RESUMEN
The development of new anti-tubercular agents represents a constant challenge mostly due to the insurgency of resistance to the currently available drugs. In this study, a set of 60 molecules were selected by screening the Asinex and the ZINC collections and an in house library by means of in silico ligand-based approaches. Biological assays in Mycobacterium tuberculosis H37Ra ATCC 25177 strain highlighted (±)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethyl-4-(3,4-dichlorophenyl)piperazine-1-carboxylate (5i) and 3-(4-chlorophenyl)-5-(2,4-dimethylpyrimidin-5-yl)-2-methylpyrazolo[1.5-a]pyrimidin-7(4H)-one (42) as the most potent compounds, having a Minimum Inhibitory Concentration (MIC) of 4 and 2 µg/mL respectively. These molecules represent a good starting point for further optimization of effective anti-TB agents.
Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Simulación por Computador , Descubrimiento de Drogas , Ligandos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Bibliotecas de Moléculas PequeñasRESUMEN
Sterol 14α-demethylase (CYP51) is a key enzyme involved in the survival and virulence of many parasite protozoa, such as Trypanosoma and Leishmania species, thus representing a valuable drug target for the treatment of Kinetoplastid diseases. A set of azole-based compounds selected from an in-house compound library was in vitro screened against different human protozoan parasites. Several compounds showed selective activity against Trypanosoma cruzi, with compound 7 being the most active (IC50 = 40 nM). Given the structural similarity between the compounds here reported and known CYP51 inhibitors, a molecular docking study was performed to assess their binding with protozoal target and to rationalize the biological activity data.
Asunto(s)
Antiprotozoarios/farmacología , Imidazoles/farmacología , Alcohol Feniletílico/análogos & derivados , Trypanosoma cruzi/efectos de los fármacos , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Línea Celular , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Fibroblastos/efectos de los fármacos , Humanos , Imidazoles/síntesis química , Imidazoles/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Alcohol Feniletílico/síntesis química , Alcohol Feniletílico/química , Alcohol Feniletílico/farmacología , Relación Estructura-ActividadRESUMEN
A series of N-aryl-naphthylamines, exemplified by the structures 11-16, were chosen for an in-house library screening to assay their ability to disrupt the interaction between the LEDGF cofactor and the HIV integrase. Structure modification led also to design and synthesize new compounds 17a-f. Compounds 11e,h,k,n, 13b, and 14 showed good activity in AlphaScreen assay. The most active compound 11e (IC50 = 2.5 µM) was selected for molecular modeling studies and showed a binding mode similar to the one of the known LEDGIN 8.
Asunto(s)
1-Naftilamina/análogos & derivados , Descubrimiento de Drogas , Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , para-Aminobenzoatos/farmacología , 1-Naftilamina/síntesis química , 1-Naftilamina/química , 1-Naftilamina/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/química , Humanos , Modelos Moleculares , Estructura Molecular , Unión Proteica/efectos de los fármacos , Relación Estructura-Actividad , Células Tumorales Cultivadas , para-Aminobenzoatos/síntesis química , para-Aminobenzoatos/químicaRESUMEN
Bifunctional quinolinonyl DKA derivatives were first described as nonselective inhibitors of 3'-processing (3'-P) and strand transfer (ST) functions of HIV-1 integrase (IN), while 7-aminosubstituted quinolinonyl derivatives were proven IN strand transfer inhibitors (INSTIs) that also displayed activity against ribonuclease H (RNase H). In this study, we describe the design, synthesis, and biological evaluation of new quinolinonyl diketo acid (DKA) derivatives characterized by variously substituted alkylating groups on the nitrogen atom of the quinolinone ring. Removal of the second DKA branch of bifunctional DKAs, and the amino group in position 7 of quinolinone ring combined with a fine-tuning of the substituents on the benzyl group in position 1 of the quinolinone, increased selectivity for IN ST activity. In vitro, the most potent compound was 11j (IC50 = 10 nM), while the most active compounds against HIV infected cells were ester derivatives 10j and 10l. In general, the activity against RNase H was negligible, with only a few compounds active at concentrations higher than 10 µM. The binding mode of the most potent IN inhibitor 11j within the IN catalytic core domain (CCD) is described as well as its binding mode within the RNase H catalytic site to rationalize its selectivity.
Asunto(s)
Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/química , Cetoácidos/farmacología , Quinolonas/farmacología , ADN Polimerasa Dirigida por ARN/química , Ribonucleasa H/antagonistas & inhibidores , Dominio Catalítico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Inhibidores de Integrasa VIH/química , VIH-1/efectos de los fármacos , Células HeLa , Humanos , Cetoácidos/química , Modelos Moleculares , Estructura Molecular , Quinolonas/química , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
The development of HIV-1 dual inhibitors is a highly innovative approach aimed at reducing drug toxic side effects as well as therapeutic costs. HIV-1 integrase (IN) and reverse transcriptase-associated ribonuclease H (RNase H) are both selective targets for HIV-1 chemotherapy, and the identification of dual IN/RNase H inhibitors is an attractive strategy for new drug development. We newly synthesized pyrrolyl derivatives that exhibited good potency against IN and a moderate inhibition of the RNase H function of RT, confirming the possibility of developing dual HIV-1 IN/RNase H inhibitors and obtaining new information for the further development of more effective dual HIV-1 inhibitors.
Asunto(s)
Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/metabolismo , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH/efectos de los fármacos , Pirroles/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Ribonucleasa H/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , VIH/enzimología , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/química , Transcriptasa Inversa del VIH/química , Transcriptasa Inversa del VIH/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Estructura Terciaria de Proteína/efectos de los fármacos , Pirroles/síntesis química , Pirroles/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Ribonucleasa H/metabolismo , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Metal ions, especially copper, zinc and iron, play an important role in the neurodegeneration process because they can affect protein misfolding, leading to the formation of the amyloid deposits and oxidative stress leading to reactive oxygen species (ROS). Here we report the synthesis and evaluation as antioxidant and metal chelating agents of 3,4-dihydroxybenzoic acid derivatives. Synthesized compounds were tested by the 2,2-diphenyl-2-picrylhydrazyl (DPPH) method showing a radical scavenging ability (EC50=0.093-0.118 µM) higher than Trolox used as reference. Furthermore, these compounds were able to bind both iron and copper, especially the iron (III), by the formation of hexa-coordinated complexes. Synthesized compounds were tested to evaluate their ability to inhibit acetyl- and butyryl-cholinesterase; the obtained results have demonstrated that they are selective inhibitors of AChE (Ki=1.5-18.9 µM) and result weakly active versus butyrylcholinesterase (BChE).
Asunto(s)
Acetilcolinesterasa/química , Antioxidantes/síntesis química , Quelantes/síntesis química , Inhibidores de la Colinesterasa/síntesis química , Hidroxibenzoatos/síntesis química , Animales , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , Butirilcolinesterasa/química , Quelantes/química , Inhibidores de la Colinesterasa/química , Cromanos/química , Complejos de Coordinación/química , Cobre/química , Diseño de Fármacos , Hidroxibenzoatos/química , Hierro/química , Cinética , Simulación del Acoplamiento Molecular , Picratos/antagonistas & inhibidores , Relación Estructura-Actividad , TorpedoRESUMEN
Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14α-demethylase (CYP51) inhibitors. Here we explore the spectral binding parameters, inhibitory effects on T. cruzi CYP51 activity, and antiparasitic potencies of a new set of ß-phenyl imidazoles. Comparative structural characterization of the T. cruzi CYP51 complexes with the three most potent inhibitors reveals two opposite binding modes of the compounds ((R)-6, EC50=1.2 nM, vs (S)-2/(S)-3, EC50=1.0/5.5 nM) and suggests the entrance into the CYP51 substrate access channel and the heme propionate-supporting ceiling of the binding cavity as two distinct areas of the protein that enhance molecular recognition and therefore could be used for the development of more effective antiparasitic drugs.
Asunto(s)
Inhibidores de 14 alfa Desmetilasa/química , Carbamatos/química , Imidazoles/química , Esterol 14-Desmetilasa/metabolismo , Tripanocidas/química , Trypanosoma cruzi/enzimología , Inhibidores de 14 alfa Desmetilasa/síntesis química , Inhibidores de 14 alfa Desmetilasa/farmacología , Carbamatos/síntesis química , Carbamatos/farmacología , Cristalografía por Rayos X , Diseño de Fármacos , Imidazoles/síntesis química , Imidazoles/farmacología , Modelos Moleculares , Unión Proteica , Conformación Proteica , Estereoisomerismo , Esterol 14-Desmetilasa/química , Tripanocidas/síntesis química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacosRESUMEN
The use of electrogenerated acetonitrile anion allows the alkylation of N-Boc-4-aminopyridine in very high yields, under mild conditions and without by-products. The high reactivity of this base is due to its large tetraethylammonium counterion, which leaves the acetonitrile anion "naked." The deprotection of the obtained compounds led to high yields in N-alkylated 4-aminopyridines. Nonsymmetrically dialkylated 4-aminopyridines were obtained by subsequent reaction of monoalkylated ones with t-BuOK and alkyl halides, while symmetrically dialkylated 4-aminopyridines were obtained by direct reaction of 4-aminopyridine with an excess of t-BuOK and alkyl halides. Some mono- and dialkyl-4-aminopyridines were selected to evaluate antifungal and antiprotozoal activity; the dialkylated 4-aminopyridines 3ac, 3ae and 3ff showed antifungal towards Cryptococcus neoformans; whereas 3cc, 3ee and 3ff showed antiprotozoal activity towards Leishmania infantum and Plasmodium falciparum.
RESUMEN
A series of antiviral basic quinolinonyl diketo acid derivatives were developed as inhibitors of HIV-1 IN. Compounds 12d,f,i inhibited HIV-1 IN with IC50 values below 100 nM for strand transfer and showed a 2 order of magnitude selectivity over 3'-processing. These strand transfer selective inhibitors also inhibited HIV-1 RNase H with low micromolar potencies. Molecular modeling studies based on both the HIV-1 IN and RNase H catalytic core domains provided new structural insights for the future development of these compounds as dual HIV-1 IN and RNase H inhibitors.
Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , Quinolonas/síntesis química , Ribonucleasa H/antagonistas & inhibidores , Inhibidores de Integrasa VIH/farmacología , Modelos Moleculares , Quinolonas/farmacología , Relación Estructura-ActividadRESUMEN
The aim of this study was to evaluate the caffeic acid (1) and ester derivatives (2-10) against Candida albicans biofilm and to investigate whether these compounds are able to inhibit the biofilm formation or destroy pre-formed biofilm. Caffeic acid ester 7, cinnamic acid ester 8 and 3,4-dihydroxybenzoic acid ester 10 are more active than fluconazole, used as reference drug, both on biofilm in formation with MIC50 values of 32, 32 and 16µg/mL, respectively, and in the early stage of biofilm formation (4h) with MIC50 values of 64, 32 and 64µg/mL, respectively. These esters result also more active than fluconazole on mature biofilm (24h), especially 8 and 10 with MIC50 values of 64µg/mL.
Asunto(s)
Antifúngicos/química , Antifúngicos/farmacología , Biopelículas/efectos de los fármacos , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacología , Candida albicans/fisiología , Antifúngicos/síntesis química , Ácidos Cafeicos/síntesis química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
The increasing efficiency of HAART has helped to transform HIV/AIDS into a chronic disease. Still, resistance and drug-drug interactions warrant the development of new anti-HIV agents. We previously discovered hit 6, active against HIV-1 replication and targeting RNase H in vitro. Because of its diketo-acid moiety, we speculated that this chemotype could serve to develop dual inhibitors of both RNase H and integrase. Here, we describe a new series of 1-benzyl-pyrrolyl diketohexenoic derivatives, 7a-y and 8a-y, synthesized following a parallel solution-phase approach. Those 50 analogues have been tested on recombinant enzymes (RNase H and integrase) and in cell-based assays. Approximately half (22) exibited inhibition of HIV replication. Compounds 7b, 7u, and 8g were the most active against the RNase H activity of reverse-transcriptase, with IC50 values of 3, 3, and 2.5 µM, respectively. Compound 8g was also the most potent integrase inhibitor with an IC50 value of 26 nM.
Asunto(s)
Fármacos Anti-VIH/farmacología , Inhibidores Enzimáticos/farmacología , Integrasa de VIH/metabolismo , VIH-1/efectos de los fármacos , Cetoácidos/farmacología , Pirroles/farmacología , Ribonucleasa H/antagonistas & inhibidores , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Células HeLa , Humanos , Cetoácidos/síntesis química , Cetoácidos/química , Estructura Molecular , Pirroles/síntesis química , Pirroles/química , Ribonucleasa H/metabolismo , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Terminal deoxynucletidyl transferase (TdT) is overexpressed in some cancer types, where it might compete with pol µ during the mutagenic repair of double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. Here we report the discovery and characterization of pyrrolyl and indolyl diketo acids that specifically target TdT and behave as nucleotide-competitive inhibitors. These compounds show a selective toxicity toward MOLT-4 compared to HeLa cells that correlate well with in vitro selectivity for TdT. The binding site of two of these inhibitors was determined by cocrystallization with TdT, explaining why these compounds are competitive inhibitors of the deoxynucleotide triphosphate (dNTP). In addition, because of the observed dual localization of the phenyl substituent, these studies open the possibility of rationally designing more potent compounds.
Asunto(s)
Unión Competitiva , ADN Nucleotidilexotransferasa/antagonistas & inhibidores , ADN Nucleotidilexotransferasa/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Nucleótidos/metabolismo , Apoptosis/efectos de los fármacos , Dominio Catalítico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Cristalografía por Rayos X , ADN Nucleotidilexotransferasa/química , ADN de Cadena Simple/química , ADN de Cadena Simple/metabolismo , Nucleótidos de Desoxiadenina/metabolismo , Didesoxinucleótidos/metabolismo , Descubrimiento de Drogas , Inhibidores Enzimáticos/metabolismo , Ácidos Hexurónicos/química , Ácidos Hexurónicos/metabolismo , Ácidos Hexurónicos/farmacología , Humanos , Modelos MolecularesRESUMEN
Pharmacophoric mapping is a useful procedure to frame, especially when crystallographic receptor structures are unavailable as in ligand-based studies, the hypothetical site of interaction. In this study, 71 pyrrole derivatives active against M. tuberculosis were used to derive through a recent new 3-D QSAR protocol, 3-D QSAutogrid/R, several predictive 3-D QSAR models on compounds aligned by a previously reported pharmacophoric application. A final multiprobe (MP) 3-D QSAR model was then obtained configuring itself as a tool to derive pharmacophoric quantitative models. To stress the applicability of the described models, an external test set of unrelated and newly synthesized series of R-4-amino-3-isoxazolidinone derivatives found to be active at micromolar level against M. tuberculosis was used, and the predicted bioactivities were in good agreement with the experimental values. The 3-D QSAutogrid/R procedure proved to be able to correlate by a single multi-informative scenario the different activity molecular profiles thus confirming its usefulness in the rational drug design approach.
Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Pirroles/química , Pirroles/farmacología , Relación Estructura-Actividad Cuantitativa , Diseño de Fármacos , Humanos , Modelos Moleculares , Oxazolidinonas/química , Oxazolidinonas/farmacología , Tuberculosis/tratamiento farmacológicoRESUMEN
The antiparasitic activity of azole and new 4-aminopyridine derivatives has been investigated. The imidazoles 1 and 3-5 showed a potent in vitro antichagasic activity with IC50 values in the low nanomolar concentration range. The (S)-1, (S)-3, and (S)-5 enantiomers showed (up to) a thousand-fold higher activity than the reference drug benznidazole and furthermore low cytotoxicity on rat myogenic L6 cells.
RESUMEN
A new series of aromatic ester and carbamate derivatives of 2-(1H-imidazol-1-yl)-1-phenylethanol were synthesized and evaluated for their antifungal activity towards Candida albicans and non-albicans Candida species strains. The aromatic biphenyl ester derivatives 6a-c were more active than the reference compound fluconazole. 6c possesses a MIC mean values of 1.7 ± 1.4 µg mL(-1)vs C. albicans and 1.9 ± 2.0 µg mL(-1)vs non-albicans Candida species strains. The racemic mixtures of 6a, b were purified to afford the pure enantiomers. The (-) isomers were up to 500 times more active than (+) isomers. (-)-6a and (-)-6b were thirty and ninety times more active than fluconazole towards C. krusei strain respectively. The racemates of 6a-c showed low cytotoxicity against human monocytic cell line (U937) with 6a demonstrating a CC(50) greater than 128 µg mL(-1).
Asunto(s)
Antifúngicos/química , Antifúngicos/farmacología , Candida/efectos de los fármacos , Alcohol Feniletílico/química , Alcohol Feniletílico/farmacología , Antifúngicos/síntesis química , Candida albicans/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Línea Celular , Humanos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacología , Pruebas de Sensibilidad Microbiana , Alcohol Feniletílico/síntesis químicaRESUMEN
The electroencephalographic (EEG) effects of two choline pivaloyl esters, [2-(2,2-dimethylpropionyloxy)ethyl]trimethylammonium iodide (1) and [2-(2,2-dimethylpropionyloxy)ethyl]trimethylammonium 2,2-dimethylpropionate (2), were evaluated in scopolamine-treated or nucleus basalis magnocellularis (NBM) lesioned rats. In scopolamine-treated animals, Compounds 1 and 2 prevented or reduced EEG effects, such as increased amplitude of total spectra and high-voltage spindle (HVS) activity as well. Furthermore, choline esters showed a noticeable effectiveness in reversing the EEG changes produced in rats by AMPA-induced lesion of NBM. Indeed, Compounds 1 and 2 were able to induce EEG desynchronisation, a significant decrease in the total EEG power (0.25-16 Hz) and in the lower frequency delta and theta bands (0.25-3 and 3-6 Hz, respectively). The EEG effects produced by Compounds 1 and 2 were well comparable with that evoked by Tacrine, used as a reference compound. The results of the present work allow us to put forward the hypothesis that the EEG effects observed are most likely mediated through the stimulation of the cholinergic neurotransmission ensuing from enhanced cerebral levels of acetylcholine (ACh) consequent upon acetylcholinesterase (AChE) inhibition by choline pivaloyl esters.