RESUMEN
In the context of Alzheimer's disease, copper (Cu) can be loosely bound to the amyloid-ß (Aß) peptide, leading to the formation of CuAß, which can catalytically generate reactive oxygen species that contribute to oxidative stress. To fight against this phenomenon, the chelation therapy approach has been developed and consists of using a ligand able to remove Cu from Aß and to redox-silence it, thus stopping the reactive oxygen species (ROS) production. A large number of Cu(II) chelators has been studied, allowing us to define and refine the properties required to design a "good" ligand, but without strong therapeutic outcomes to date. Those chelators targeted the Cu(II) redox state. Herein, we explore a parallel and relevant alternative pathway by designing a chelator able to target the Cu(I) redox state. To that end, we designed LH2 ([1N3S] binding set) and demonstrated that (i) it is perfectly able to extract Cu(I) from Cu(I)Aß even in the presence of an excess of Zn(II) and (ii) it redox-silences the Cu, preventing the formation of ROS. We showed that LH2 that is sensitive to oxidation can efficiently replace the [Zn(II)L] complex without losing its excellent ability to stop the ROS production while increasing its resistance to oxidation.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ligandos , Péptidos beta-Amiloides/química , Cobre/química , Quelantes/químicaRESUMEN
Hura crepitans L. (Euphorbiaceae) is a thorn-covered tree widespread in South America, Africa and Asia which produces an irritating milky latex containing numerous secondary metabolites, notably daphnane-type diterpenes known as Protein Kinase C activators. Fractionation of a dichloromethane extract of the latex led to the isolation of five new daphnane diterpenes (1-5), along with two known analogs (6-7) including huratoxin. Huratoxin (6) and 4',5'-epoxyhuratoxin (4) were found to exhibit significant and selective cell growth inhibition against colorectal cancer cell line Caco-2 and primary colorectal cancer cells cultured as colonoids. The underlying mechanism of 4 and 6 was further investigated revealing the involvement of PKCζ in the cytostatic activity.
Asunto(s)
Neoplasias Colorrectales , Diterpenos , Euphorbiaceae , Humanos , Látex , Células CACO-2 , Diterpenos/farmacología , Neoplasias Colorrectales/tratamiento farmacológicoRESUMEN
Biofilm formation is considered a major cause of therapeutic failure because bacteria in biofilms have higher protection against antimicrobials. Thus, biofilm-related infections are extremely challenging to treat and pose major concerns for public health, along with huge economic impacts. Pseudomonas aeruginosa, in particular, is a "critical priority" pathogen, responsible for severe infections, especially in cystic fibrosis patients because of its capacity to form resistant biofilms. Therefore, new therapeutic approaches are needed to complete the pipeline of molecules offering new targets and modes of action. Biofilm formation is mainly controlled by Quorum Sensing (QS), a communication system based on signaling molecules. In the present study, we employed a molecular docking approach (Autodock Vina) to assess two series of chromones-based compounds as possible ligands for PqsR, a LuxR-type receptor. Most compounds showed good predicted affinities for PqsR, higher than the PQS native ligand. Encouraged by these docking results, we synthesized a library of 34 direct and 25 retro chromone carboxamides using two optimized routes from 2-chromone carboxylic acid as starting material for both series. We evaluated the synthesized carboxamides for their ability to inhibit the biofilm formation of P. aeruginosa in vitro. Overall, results showed several chromone 2-carboxamides of the retro series are potent inhibitors of the formation of P. aeruginosa biofilms (16/25 compound with % inhibition ≥ 50% at 50 µM), without cytotoxicity on Vero cells (IC50 > 1.0 mM). The 2,4-dinitro-N-(4-oxo-4H-chromen-2-yl) benzamide (6n) was the most promising antibiofilm compound, with potential for hit to lead optimization.
RESUMEN
G-quadruplex nucleic acids (G4s) are RNA and DNA secondary structures involved in the regulation of multiple key biological processes. They can be found in telomeres, oncogene promoters, RNAs, but also in viral genomes. Due to their unique structural features, very distinct from the canonical duplexes or single-strands, G4s represent promising pharmacological targets for small molecules, namely G4-ligands. Gold(III) penta-cationic porphyrins, as specific G4 ligands, are able to inhibit HIV-1 infectivity and their antiviral activity correlates with their affinity for G4s. Up to now, one of the best antiviral compounds is meso-5,10,15,20-tetrakis[4-(N-methyl-pyridinium-2-yl)phenyl]porphyrinato gold(III) (1). Starting from this compound, we report a structure/affinity relationship study of gold(III) cationic porphyrins to find out the best porphyrin candidate for functionalization, in order to study the antiviral mechanism of action of these gold(III) porphyrins.
Asunto(s)
Fármacos Anti-VIH/metabolismo , ADN/metabolismo , G-Cuádruplex , Metaloporfirinas/metabolismo , Fármacos Anti-VIH/síntesis química , ADN/genética , Oro/química , VIH-1/química , Metaloporfirinas/síntesis química , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Cyclic polymers display unique physicochemical and biological properties. However, their development is often limited by their challenging preparation. In this work, we present a simple route to cyclic poly(α-peptoids) from N-alkylated-N-carboxyanhydrides (NNCA) using LiHMDS promoted ring-expansion polymerization (REP) in DMF. This new method allows the unprecedented use of lysine-like monomers in REP to design bioactive macrocycles bearing pharmaceutical potential against Clostridioides difficile, a bacterium responsible for nosocomial infections.
Asunto(s)
Peptoides/química , Polímeros/química , Compuestos de Trimetilsililo/química , Catálisis , Línea Celular , Supervivencia Celular/efectos de los fármacos , Clostridioides difficile/efectos de los fármacos , Ciclización , Teoría Funcional de la Densidad , Humanos , Pruebas de Sensibilidad Microbiana , Polimerizacion , Polímeros/síntesis química , Polímeros/farmacologíaRESUMEN
While depsidones, depsides or dibenzofuran-like compounds dominate the chemical composition of lichens, the cyanolichen Nephroma laevigatum affords a diversity of quinoid pigments represented by chlorinated anthraquinones derived from emodin and new bianthrones resulting from the homo- or heterodimerization of monomers. Bianthrones were pointed out from the dichloromethane extract by MS/MS-based molecular networking, then isolated and characterized on the basis of extensive spectroscopic analyzes and GIAO NMR shift calculation followed by CP3 analyzes.
Asunto(s)
Antracenos/química , Antraquinonas/química , Ascomicetos/química , Líquenes/química , Antracenos/aislamiento & purificación , Antraquinonas/aislamiento & purificación , Francia , Espectroscopía de Resonancia Magnética , Estructura Molecular , Espectrometría de Masas en TándemRESUMEN
Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs.
Asunto(s)
Antihelmínticos , Antimaláricos , Plasmodium falciparum/crecimiento & desarrollo , Schistosoma mansoni/crecimiento & desarrollo , Animales , Antihelmínticos/síntesis química , Antihelmínticos/química , Antihelmínticos/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Antimaláricos/farmacología , HumanosRESUMEN
To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program.
Asunto(s)
Imidazoles/química , Imidazoles/farmacología , Piridinas/química , Piridinas/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Animales , Daño del ADN/efectos de los fármacos , Descubrimiento de Drogas , Células Hep G2 , Humanos , Imidazoles/metabolismo , Imidazoles/farmacocinética , Concentración 50 Inhibidora , Ratones , Pruebas de Sensibilidad Parasitaria , Piridinas/metabolismo , Piridinas/farmacocinética , Albúmina Sérica/metabolismo , Relación Estructura-Actividad , Tripanocidas/metabolismo , Tripanocidas/farmacocinéticaRESUMEN
An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC50 blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs. Among these hit molecules, compound 19 also showed the same level of activity against T. cruzi (EC50 amastigotes = 1.2 µM) as benznidazole and fexinidazole. An in vitro comet assay showed that nitroaromatic derivative 19 was not genotoxic. It displayed a low redox potential value (-0.68 V/NHE) and was shown to be bioactivated by type 1 nitroreductases both in Leishmania and Trypanosoma. The SAR study indicated that an alcohol function improved aqueous solubility while maintaining good activity and low cytotoxicity when the hydroxyl group was at position beta of the alkyne triple bond. Hit-compound 19 was also evaluated regarding in vitro pharmacokinetic data: 19 is BBB permeable (PAMPA assay), has a 16 min microsomal half-life and a high albumin binding (98.5%). Moreover, compound 19 was orally absorbed and was well tolerated in mouse after both single and repeated administrations at 100 mg/kg. Its mouse plasma half-life (10 h) is also quite encouraging, paving the way toward further efficacy evaluations in parasitized mouse models, looking for a novel antitrypanosomal lead compound.
Asunto(s)
Nitroimidazoles/farmacología , Piridinas/farmacología , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estructura Molecular , Nitroimidazoles/síntesis química , Nitroimidazoles/química , Pruebas de Sensibilidad Parasitaria , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/químicaRESUMEN
An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC50 ≤ 13 µM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = -0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds.
RESUMEN
Tyrosine kinase inhibitors (TKI) are targeted anticancer drugs that have been successfully developed over the past 2 decades. To date, many of them (around 70%) require warnings for liver injury and five of them, including pazopanib and sunitinib, have Black Box Warning (BBW) labels. Although TKI-induced hepatotoxicity is the first cause of drug failures in clinical trials, BBW labels, and market withdrawals, the underlying mechanisms remain unclear. However, the recent discovery of new reactive metabolites (RM) with aldehyde structures during pazopanib and sunitinib metabolism offers new perspectives for investigating their involvement in the toxicity of these two TKI. These hard electrophiles have a high reactivity potential toward proteins and are thought to be responsible for cytochrome P450 inactivation, drug-drug interactions (DDI), and liver toxicity. We report here, for the first time, the presence of these aldehyde RM in human plasma samples obtained during drug monitoring. Docking experiments in the CYP3A4 active site were performed and showed that pazopanib and sunitinib fitting in the catalytic site are in accordance with their regioselective oxidation to aldehydes. They also suggested that aldehyde RM may react with lysine and arginine residues. Based on these results, we studied the reactivity of the aldehyde RM toward lysine and arginine residues as potential targets on the protein framework to better understand how these RM could be involved in liver toxicity and drug-drug interactions. Adduct formation with different hepatic and plasma proteins was investigated by LC-MS/MS, and adducts between pazopanib or sunitinib aldehyde derivatives and lysine residues on both CYP3A4 and plasma proteins were indeed shown for the first time.
Asunto(s)
Aldehídos/metabolismo , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/farmacocinética , Sulfonamidas/farmacocinética , Sunitinib/farmacocinética , Aldehídos/sangre , Inhibidores de la Angiogénesis/efectos adversos , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Humanos , Indazoles , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Proteínas Recombinantes/metabolismo , Albúmina Sérica Humana/metabolismo , Sulfonamidas/efectos adversos , Sunitinib/efectos adversosRESUMEN
Porphyrins represent a valuable class of ligands for G-quadruplex nucleic acids. Herein, we evaluate the binding of cationic porphyrins metallated with gold(iii) to G-quadruplex DNA and we compare it with other porphyrin derivatives. The G-quadruplex stabilization capacity and the selectivity of the various porphyrins were evaluated by biophysical and biochemical assays. The porphyrins were also tested as inhibitors of telomerase. It clearly appeared that the insertion of gold(iii) ion in the center of the porphyrin increases the binding affinity of the porphyrin for the G-quadruplex target. Together with modelling studies, it is possible to propose that the insertion of the square planar gold(iii) ion adds an extra positive charge on the complex and decreases the electron density in the porphyrin aromatic macrocycle, both properties being in favour of stronger electrostatic and π-staking interactions.
RESUMEN
Three thiodiketopiperazines, botryosulfuranols A-C (1-3) were isolated from the endophytic fungus Botryosphaeria mamane. The three compounds present sulfur atoms on α- and ß-positions of phenylalanine derived residues and unprecedented two spirocyclic centers at C-4 and C-2'. Their planar structures were determined by spectroscopic analysis and absolute configurations were achieved by X-ray diffraction analysis and ECD and NMR chemical shifts calculations. Botryosulfuranol A (1) was the most cytotoxic compound against four cancer cell lines (HT-29, HepG2, Caco-2, HeLa) and two healthy cell lines (IEC6, Vero) highlighting the importance of an electrophilic center for cell growth inhibition.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Ascomicetos/química , Dicetopiperazinas/química , Dicetopiperazinas/farmacología , Antineoplásicos/aislamiento & purificación , Ascomicetos/fisiología , Bixaceae/microbiología , Células CACO-2 , Línea Celular , Dicroismo Circular , Cristalografía por Rayos X , Dicetopiperazinas/aislamiento & purificación , Ensayos de Selección de Medicamentos Antitumorales , Endófitos/química , Células HT29 , Células HeLa , Células Hep G2 , Humanos , Espectroscopía de Resonancia Magnética , Estructura MolecularRESUMEN
Oxidative RNA damage is linked to cell dysfunction and diseases. The present work focuses on the in vitro oxidation of 5-methylaminomethyl uridine (mnm5U), which belongs to the numerous post-transcriptional modifications that are found in tRNA. The reaction of oxone with mnm5U in water at pH 7.5 leads to two aldonitrone derivatives. They form by two oxidation steps and one dehydration step. Therefore, the potential oxidation products of mnm5U in vivo may not be only aldonitrones, but also hydroxylamine and imine derivatives (which may be chemically more reactive). Irradiation of aldonitrone leads to unstable oxaziridine derivatives that are susceptible to isomerization to amide or to hydrolysis to aldehyde derivative.
Asunto(s)
Aldehídos/química , Ácidos Sulfúricos/farmacología , Uridina/análogos & derivados , Oscuridad , Conformación Molecular , Oxidación-Reducción , Procesos Fotoquímicos , Espectroscopía de Protones por Resonancia Magnética , Espectrofotometría Ultravioleta , Uridina/metabolismoRESUMEN
Incorporating charged amino acid side chains in polypeptide polymer backbones to improve solubility usually leads to reduced secondary structuring. Here we show that highly water soluble (>15 mg.mL-1) ß-sheets can be obtained via nucleotide monophosphate grafting onto simple poly(γ-propargyl- L-glutamate) backbone. This synthetic methodology has been applied to the synthesis of thymidine-based nucleopolypeptides presenting stable ß-sheet conformation in aqueous solutions with pH values comprised between 4 and 8. These polymeric analogues of nucleoproteins exhibited selective interaction with simple DNA sequences displaying adenine.
Asunto(s)
ADN/química , ADN/metabolismo , Péptidos/química , Polímeros/química , Agua/química , Concentración de Iones de Hidrógeno , Iones , Modelos Moleculares , Estructura Molecular , Conformación Proteica en Lámina betaRESUMEN
Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3⯵M range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L. donovani. The two molecules presented a good activity (IC50â¯=â¯1.2-1.3⯵M) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3⯵M), slightly lower than the one of miltefosine (IC50â¯=â¯4.3⯵M). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50â¯=â¯0.04-0.16⯵M) and selective (SI = >313 to 550) molecules toward T. brucei brucei, in comparison with drug-candidate fexinidazole (IC50â¯=â¯0.6 & SIâ¯>â¯333) or reference drugs suramin and eflornithine (respective IC50â¯=â¯0.03 and 13.3⯵M). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L. donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTR1), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83â¯V), ranging from -0.70 to -0.64â¯V.
Asunto(s)
Antineoplásicos/farmacología , Leishmania donovani/efectos de los fármacos , Nitrorreductasas/metabolismo , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Leishmania donovani/metabolismo , Modelos Moleculares , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Tripanocidas/química , Tripanocidas/metabolismo , Trypanosoma brucei brucei/metabolismoRESUMEN
To study the antiparasitic 8-nitroquinolin-2(1H)-one pharmacophore, a series of 31 derivatives was synthesized in 1-5 steps and evaluated in vitro against both Leishmania infantum and Trypanosoma brucei brucei. In parallel, the reduction potential of all molecules was measured by cyclic voltammetry. Structure-activity relationships first indicated that antileishmanial activity depends on an intramolecular hydrogen bond (described by X-ray diffraction) between the lactam function and the nitro group, which is responsible for an important shift of the redox potential (+0.3 V in comparison with 8-nitroquinoline). With the assistance of computational chemistry, a set of derivatives presenting a large range of redox potentials (from -1.1 to -0.45 V) was designed and provided a list of suitable molecules to be synthesized and tested. This approach highlighted that, in this series, only substrates with a redox potential above -0.6 V display activity toward L. infantum. Nevertheless, such relation between redox potentials and in vitro antiparasitic activities was not observed in T. b. brucei. Compound 22 is a new hit compound in the series, displaying both antileishmanial and antitrypanosomal activity along with a low cytotoxicity on the human HepG2 cell line. Compound 22 is selectively bioactivated by the type 1 nitroreductases (NTR1) of L. donovani and T. brucei brucei. Moreover, despite being mutagenic in the Ames test, as most of nitroaromatic derivatives, compound 22 was not genotoxic in the comet assay. Preliminary in vitro pharmacokinetic parameters were finally determined and pointed out a good in vitro microsomal stability (half-lifeâ¯>â¯40â¯min) and a 92% binding to human albumin.
Asunto(s)
Antiprotozoarios/farmacología , Técnicas Electroquímicas , Kinetoplastida/efectos de los fármacos , Nitroquinolinas/farmacología , Nitrorreductasas/metabolismo , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Kinetoplastida/enzimología , Leishmania infantum/efectos de los fármacos , Leishmania infantum/enzimología , Estructura Molecular , Nitroquinolinas/síntesis química , Nitroquinolinas/química , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma brucei brucei/enzimologíaRESUMEN
Synthetic polypeptides are versatile polymers outstandingly relevant to prepare bioinspired materials. In this work, we present a new class of smart polypeptide polymers, called nucleopolypeptides, having lateral chains functionalized with thymidine nucleobases. Structural studies performed by circular dichroism have revealed that the secondary structure of the polymers was influenced by nucleotide interaction and DNA sequence variation affording a selective helix-to-beta sheet transition with oligo(AAAAA)6.
Asunto(s)
ADN/química , Péptidos/química , Dicroismo Circular , Estructura Secundaria de ProteínaRESUMEN
Polypeptide polymers can adopt natural protein secondary structures such as α-helices or ß-sheets, and this unique feature is at the origin of some intriguing physicoâ»chemical properties. In this work, we present how side chain imidazoylation of a poly(l-lysine) scaffold affords the preparation of poly(histidine) counterparts exhibiting α-helix conformation. This structuring behavior is reversible and can be controlled by means of pH and or temperature changes.
RESUMEN
Inhibitors of the Mycobacterium tuberculosis enoyl-ACP reductase (InhA) are considered as potential promising therapeutics for the treatment of tuberculosis. Previously, we reported that azaisoindolinone-type compounds displayed, in vitro, inhibitory activity toward InhA. Herein, we describe chemical modifications of azaisoindolinone scaffold, the synthesis of 15 new compounds and their evaluations toward the in vitro InhA activity. Based on these results, a structure-InhA inhibitory activity relationship analysis and a molecular docking study, using the conformation of InhA found in the 2H7M crystal structure, were carried out to predict a possible mode of interaction of the best (aza)isoindolinone-type inhibitors with InhA in vitro. Then, the work was extended toward evaluations of these compounds against Mycobacterium tuberculosis (Mtb) growth, and finally, some of them were also investigated in respect of their ability to inhibit mycolic acid biosynthesis inside mycobacteria. Although, some azaisoindolinones were able to inhibit InhA activity and Mtb growth in vitro, they did not inhibit the mycolic acid biosynthesis inside Mtb.