RESUMEN
Molecular dynamics with orientational constraints (MDOC) simulations use NMR parameters as tensorial constraints in the stereochemical analysis of small molecules. 13C-31P Residual dipolar couplings-aided MDOC simulations of small phosphorus molecules determined the relative configurations of rigid molecules after including 3JH-H-couplings as additional constraints. However, flexible molecules remain a problem.
RESUMEN
Purine nucleoside phosphorylase (PNP) is a well-known molecular target with potential therapeutic applications in the treatment of T-cell malignancies and/or bacterial/parasitic infections. Here, we report the design, development of synthetic methodology, and biological evaluation of a series of 30 novel PNP inhibitors based on acyclic nucleoside phosphonates bearing a 9-deazahypoxanthine nucleobase. The strongest inhibitors exhibited IC50 values as low as 19 nM (human PNP) and 4 nM (Mycobacterium tuberculosis (Mt) PNP) and highly selective cytotoxicity toward various T-lymphoblastic cell lines with CC50 values as low as 9 nM. No cytotoxic effect was observed on other cancer cell lines (HeLa S3, HL60, HepG2) or primary PBMCs for up to 10 µM. We report the first example of the PNP inhibitor exhibiting over 60-fold selectivity for the pathogenic enzyme (MtPNP) over hPNP. The results are supported by a crystallographic study of eight enzyme-inhibitor complexes and by ADMET profiling in vitro and in vivo.
Asunto(s)
Inhibidores Enzimáticos , Purina-Nucleósido Fosforilasa , Humanos , Purina-Nucleósido Fosforilasa/metabolismo , Inhibidores Enzimáticos/química , CristalografíaRESUMEN
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds 2, 4, and 6 carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC50 = 2.5, 2.7, and 3.0 nM, respectively), where the low nanomolar activity was retained against HXB2 (EC50 = 2.2-2.8 nM) and the K103N and Y181C mutated strains (fold change, 1.2-6.7×). Most importantly, compound 2 exhibited significantly improved phosphate-buffered saline solubility (10.4 µM) compared to ETV and RPV (âª1 µM). Additionally, the binding modes of compounds 2, 4, and 6 to the reverse transcriptase were studied by X-ray crystallography.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Fármacos Anti-VIH/química , VIH-1/metabolismo , Inhibidores de la Transcriptasa Inversa , Transcriptasa Inversa del VIH/metabolismo , Infecciones por VIH/tratamiento farmacológico , Rilpivirina/uso terapéutico , Diseño de FármacosRESUMEN
Ketoconazole (KTZ) is an imidazole drug applied topically to treat numerous skin infections. However, as a systemic antifungal, KTZ' efficacy and safety no longer justify its use as a first-line treatment. Azole conjugates often display higher solubility and better antifungal activities than their parent azoles. Accordingly, we aimed at developing suitable linkers for clickable azole conjugation with a second antifungal molecule, and targeted drug delivery towards improving antifungal activity. For its low price and high availability, we selected KTZ as a molecular scaffold to introduce such chemical modifications. We prepared a series of piperazine-modified KTZ derivatives and we evaluated their inâ vitro antifungal and antitrypanosomal activity against fourteen strains of pathogenic fungi and two strains of Trypanosoma parasites. Several compounds were more effective against the pathogens than KTZ. Compound 5 was 24â times more potent against Aspergillus flavus and 8â times more potent against A. fumigatus than KTZ, with similarly low cytotoxicity to HEK cells up to 100â µM. Derivative 6 had 9- and 7-fold higher activity against T. brucei gambiense and T. brucei brucei than KTZ, respectively, and inhibited trypanosoma growth at single micromolar EC50 values. Combined, our findings will foster further research of piperazine-modified KTZs as promising antifungal and antiparasitic drugs towards enhancing the properties of both KTZ and other azole derivatives.
Asunto(s)
Antifúngicos , Cetoconazol , Cetoconazol/farmacología , Cetoconazol/química , Antifúngicos/farmacología , Antifúngicos/química , AzolesRESUMEN
Conventional Nuclear Magnetic Resonance (NMR) analysis relies on H-H/C-H interactions. However, these interactions are sometimes insufficient for an accurate and precise NMR analysis. In this study, we show that 31P NMR parameters can provide critical structural insights into the stereochemistry of phosphorus-containing compounds. For this purpose, we prepared a set of model phosphorus-based proline derivatives, separated diastereoisomers, and determined their absolute configuration by single-crystal X-ray diffraction. After supplementing these results by electronic circular dichroism (ECD) spectroscopy, we combined experimental data and DFT calculations from our model compounds to perform a detailed conformational analysis, thereby determining their relative configuration. Overall, our findings establish an experimental paradigm for combining 31P NMR spectroscopy with other optical methods to facilitate the stereochemical analysis of phosphorus-containing compounds.
Asunto(s)
Fósforo , Dicroismo Circular , Espectroscopía de Resonancia Magnética , Conformación Molecular , EstereoisomerismoRESUMEN
Nucleos(t)ide analogues entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line monotherapies for chronic hepatitis B (CHB). Multiple HBV genotypes/subgenotypes have been described, but their impact on treatment response remains largely elusive. We investigated the effectiveness of ETV/TDF on HBV/D-subgenotypes, D1/D2/D3/D5, studied the structural/functional differences in subgenotype-specific reverse transcriptase (RT) domains of viral polymerase, and identified novel molecules with robust inhibitory activity on various D-subgenotypes. Transfection of Huh7 cells with full-length D1/D2/D3/D5 and in vitro TDF/ETV susceptibility assays demonstrated that D1/D2 had greater susceptibility to TDF/ETV while D3/D5 exhibited poorer response. Additionally, HBV load was substantially reduced in TDF-treated CHB patients carrying D1/D2 but minimally reduced in D3/D5-infected patients. Comparison of RT sequences of D-subgenotypes led to identification of unique subgenotype-specific residues, and molecular modeling/docking/simulation studies depicted differential bindings of TDF/ETV to the active site of their respective RTs. Replacement of signature residues in D3/D5 HBV clones with corresponding amino acids seen in D1/D2 improved their susceptibility to TDF/ETV. Using high throughput virtual screening, we identified N(9)-[3-fluoro-2-(phosphonomethoxy)propyl] (FPMP) derivatives of purine bases, including N6-substituted (S)-FPMP derivative of 2,6-diaminopurine (DAP) (OB-123-VK), as potential binders of RT of different D-subgenotypes. We synthesized (S)-FPMPG prodrugs (FK-381-FEE/FK-381-SEE/FK-382) and tested their effectiveness along with OB-123-VK. Both OB-123-VK and FK-381-FEE exerted similar antiviral activities against all D-subgenotypes, although FK-381-FEE was more potent. Our study highlighted the natural variation in therapeutic response of D1/D2/D3/D5 and emphasized the need for HBV subgenotype determination before treatment. Novel molecules described here could benefit future design/discovery of pan-D-subgenotypic inhibitors. IMPORTANCE Current treatment of chronic hepatitis B relies heavily on nucleotide/nucleoside analogs in particular, tenofovir disoproxil fumarate (TDF) and entecavir (ETV) to keep HBV replication under control and prevent end-stage liver diseases. However, it was unclear whether the therapeutic effects of TDF/ETV differ among patients infected with different HBV genotypes and subgenotypes. HBV genotype D is the most widespread of all HBV genotypes and multiple D-subgenotypes have been described. We here report that different subgenotypes of HBV genotype-D exhibit variable response toward TDF and ETV and this could be attributed to naturally occurring amino acid changes in the reverse transcriptase domain of the subgenotype-specific polymerase. Further, we identified novel molecules and also synthesized prodrugs that are equally effective on different D-subgenotypes and could facilitate management of HBV/D-infected patients irrespective of D-subgenotype.
Asunto(s)
Antivirales/farmacología , Diseño de Fármacos , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa/farmacología , Antivirales/química , Antivirales/uso terapéutico , Farmacorresistencia Viral/efectos de los fármacos , Farmacorresistencia Viral/genética , Genotipo , Guanina/análogos & derivados , Guanina/química , Guanina/farmacología , Guanina/uso terapéutico , Virus de la Hepatitis B/enzimología , Virus de la Hepatitis B/genética , Hepatitis B Crónica/virología , Humanos , Mutación , Organofosfonatos/química , Organofosfonatos/farmacología , Profármacos , Dominios Proteicos , ADN Polimerasa Dirigida por ARN/química , ADN Polimerasa Dirigida por ARN/genética , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Tenofovir/química , Tenofovir/farmacología , Tenofovir/uso terapéutico , Carga Viral/efectos de los fármacosRESUMEN
This study describes the discovery of novel prodrugs bearing tyrosine derivatives instead of the phenol moiety present in FDA-approved tenofovir alafenamide fumarate (TAF). The synthesis was optimized to afford diastereomeric mixtures of novel prodrugs in one pot (yields up to 86%), and the epimers were resolved using a chiral HPLC column into fast-eluting and slow-eluting epimers. In human lymphocytes, the most efficient tyrosine-based prodrug reached a single-digit picomolar EC50 value against HIV-1 and nearly 300-fold higher selectivity index (SI) compared to TAF. In human hepatocytes, the most efficient prodrugs exhibited subnanomolar EC50 values for HBV and up to 26-fold higher SI compared to TAF. Metabolic studies demonstrated markedly higher cellular uptake of the prodrugs and substantially higher levels of released tenofovir inside the cells compared to TAF. These promising results provide a strong foundation for further evaluation of the reported prodrugs and their potential utility in the development of highly potent antivirals.
Asunto(s)
Amidas/química , Antivirales/farmacología , Descubrimiento de Drogas , Ácidos Fosfóricos/química , Profármacos/farmacología , Tenofovir/farmacología , Antivirales/química , VIH-1/efectos de los fármacos , Virus de la Hepatitis B/efectos de los fármacos , Hepatocitos/virología , Humanos , Pruebas de Sensibilidad Microbiana , Fenol/química , Profármacos/química , Estereoisomerismo , Tenofovir/química , Tirosina/químicaRESUMEN
Amine-containing drugs often show poor pharmacological properties, but these disadvantages can be overcome by using a prodrug approach involving self-immolative linkers. Accordingly, we designed l-lactate linkers as ideal candidates for amine delivery. Furthermore, we designed linkers bearing two different cargos (aniline and phenol) for preferential amine cargo release within 15 min. Since the linkers carrying secondary amine cargo showed high stability at physiological pH, we used our strategy to prepare phosphate-based prodrugs of the antibiotic Ciprofloxacin. Therefore, our study will facilitate the rational design of new and more effective drug delivery systems for amine-containing drugs.
Asunto(s)
Aminas/química , Preparaciones Farmacéuticas/química , Fosfatos/química , Profármacos/química , Antibacterianos/química , Ciprofloxacina/química , Sistemas de Liberación de Medicamentos/métodos , Concentración de Iones de Hidrógeno , Ácido Láctico/químicaRESUMEN
Invited for the cover of this issue are Eliska Procházková, Ondrej Baszczynski, and colleagues at IOCB (Prague) and Charles University (Prague). The image depicts phosphorus-based, double-cargo, self-immolative linkers capable of releasing both cargos sequentially after activation by light. Read the full text of the article at 10.1002/chem.202101805.
Asunto(s)
Fosfatos , HumanosRESUMEN
Phosphorus-based self-immolative (SI) linkers offer a wide range of applications, such as smart materials and drug-delivery systems. Phosphorus SI linkers are ideal candidates for double-cargo delivery platforms because they have a higher valency than carbon. A series of substituted phosphate linkers was designed for releasing two phenolic cargos through SI followed by chemical hydrolysis. Suitable modifications of the lactate spacer increased the cargo release rate significantly, from 1â day to 2â hours or 5â minutes, as shown for linkers containing p-fluoro phenol. In turn, double cargo linkers bearing p-methyl phenol released their cargo more slowly (4â days, 4â hours, and 15â minutes) than their p-fluoro analogues. The α-hydroxyisobutyrate linker released both cargos in 25â minutes. Our study expands the current portfolio of SI constructs by providing a double cargo delivery option, which is crucial to develop universal SI platforms.
Asunto(s)
Sistemas de Liberación de Medicamentos , FosfatosRESUMEN
Helicobacter pylori (Hp) is a human pathogen that lives in the gastric mucosa of approximately 50% of the world's population causing gastritis, peptic ulcers, and gastric cancer. An increase in resistance to current drugs has sparked the search for new Hp drug targets and therapeutics. One target is the disruption of nucleic acid production, which can be achieved by impeding the synthesis of 6-oxopurine nucleoside monophosphates, the precursors of DNA and RNA. These metabolites are synthesized by Hp xanthine-guanine-hypoxanthine phosphoribosyltransferase (XGHPRT). Here, nucleoside phosphonates have been evaluated, which inhibit the activity of this enzyme with Ki values as low as 200 nM. The prodrugs of these compounds arrest the growth of Hp at a concentration of 50 µM in cell-based assays. The kinetic properties of HpXGHPRT have been determined together with its X-ray crystal structure in the absence and presence of 9-[(N-3-phosphonopropyl)-aminomethyl-9-deazahypoxanthine, providing a basis for new antibiotic development.
Asunto(s)
Antibacterianos/química , Proteínas Bacterianas/metabolismo , Pentosiltransferasa/metabolismo , Secuencia de Aminoácidos , Antibacterianos/metabolismo , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Proteínas Bacterianas/química , Sitios de Unión , Cristalografía por Rayos X , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedades Gastrointestinales/microbiología , Enfermedades Gastrointestinales/patología , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/patología , Helicobacter pylori/efectos de los fármacos , Helicobacter pylori/enzimología , Humanos , Hipoxantina Fosforribosiltransferasa/química , Hipoxantina Fosforribosiltransferasa/metabolismo , Hipoxantinas/química , Hipoxantinas/metabolismo , Hipoxantinas/farmacología , Hipoxantinas/uso terapéutico , Cinética , Simulación de Dinámica Molecular , Organofosfonatos/química , Organofosfonatos/metabolismo , Organofosfonatos/farmacología , Organofosfonatos/uso terapéutico , Pentosiltransferasa/química , Profármacos/química , Profármacos/metabolismo , Profármacos/farmacología , Profármacos/uso terapéutico , Alineación de Secuencia , Relación Estructura-ActividadRESUMEN
Self-immolation (SI) is the key principle of ProTide nucleotide prodrugs such as remdesivir, which is currently used to treat COVID-19 patients. Developing novel tailor-made SI systems requires new analytical methods for the detection and monitoring of SI. We developed a robust method for SI analysis using novel phosphate-based SI linkers with NMR traceable cyclic intermediates to distinguish SI from alternative fragmentation pathways and to monitor cargo release in real time.
RESUMEN
Naphthoquinones isolated from Quambalaria cyanescens (quambalarines) are natural pigments possessing significant cytotoxic and antimicrobial properties. Determining the structure of naphthoquinone compounds is important for the understanding of their biological activities and the informed synthesis of related analogues. Identifying quambalarines is challenging, because they contain a hydroxylated naphthoquinone scaffold and have limited solubility. Here, we report a detailed structural study of quambalarine derivatives, which form strong intramolecular hydrogen bonds (IMHBs) that enable the formation of several tautomers; these tautomers may complicate structural investigation due to their fast interconversion. To investigate tautomeric equilibria and identify new quambalarines, we complemented the experimental NMR spectroscopy data with density functional theory (DFT) calculations.
Asunto(s)
Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Basidiomycota/química , Naftoquinonas/farmacología , Antiinfecciosos/química , Antiinfecciosos/aislamiento & purificación , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Enlace de Hidrógeno , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Estructura Molecular , Naftoquinonas/química , Naftoquinonas/aislamiento & purificaciónRESUMEN
Adenosine 5'-diphosphate ribose (ADPR) is an intracellular signalling molecule generated from nicotinamide adenine dinucleotide (NAD+). Synthetic ADPR analogues can shed light on the mechanism of activation of ADPR targets and their downstream effects. Such chemical biology studies, however, are often challenging due to the negatively charged pyrophosphate, also sensitive to cellular pyrophosphatases, and prior work on an initial ADPR target, the transient receptor potential cation channel TRPM2, showed complete pyrophosphate group replacement to be a step too far in maintaining biological activity. Thus, we designed ADPR analogues with just one of the negatively charged phosphate groups removed, by employing a phosphonoacetate linker. Synthesis of two novel phosphonoacetate ADPR analogues is described via tandem N,N'-dicyclohexylcarbodiimide coupling to phosphonoacetic acid. Neither analogue, however, showed significant agonist or antagonist activity towards TRPM2, underlining the importance of a complete pyrophosphate motif in activation of this particular receptor.
RESUMEN
TRPM2 (transient receptor potential cation channel, subfamily M, member 2) is a nonselective cation channel involved in the response to oxidative stress and in inflammation. Its role in autoimmune and neurodegenerative diseases makes it an attractive pharmacological target. Binding of the nucleotide adenosine 5'-diphosphate ribose (ADPR) to the cytosolic NUDT9 homology (NUDT9 H) domain activates the channel. A detailed understanding of how ADPR interacts with the TRPM2 ligand binding domain is lacking, hampering the rational design of modulators, but the terminal ribose of ADPR is known to be essential for activation. To study its role in more detail, we designed synthetic routes to novel analogues of ADPR and 2'-deoxy-ADPR that were modified only by removal of a single hydroxyl group from the terminal ribose. The ADPR analogues were obtained by coupling nucleoside phosphorimidazolides to deoxysugar phosphates. The corresponding C2â³-based analogues proved to be unstable. The C1â³- and C3â³-ADPR analogues were evaluated electrophysiologically by patch-clamp in TRPM2-expressing HEK293 cells. In addition, a compound with all hydroxyl groups of the terminal ribose blocked as its 1â³-ß- O-methyl-2â³,3â³- O-isopropylidene derivative was evaluated. Removal of either C1â³ or C3â³ hydroxyl groups from ADPR resulted in loss of agonist activity. Both these modifications and blocking all three hydroxyl groups resulted in TRPM2 antagonists. Our results demonstrate the critical role of these hydroxyl groups in channel activation.
Asunto(s)
Adenosina Difosfato Ribosa/análogos & derivados , Sondas Moleculares/síntesis química , Sondas Moleculares/metabolismo , Canales Catiónicos TRPM/metabolismo , Técnicas de Química Sintética , Células HEK293 , Humanos , Modelos Moleculares , Sondas Moleculares/química , Conformación Proteica , Canales Catiónicos TRPM/químicaRESUMEN
With the worldwide number of human immunodeficiency virus positive patients stagnant and the increasing emergence of viral strains resistant to current treatment, the development of novel anti-human immunodeficiency virus drug candidates is a perpetual quest of medicinal chemists. Herein, we report a novel group of diarylpyrimidines, non-nucleoside reverse transcriptase inhibitors, which represents an important class of current anti-human immunodeficiency virus therapy. Series of diarylpyrimidines containing o, o-difluorophenyl (A-arm), 4-cyanophenylamino (B-arm), and a small substituent (e.g. NH2, OMe) at positions 2, 4, and 6 of the pyrimidine ring were prepared. The A-arm was modified in the para position (F or OMe) and linked to the central pyrimidine core with a variable spacer (CO, O, NH). Antiviral activities of 20 compounds were measured against wild type human immunodeficiency virus-1 and mutant reverse transcriptase strains (K103N, Y181C) using a cytoprotection assay. To the most promising structural motives belong the o, o-difluoro- p-methoxy A-arm in position 4, and the amino group in position 6 of pyrimidine. Single digit nanomolar activities with no significant toxicity (CC50 > 17,000 nM) were found for compounds 35 (EC50 = 2 nM), 37 (EC50 = 3 nM), and 13 (EC50 = 4 nM) having O, NH, and CO linkers, respectively.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Línea Celular , Cristalografía por Rayos X , Desarrollo de Medicamentos , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , VIH-1/enzimología , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Espectroscopía de Protones por Resonancia Magnética , Pirimidinas/química , Inhibidores de la Transcriptasa Inversa/químicaRESUMEN
Nucleotide prodrugs (ProTides) based on phosphate or phosphonate compounds are potent and successfully marketed antiviral drugs. Although their biological properties are well explored, experimental evidence on the mechanism of their activation pathway is still missing. In this study, we synthesized two ProTide analogues, which can be activated by UV light. Using 31P and 13C NMR spectroscopy with in situ irradiation, we followed the ProTide activation pathway in various solvents, and we detected the first proposed intermediate and the monoamidate product. Furthermore, we used mass spectrometry (MS) coupled with infrared spectroscopy in the gas phase to detect and to characterize the elusive cyclic pentavalent phosphorane and cyclic acyl phosphoramidate intermediates. Our combined NMR and MS data provided the first experimental evidence of the cyclic intermediates in the activation pathway of ProTide prodrugs.
Asunto(s)
Antivirales/química , Nucleótidos/química , Fosforanos/química , Profármacos/química , Amidas/química , Ciclización , Espectroscopía de Resonancia Magnética , Ácidos Fosfóricos/química , Fotólisis , Rayos UltravioletaRESUMEN
While noncanonic xanthine nucleotides XMP/dXMP play an important role in balancing and maintaining intracellular purine nucleotide pool as well as in potential mutagenesis, surprisingly, acyclic nucleoside phosphonates bearing a xanthine nucleobase have not been studied so far for their antiviral properties. Herein, we report the synthesis of a series of xanthine-based acyclic nucleoside phosphonates and evaluation of their activity against a wide range of DNA and RNA viruses. Two acyclic nucleoside phosphonates within the series, namely 9-[2-(phosphonomethoxy)ethyl]xanthine (PMEX) and 9-[3-hydroxy-2-(phosphonomethoxy)propyl]xanthine (HPMPX), were shown to possess activity against several human herpesviruses. The most potent compound was PMEX, a xanthine analogue of adefovir (PMEA). PMEX exhibited a single digit µM activity against VZV (EC50 = 2.6 µM, TK+ Oka strain) and HCMV (EC50 = 8.5 µM, Davis strain), while its hexadecyloxypropyl monoester derivative was active against HSV-1 and HSV-2 (EC50 values between 1.8 and 4.0 µM). In contrast to acyclovir, PMEX remained active against the TK- VZV 07-1 strain with EC50 = 4.58 µM. PMEX was suggested to act as an inhibitor of viral DNA polymerase and represents the first reported xanthine-based acyclic nucleoside phosphonate with potent antiviral properties.
Asunto(s)
Antivirales/farmacología , Citomegalovirus/efectos de los fármacos , Herpesvirus Humano 3/efectos de los fármacos , Nucleósidos/farmacología , Organofosfonatos/farmacología , Xantina/farmacología , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Nucleósidos/síntesis química , Nucleósidos/química , Organofosfonatos/síntesis química , Organofosfonatos/química , Relación Estructura-Actividad , Xantina/síntesis química , Xantina/químicaRESUMEN
Acyclic nucleoside phosphonates (ANPs) are an important class of therapeutic drugs that act as antiviral agents by inhibiting viral DNA polymerases and reverse transcriptases. ANPs containing a 6-oxopurine unit instead of a 6-aminopurine or pyrimidine base are inhibitors of the purine salvage enzyme, hypoxanthine-guanine-[xanthine] phosphoribosyltransferase (HG[X]PRT). Such compounds, and their prodrugs, are able to arrest the growth of Plasmodium falciparum (Pf) in cell culture. A new series of ANPs were synthesized and tested as inhibitors of human HGPRT, PfHGXPRT, and Plasmodium vivax (Pv) HGPRT. The novelty of these compounds is that they contain a five-membered heterocycle (imidazoline, imidazole, or triazole) inserted between the acyclic linker(s) and the nucleobase, namely, 9-deazahypoxanthine. Five of the compounds were found to be micromolar inhibitors of PfHGXPRT and PvHGPRT, but no inhibition of human HGPRT was observed under the same assay conditions. This demonstrates selectivity of these types of compounds for the two parasitic enzymes compared to the human counterpart and confirms the importance of the chemical nature of the acyclic moiety in conferring affinity/selectivity for these three enzymes.
Asunto(s)
Antimaláricos/síntesis química , Hipoxantinas/química , Nucleósidos/síntesis química , Organofosfonatos/síntesis química , Pentosiltransferasa/antagonistas & inhibidores , Plasmodium falciparum/enzimología , Plasmodium vivax/enzimología , Antimaláricos/química , Humanos , Hipoxantina Fosforribosiltransferasa/antagonistas & inhibidores , Modelos Moleculares , Nucleósidos/química , Organofosfonatos/química , Relación Estructura-ActividadRESUMEN
To elucidate the structure-geometry-activity relationship in diarylpyrimidine family (DAPYs) containing carbonyl linker between the central pyrimidine core and phenyl type B-arm, a series of (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones was designed, prepared and tested for their anti-HIV-1 activity. The carbonyl linker bearing B phenyl arm was successfully attached at both C-2 and C-4 positions of the central pyrimidine ring using a new synthetic approach. Further modifications of target compounds are present at C-5 position of the pyrimidine ring. In vitro anti-HIV-1 activity study performed on a series of 22 compounds confirmed the crucial importance of both conformational rigidity between phenyl B arm and the pyrimidine core linked through the carbonyl bridge, as well as presence of fluoro substituents in ortho-positions of phenyl B moiety. The most potent derivative of the series, compound 17, having almost perpendicular angle within the two planes made from the B aromatic arm and the pyrimidine ring, exhibited low nanomolar anti-HIV-1 activity (EC50 = 4 nM) with no significant toxicity (CC50 > 57.1 µM).