RESUMEN
In the context of growing impetus to develop new molecular scaffolds as well as a variety of 3D fragments to escape from flatland, we have reintroduced the accessibility of the underexplored azaheterocyclic amidrazones as promising bioisosteres. Herein, we present an original and versatile approach to synthesize cyclic amidrazones functionalized at different positions of the scaffold in view of diversifying the substitution pattern towards multifunctionalization, extension or fusion of the ring system and 3D-shaping of fragments. This unprecedented synthetic route represents a sweet achievement to cover further lead-like chemical space.
RESUMEN
A linear sequence to access a novel series of C-nucleosides bearing a quaternary carbon at the anomeric position tethered to a 4-substituted 1,2,3-triazole ring is described. Most of the compounds were obtained from a C-1 alkynyl furanoside, by a tandem or two-step CuAAC/functionalisation sequence, along with a diastereoselective cyanation of the furanoside derivatives in acidic conditions.
Asunto(s)
Antivirales , Nucleósidos , Antivirales/farmacología , TriazolesRESUMEN
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
Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. Mycobacterium tuberculosis, the pathogen responsible for TB, uses diverse strategies to survive in a variety of host lesions and to evade immune surveillance. A key question is how robust are our approaches to discovering new TB drugs, and what measures could be taken to reduce the long and protracted clinical development of new drugs. The emergence of multi-drug-resistant strains of M. tuberculosis makes the discovery of new molecular scaffolds a priority, and the current situation even necessitates the re-engineering and repositioning of some old drug families to achieve effective control. Whatever the strategy used, success will depend largely on our proper understanding of the complex interactions between the pathogen and its human host. In this review, we discuss innovations in TB drug discovery and evolving strategies to bring newer agents more quickly to patients.
Asunto(s)
Antituberculosos/uso terapéutico , Descubrimiento de Drogas , Tuberculosis/tratamiento farmacológico , Antituberculosos/química , Antituberculosos/farmacología , Respiración de la Célula/efectos de los fármacos , Ensayos Clínicos como Asunto , Farmacorresistencia Bacteriana , Resistencia a Múltiples Medicamentos , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Mycobacterium tuberculosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Recently, Brinster et al. suggested that type II fatty-acid biosynthesis (FASII) is not a suitable antibacterial target for Gram-positive pathogens because they use fatty acids directly from host serum rather than de novo synthesis. Their findings, if confirmed, are relevant for further scientific and financial investments in the development of new drugs targeting FASII. We present here in vitro and in vivo data demonstrating that their observations do not hold for Staphylococcus aureus, a major Gram-positive pathogen causing several human infections. The observed differences among Gram-positive pathogens in FASII reflects heterogeneity either in fatty-acid synthesis or in the capacity for fatty-acid uptake from the environment.
Asunto(s)
Ácidos Grasos/biosíntesis , Staphylococcus aureus/metabolismo , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Bacteriemia/tratamiento farmacológico , Bacteriemia/microbiología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Ácidos Grasos/metabolismo , Ácidos Grasos/farmacología , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Ratones , Reproducibilidad de los Resultados , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidad , Triclosán/farmacologíaRESUMEN
Respiratory syncytial virus (RSV) is an RNA virus infecting the upper and lower respiratory tract and is recognized as a major respiratory health threat, particularly to older adults, immunocompromised individuals, and young children. Around 64 million children and adults are infected every year worldwide. Despite two vaccines and a new generation monoclonal antibody recently approved, no effective antiviral treatment is available. In this manuscript, we present the medicinal chemistry efforts resulting in the identification of compound 28 (JNJ-8003), a novel RSV non-nucleoside inhibitor displaying subnanomolar activity in vitro as well as prominent efficacy in mice and a neonatal lamb models.
RESUMEN
Emergence of drug-resistant bacteria represents a high, unmet medical need, and discovery of new antibacterials acting on new bacterial targets is strongly needed. ATP synthase has been validated as an antibacterial target in Mycobacterium tuberculosis, where its activity can be specifically blocked by the diarylquinoline TMC207. However, potency of TMC207 is restricted to mycobacteria with little or no effect on the growth of other Gram-positive or Gram-negative bacteria. Here, we identify diarylquinolines with activity against key Gram-positive pathogens, significantly extending the antibacterial spectrum of the diarylquinoline class of drugs. These compounds inhibited growth of Staphylococcus aureus in planktonic state as well as in metabolically resting bacteria grown in a biofilm culture. Furthermore, time-kill experiments showed that the selected hits are rapidly bactericidal. Drug-resistant mutations were mapped to the ATP synthase enzyme, and biochemical analysis as well as drug-target interaction studies reveal ATP synthase as a target for these compounds. Moreover, knockdown of the ATP synthase expression strongly suppressed growth of S. aureus, revealing a crucial role of this target in bacterial growth and metabolism. Our data represent a proof of principle for using the diarylquinoline class of antibacterials in key Gram-positive pathogens. Our results suggest that broadening the antibacterial spectrum for this chemical class is possible without drifting off from the target. Development of the diarylquinolines class may represent a promising strategy for combating Gram-positive pathogens.
Asunto(s)
Complejos de ATP Sintetasa/antagonistas & inhibidores , Antibacterianos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Quinolinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Complejos de ATP Sintetasa/genética , Adenosina Trifosfato/biosíntesis , Secuencia de Aminoácidos , Biopelículas/efectos de los fármacos , Línea Celular Tumoral , Farmacorresistencia Bacteriana/genética , Bacterias Grampositivas/crecimiento & desarrollo , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/crecimiento & desarrollo , Quinolinas/química , Quinolinas/toxicidad , Alineación de Secuencia , Staphylococcus aureus/crecimiento & desarrolloRESUMEN
MurF catalyzes the last cytoplasmic step of bacterial cell wall synthesis and is essential for bacterial survival. Our previous studies used a pharmacophore model of a MurF inhibitor to identify additional inhibitors with improved properties. We now present the characterization of two such inhibitors, the diarylquinolines DQ1 and DQ2. DQ1 inhibited Escherichia coli MurF (50% inhibitory concentration, 24 microM) and had modest activity (MICs, 8 to 16 microg/ml) against lipopolysaccharide (LPS)-defective E. coli and wild-type E. coli rendered permeable with polymyxin B nonapeptide. DQ2 additionally displayed activity against gram-positive bacteria (MICs, 8 to 16 microg/ml), including methicillin (meticillin)-susceptible and -resistant Staphylococcus aureus isolates and vancomycin-susceptible and -resistant Enterococcus faecalis and Enterococcus faecium isolates. Treatment of LPS-defective E. coli cells with >or=2x MIC of DQ1 resulted in a 75-fold-greater accumulation of the MurF substrate compared to the control, a 70% decline in the amount of the MurF product, and eventual cell lysis, consistent with the inhibition of MurF within bacteria. DQ2 treatment of S. aureus resulted in similar effects on the MurF substrate and product quantities. At lower levels of DQ1 (Asunto(s)
Antibacterianos/farmacología
, Bacterias/efectos de los fármacos
, Inhibidores Enzimáticos/farmacología
, Péptido Sintasas/antagonistas & inhibidores
, Quinolinas/farmacología
, Antibacterianos/química
, Enterococcus faecalis/efectos de los fármacos
, Enterococcus faecium/efectos de los fármacos
, Inhibidores Enzimáticos/química
, Escherichia coli/efectos de los fármacos
, Pruebas de Sensibilidad Microbiana
, Estructura Molecular
, Péptido Sintasas/genética
, Péptido Sintasas/fisiología
, Quinolinas/química
, Staphylococcus aureus/efectos de los fármacos
RESUMEN
The diarylquinoline TMC207 kills Mycobacterium tuberculosis by specifically inhibiting ATP synthase. We show here that human mitochondrial ATP synthase (50% inhibitory concentration [IC(50)] of >200 microM) displayed more than 20,000-fold lower sensitivity for TMC207 compared to that of mycobacterial ATP synthase (IC(50) of 10 nM). Also, oxygen consumption in mouse liver and bovine heart mitochondria showed very low sensitivity for TMC207. These results suggest that TMC207 may not elicit ATP synthesis-related toxicity in mammalian cells. ATP synthase, although highly conserved between prokaryotes and eukaryotes, may still qualify as an attractive antibiotic target.
Asunto(s)
Antituberculosos/farmacología , Células Eucariotas/enzimología , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Quinolinas/farmacología , Animales , Bovinos , Línea Celular , Línea Celular Tumoral , Diarilquinolinas , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Ratones , Mitocondrias Cardíacas/metabolismo , Mitocondrias Hepáticas/metabolismo , ATPasas de Translocación de Protón Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/aislamiento & purificación , Consumo de Oxígeno/efectos de los fármacos , Sensibilidad y EspecificidadRESUMEN
Mycobacterium tuberculosis infection results in more than two million deaths per year and is the leading cause of mortality in people infected with HIV. A new structural class of antimycobacterials, the diarylquinolines, has been synthesized and is being highly effective against both M. tuberculosis and multidrug-resistant tuberculosis. As diarylquinolines are biologically active only under their ( R,S) stereoisomeric form, it is essential to differentiate the stereoisomers ( R,S) and ( R,R). To achieve this, tandem mass spectrometry and ion mobility spectrometry-mass spectrometry have been performed with 10 diarylquinoline diastereomers couples. In this study, we investigated cationization with alkali metal cations and several ion mobility drift gases in order to obtain diastereomer differentiations. We have shown that diastereomers of the diarylquinolines family can be differentiated separately by tandem mass spectrometry and in mixture by ion mobility spectrometry-mass spectrometry. However, although the structure of each diastereomer is close, several behaviors could be observed concerning the cationization and the ion mobility spectrometry separation. The ion mobility spectrometry isomer separation efficiency is not easily predictable; it was however observed for all diastereomeric couples with a significant improvement of separation using alkali adducts compared to protonated molecules. With the use of drift gas with higher polarizability only an improvement of separation was obtained in a few cases. Finally, a good correlation of the experimental collision cross section (relative to three-dimensional structure of ions) and the theoretical collision cross section has been shown.
Asunto(s)
Antituberculosos/química , Diarilquinolinas/química , Espectrometría de Movilidad Iónica/métodos , Antituberculosos/uso terapéutico , Diarilquinolinas/uso terapéutico , Humanos , Estructura Molecular , Estereoisomerismo , Tuberculosis/tratamiento farmacológicoRESUMEN
In the search for novel influenza inhibitors we evaluated 7-fluoro-substituted indoles as bioisosteric replacements for the 7-azaindole scaffold of Pimodivir, a PB2 (polymerase basic protein 2) inhibitor currently in clinical development. Specifically, a 5,7-difluoroindole derivative 11a was identified as a potent and metabolically stable influenza inhibitor. 11a demonstrated a favorable oral pharmacokinetic profile and in vivo efficacy in mice. In addition, it was found that 11a was not at risk of metabolism via aldehyde oxidase, an advantage over previously described inhibitors of this class. The crystal structure of 11a bound to influenza A PB2 cap region is disclosed here and deposited to the PDB.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Diseño de Fármacos , Indoles/síntesis química , Indoles/farmacología , Proteínas Virales/efectos de los fármacos , Células A549 , Animales , Antivirales/química , Antivirales/farmacocinética , Cristalografía por Rayos X , Perros , Humanos , Indoles/química , Indoles/farmacocinética , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Células de Riñón Canino Madin Darby , Pruebas de Sensibilidad Microbiana , Estructura MolecularRESUMEN
Diarylquinolines (DARQs) are a new class of potent inhibitors of the ATPase of Mycobacterium tuberculosis. We have created a homology model of a binding site for this class of compounds located on the contact area of the a-subunit (gene atpB) and c-subunits (gene atpE) of Mycobacterium tuberculosis ATPase. The binding pocket that was identified from the analysis of the homology model is formed by 4 helices of three c-subunits and 2 helices of the a-subunit. The lead compound of the DARQ series, R207910, was docked into the pocket using a simulated annealing, multiple conformer, docking algorithm. Different stereoisomers were treated separately. The best docking pose for each stereoisomer was optimized by molecular dynamics simulation on the 5300 atoms of the binding region and ligand. The interaction energies in the computed complexes enable us to rank the different stereoisomers in order of interaction strength with the ATPase binding pockets. We propose that the activity of R207910 against Mycobacterium tuberculosis is based on interference of the compound with the escapement geometry of the proton transfer chain. Upon binding the compound mimics the conserved Arg-186 residue of the a-subunit and interacts in its place with the conserved acidic residue Glu-61 of the c-subunit. This mode of action is corroborated by the good agreement between the computed interaction energies and the observed pattern of stereo-specificity in the model of the binding region.
Asunto(s)
Adenosina Trifosfatasas/antagonistas & inhibidores , Adenosina Trifosfatasas/metabolismo , Simulación por Computador , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Mycobacterium tuberculosis/enzimología , Quinolinas/química , Quinolinas/farmacología , Adenosina Trifosfatasas/química , Secuencia de Aminoácidos , Sitios de Unión , Diarilquinolinas , Fenfluramina , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica , Pliegue de Proteína , Estructura Cuaternaria de Proteína , Subunidades de Proteína/química , Subunidades de Proteína/metabolismo , Alineación de Secuencia , Homología de Secuencia de AminoácidoRESUMEN
We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomolar activity against respiratory syncytial virus (Andries, K.; et al. Antiviral Res. 2003, 60, 209-219). A lead compound of the series was selected for preclinical evaluation. This drug candidate, JNJ-2408068 (formerly R170591, 1), showed long tissue retention times in several species (rat, dog, and monkey), creating cause for concern. We herein describe the optimization program to develop compounds with improved properties in terms of tissue retention. We have identified the aminoethyl-piperidine moiety as being responsible for the long tissue retention time of 1. We have investigated the replacement or the modification of this group, and we suggest that the pKa of this part of the molecules influences both the antiviral activity and the pharmacokinetic profile. We were able to identify new respiratory syncytial virus inhibitors with shorter half-lives in lung tissue.
Asunto(s)
Antivirales/síntesis química , Bencimidazoles/síntesis química , Piperidinas/síntesis química , Piridinas/síntesis química , Virus Sincitiales Respiratorios/efectos de los fármacos , Proteínas Virales de Fusión/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Células HeLa , Humanos , Riñón/metabolismo , Hígado/metabolismo , Pulmón/metabolismo , Masculino , Piperidinas/farmacocinética , Piperidinas/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Distribución TisularRESUMEN
Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials.
Asunto(s)
VIH-1/efectos de los fármacos , Nitrilos/síntesis química , Nitrilos/farmacología , Pirimidinas/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Animales , Cromatografía Líquida de Alta Presión , Perros , Femenino , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas , Ratas Wistar , Rilpivirina , Espectrofotometría UltravioletaRESUMEN
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
In the treatment of AIDS, the efficacy of all drugs, including non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), has been limited by the rapid appearance of drug-resistant viruses. Lys103Asn, Tyr181Cys, and Tyr188Leu are some of the most common RT mutations that cause resistance to NNRTIs in the clinic. We report X-ray crystal structures for RT complexed with three different pyridinone derivatives, R157208, R165481, and R221239, at 2.95, 2.9, and 2.43 A resolution, respectively. All three ligands exhibit nanomolar or subnanomolar inhibitory activity against wild-type RT, but varying activities against drug-resistant mutants. R165481 and R221239 differ from most NNRTIs in that binding does not involve significant contacts with Tyr181. These compounds strongly inhibit wild-type HIV-1 RT and drug-resistant variants, including Tyr181Cys and Lys103Asn RT. These properties result in part from an iodine atom on the pyridinone ring of both inhibitors that interacts with the main-chain carbonyl oxygen of Tyr188. An acrylonitrile substituent on R165481 substantially improves the activity of the compound against wild-type RT (and several mutants) and provides a way to generate novel inhibitors that could interact with conserved elements of HIV-1 RT at the polymerase catalytic site. In R221239, there is a flexible linker to a furan ring that permits interactions with Val106, Phe227, and Pro236. These contacts appear to enhance the inhibitory activity of R221239 against the HIV-1 strains that carry the Val106Ala, Tyr188Leu, and Phe227Cys mutations.
Asunto(s)
Farmacorresistencia Viral , Transcriptasa Inversa del VIH/química , VIH-1/enzimología , Piridonas/química , Inhibidores de la Transcriptasa Inversa/química , Cristalografía por Rayos X , VIH-1/genética , Modelos Moleculares , Estructura Molecular , MutaciónRESUMEN
In a program to optimize the anti-HIV activity of the 4-benzyl and 4-benzoyl-3-dimethylaminopyridinones 9 and 10, lead compounds in a new class of highly potent non-nucleoside type inhibitors of HIV-1 reverse transcriptase, modification of the alkyl substitutents at the C-5 and C-6 positions on the pyridinone ring and of the substitutents on the C-3 amino group has been studied. Of the 17 new 5/6-modified analogues prepared, compounds 31b and 32b substituted at C-5 by an extended nonpolar chain containing an ether function and a C-6 methyl group and compound 35 bearing a C-5 ethyl/C-6 hydroxymethyl substituent pattern were selected on the basis of their in vitro activity against wild-type HIV and the three principle mutant strains, K103N, Y181C, and Y188L. When tested further, it was shown that these molecules, and in particular compound 35, are globally more active than 9, 10, and efavirenz against an additional eight single [L100I, K101E, V106A, E138K, V179E, G190A/S, and F227C] and four double HIV mutant strains [L100I + K103N, K101E + K103N, K103N + Y181C, and F227L + V106A], which are clinically relevant. Concerning modulation of the N-3 substituent, 36 new analogues were prepared. Of these, the N-methyl-N-(2-methoxyethyl)-substituted compounds 40, 42, and 62, as well as the doubly modified compounds 77a and 77b, were selected from the initial screen and were subsequently shown to be active at sub-micromolar concentrations (IC(50)'s) against all the other mutant strains except K103N + Y181C and F227L + V106A. Two possible, but distinct, modes of binding of these analogues in RT were suggested from molecular modeling studies. The preferred mode of binding for compound 62, corresponding to the predicted "orientation 1", was revealed in the X-ray crystal structure of the compound 62-RT complex.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Transcriptasa Inversa del VIH/química , VIH-1/efectos de los fármacos , Piridinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Sitios de Unión , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Transcriptasa Inversa del VIH/genética , Transcriptasa Inversa del VIH/metabolismo , VIH-1/enzimología , VIH-1/aislamiento & purificación , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Mutación , Unión Proteica , Piridinas/química , Piridinas/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
Asunto(s)
Fármacos Anti-VIH/síntesis química , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , Pirimidinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/toxicidad , Línea Celular , Farmacorresistencia Viral , Transcriptasa Inversa del VIH/genética , VIH-1/genética , Humanos , Mutación , Pirimidinas/farmacología , Pirimidinas/toxicidad , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/toxicidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
Asunto(s)
Fármacos Anti-VIH , Nitrilos , Pirimidinas , Administración Oral , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Disponibilidad Biológica , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Genoma Viral , VIH/genética , VIH/aislamiento & purificación , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Comunicación Interdisciplinaria , Modelos Moleculares , Estructura Molecular , Mutación , Nitrilos/síntesis química , Nitrilos/química , Nitrilos/farmacología , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , RilpivirinaRESUMEN
Multidrug-resistant tuberculosis (MDR-TB) is more prevalent today than at any other time in human history. Bedaquiline (BDQ), a novel Mycobacterium-specific adenosine triphosphate (ATP) synthase inhibitor, is the first drug in the last 40 years to be approved for the treatment of MDR-TB. This bactericidal compound targets the membrane-embedded rotor (c-ring) of the mycobacterial ATP synthase, a key metabolic enzyme required for ATP generation. We report the x-ray crystal structures of a mycobacterial c9 ring without and with BDQ bound at 1.55- and 1.7-Å resolution, respectively. The structures and supporting functional assays reveal how BDQ specifically interacts with the rotor ring via numerous interactions and thereby completely covers the c-ring's ion-binding sites. This prevents the rotor ring from acting as an ion shuttle and stalls ATP synthase operation. The structures explain how diarylquinoline chemicals specifically inhibit the mycobacterial ATP synthase and thus enable structure-based drug design of next-generation ATP synthase inhibitors against Mycobacterium tuberculosis and other bacterial pathogens.