent biofilm-eradicating HPs (e.g., 61: MRSA BAA-1707 MBEC = 4.69 µM). We also developed bacterial-selective prodrugs (reductively activated quinone-alkyloxycarbonyloxymethyl moiety) to afford HP 87, which demonstrated excellent antibacterial and biofilm eradication activities against MRSA BAA-1707 (MIC = 0.15 µM, MBEC = 12.5 µM). Furthermore, active HPs herein exhibit negligible cytotoxic or hemolytic effects, highlighting their potential to target biofilms.


Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Halogenación , Fenazinas/química , Fenazinas/farmacología , Ciclización , Células HeLa , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/fisiología , Pruebas de Sensibilidad Microbiana
10.
Medchemcomm ; 8(4): 720-724, 2017 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-30108790

RESUMEN

Herein, we disclose the development of a catalyst- and protecting-group-free microwave-enhanced Friedländer synthesis which permits the single-step, convergent assembly of diverse 8-hydroxyquinolines with greatly improved reaction yields over traditional oil bath heating (increased from 34% to 72%). This rapid synthesis permitted the discovery of novel biofilm-eradicating halogenated quinolines (MBECs = 1.0-23.5 µM) active against MRSA, MRSE, and VRE. These small molecules exhibit activity through mechanisms independent of membrane lysis, further demonstrating their potential as a clinically useful treatment option against persistent biofilm-associated infections.

11.
Curr Top Med Chem ; 2016 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-27966398

RESUMEN

Bacterial biofilms are surface-attached communities of slow- or non-replicating bacterial cells that display high levels of tolerance toward conventional antibiotic therapies. It is important to know that our entire arsenal of conventional antibiotics originated from screens used to identify inhibitors of bacterial growth, so it should be little surprise that our arsenal of growth-inhibiting agents have little effect on persistent biofilms. Despite this current state, a diverse collection of natural products and their related or inspired synthetic analogues are emerging that have the ability to kill persistent bacterial biofilms and persister cells in stationary cultures. Unlike conventional antibiotics that hit bacterial targets critical for rapidly-dividing bacteria (i.e., cell wall machinery, bacterial ribosomes), biofilm-eradicating agents operate through unique growth-independent mechanisms. These naturally occurring agents continue to inspire discovery efforts aimed at effectively treating chronic and recurring bacterial infections due to persistent bacterial biofilms.

12.
Int J Antimicrob Agents ; 48(2): 208-11, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27256584

RESUMEN

With the increasing prevalence of fungal infections coupled with emerging drug resistance, there is an urgent need for new and effective antifungal agents. Here we report the antifungal activities of 19 diverse halogenated quinoline (HQ) small molecules against Candida albicans and Cryptococcus neoformans. Four HQ analogues inhibited C. albicans growth with a minimum inhibitory concentration (MIC) of 100 nM, whilst 16 analogues effectively inhibited C. neoformans at MICs of 50-780 nM. Remarkably, two HQ analogues eradicated mature C. albicans and C. neoformans biofilms [minimum biofilm eradication concentration (MBEC) = 6.25-62.5 µM]. Several active HQs were found to penetrate into fungal cells, whilst one inactive analogue was unable to, suggesting that HQs elicit their antifungal activities through an intracellular mode of action. HQs are a promising class of small molecules that may be useful in future antifungal treatments.


Asunto(s)
Antifúngicos/química , Antifúngicos/farmacología , Biopelículas/efectos de los fármacos , Candida albicans/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Quinolinas/química , Quinolinas/farmacología , Candida albicans/fisiología , Cryptococcus neoformans/fisiología , Halogenación , Humanos , Pruebas de Sensibilidad Microbiana
13.
J Med Chem ; 59(8): 3808-25, 2016 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-27018907

RESUMEN

Persistent bacteria, including persister cells within surface-attached biofilms and slow-growing pathogens lead to chronic infections that are tolerant to antibiotics. Here, we describe the structure-activity relationships of a series of halogenated phenazines (HP) inspired by 2-bromo-1-hydroxyphenazine 1. Using multiple synthetic pathways, we probed diverse substitutions of the HP scaffold in the 2-, 4-, 7-, and 8-positions, providing critical information regarding their antibacterial and bacterial eradication profiles. Halogenated phenazine 14 proved to be the most potent biofilm-eradicating agent (≥99.9% persister cell killing) against MRSA (MBEC < 10 µM), MRSE (MBEC = 2.35 µM), and VRE (MBEC = 0.20 µM) biofilms while 11 and 12 demonstrated excellent antibacterial activity against M. tuberculosis (MIC = 3.13 µM). Unlike antimicrobial peptide mimics that eradicate biofilms through the general lysing of membranes, HPs do not lyse red blood cells. HPs are promising agents that effectively target persistent bacteria while demonstrating negligible toxicity against mammalian cells.


Asunto(s)
Biopelículas/efectos de los fármacos , Farmacorresistencia Bacteriana/efectos de los fármacos , Halógenos/química , Mycobacterium tuberculosis/efectos de los fármacos , Fenazinas/química , Fenazinas/farmacología , Espectroscopía de Resonancia Magnética con Carbono-13 , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Espectroscopía de Protones por Resonancia Magnética , Relación Estructura-Actividad
14.
Angew Chem Int Ed Engl ; 54(49): 14819-23, 2015 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-26480852

RESUMEN

Conventional antibiotics are ineffective against non-replicating bacteria (for example, bacteria within biofilms). We report a series of halogenated phenazines (HP), inspired by marine antibiotic 1, that targets persistent bacteria. HP 14 demonstrated the most potent biofilm eradication activities to date against MRSA, MRSE, and VRE biofilms (MBEC = 0.2-12.5 µM), as well as the effective killing of MRSA persister cells in non-biofilm cultures. Frontline MRSA treatments, vancomycin and daptomycin, were unable to eradicate MRSA biofilms or non-biofilm persisters alongside 14. HP 13 displayed potent antibacterial activity against slow-growing M. tuberculosis (MIC = 3.13 µM), the leading cause of death by bacterial infection around the world. HP analogues effectively target persistent bacteria through a mechanism that is non-toxic to mammalian cells and could have a significant impact on treatments for chronic bacterial infections.


Asunto(s)
Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/citología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Fenazinas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium tuberculosis/crecimiento & desarrollo , Fenazinas/síntesis química , Fenazinas/química , Relación Estructura-Actividad
15.
ChemMedChem ; 10(7): 1157-62, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25982664

RESUMEN

With the continued rise of drug-resistant bacterial infections coupled with the current discouraging state of the antibiotic pipeline, the need for new antibacterial agents that operate through unique mechanisms compared with conventional antibiotics and work in synergy with other agents is at an all-time high. We have discovered that gallic acid, a plant-derived phytochemical, dramatically potentiates the antibacterial activities of several halogenated quinolines (up to 11,800-fold potentiation against Staphylococcus aureus) against pathogenic bacteria, including drug-resistant clinical isolates. S. aureus demonstrated the highest sensitivity towards gallic acid-halogenated quinoline combinations, including one halogenated quinoline that demonstrated potentiation of biofilm eradication activity against a methicillin-resistant S. aureus (MRSA) clinical isolate. During our studies, we also demonstrated that these halogenated quionlines operate through an interesting metal(II) cation-dependent mechanism and display promising mammalian cytotoxicity.


Asunto(s)
Antibacterianos/farmacología , Combinación de Medicamentos , Ácido Gálico/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Fitoquímicos/farmacología , Quinolinas/farmacología , Antibacterianos/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ácido Gálico/química , Células HeLa , Humanos , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Fitoquímicos/química , Quinolinas/química , Relación Estructura-Actividad
16.
Bioorg Med Chem Lett ; 24(21): 5076-80, 2014 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-25264073

RESUMEN

Staphylococcus aureus and Staphylococcus epidermidis are recognized as the most frequent cause of biofilm-associated nosocomial and indwelling medical device infections. Biofilm-associated infections are known to be highly resistant to our current arsenal of clinically used antibiotics and antibacterial agents. To exacerbate this problem, no therapeutic option exists that targets biofilm-dependent machinery critical to Staphylococcal biofilm formation and maintenance. Here, we describe the discovery of a series of quinoline small molecules that demonstrate potent biofilm dispersal activity against methicillin-resistant S. aureus and S. epidermidis using a scaffold hopping strategy. This interesting class of quinolines also has select synthetic analogues that demonstrate potent antibacterial activity and biofilm inhibition against S. aureus and S. epidermidis.


Asunto(s)
Antibacterianos/química , Biopelículas/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Quinolinas/química , Quinolinas/farmacología , Staphylococcus epidermidis/efectos de los fármacos , Antibacterianos/farmacología , Evaluación Preclínica de Medicamentos , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad
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