RESUMEN
Malaria, a prevalent fatal disease around the world is caused by Plasmodium sp. and is transmitted by the bite of female Anopheles mosquito. It is leading cause of death in this century among most infectious diseases. Drug resistance was reported for almost every front-line drug against the deadliest species of the malarial parasite, i.e., Plasmodium falciparum. In the evolutionary arms race between parasite and existing arsenals of drugs new molecules having novel mechanism of action is urgently needed to overcome the drug resistance. In this review, we have discussed the importance of carbohydrate derivatives of different class of compounds as possible antimalarials with emphasis on mode of action, rational design, and SAR with improved efficacy. Carbohydrate-protein interactions are increasingly important for medicinal chemists and chemical biologists to understand the pathogenicity of the parasite. Less is known about the carbohydrate-protein interactions and pathogenicity in the Plasmodium parasite. With the increased knowledge on protein-sugar interaction and glycomics of Plasmodium parasites, carbohydrate derivatives can surpass the existing biochemical pathways responsible for drug resistance. The new candidates with novel mode of action will prove to be a potent antimalarial drug candidate without any parasitic resistance.
Asunto(s)
Antimaláricos , Malaria , Parásitos , Plasmodium , Animales , Femenino , Antimaláricos/farmacología , Antimaláricos/química , Antimaláricos/uso terapéutico , Malaria/tratamiento farmacológico , Carbohidratos/farmacologíaRESUMEN
The long-term treatment of tuberculosis (TB) sometimes leads to nonadherence to treatment, resulting in multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. Inadequate bioavailability of the drug is the main factor for therapeutic failure, which leads to the development of drug-resistant cases. Therefore, there is an urgent need to design and develop novel antimycobacterial agents minimizing the period of treatment and reducing the propagation of resistance at the same time. Here, we report the development of original and noncytotoxic polycationic phosphorus dendrimers essentially of generations 0 and 1, but also of generations 2-4, with pyrrolidinium, piperidinium, and related cyclic amino groups on the surface, as new antitubercular agents active per se, meaning with intrinsic activity. The strategy is based on the phenotypic screening of a newly designed phosphorus dendrimer library (generations 0-4) against three bacterial strains: attenuated Mycobacterium tuberculosis H37Ra, virulent M. tuberculosis H37Rv, and Mangora bovis BCG. The most potent polycationic phosphorus dendrimers 1G0,HCl and 2G0,HCl are active against all three strains with minimum inhibitory concentrations (MICs) between 3.12 and 25.0 µg/mL. Both are irregularly shaped nanoparticles with highly mobile branches presenting a radius of gyration of 7 Å, a diameter of maximal 25 Å, and a solvent-accessible surface area of dominantly positive potential energy with very localized negative patches arising from the central N3P3 core, which steadily interacts with water molecules. The most interesting is 2G0,HCl, showing relevant efficacy against single-drug-resistant (SDR) M. tuberculosis H37Rv, resistant to rifampicin, isoniaid, ethambutol, or streptomycin. Importantly, 2G0,HCl displayed significant in vivo efficacy based on bacterial counts in lungs of infected Balb/C mice at a dose of 50 mg/kg oral administration once a day for 2 weeks and superior efficacy in comparison to ethambutol and rifampicin. This series of polycationic phosphorus dendrimers represents first-in-class drugs to treat TB infection, could fulfill the clinical candidate pipe of this high burden of infectious disease, and play a part in addressing the continuous demand for new drugs.
Asunto(s)
Dendrímeros , Mycobacterium tuberculosis , Tuberculosis , Animales , Antituberculosos/farmacología , Dendrímeros/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Tuberculosis/tratamiento farmacológicoRESUMEN
Macrocycles cover a small segment of molecules with a vast range of biological activity in the chemotherapeutic world. Primarily, the natural sources derived from macrocyclic drug candidates with a wide range of biological activities are known. Further evolutions of the medicinal chemistry towards macrocycle-based chemotherapeutics involve the functionalization of the natural product by hemisynthesis. More recently, macrocycles based on carbohydrates have evolved a considerable interest among the medicinal chemists worldwide. Carbohydrates provide an ideal scaffold to generate chiral macrocycles with well-defined pharmacophores in a decorated fashion to achieve the desired biological activity. We have given an overview on carbohydrate-derived macrocycle involving their synthesis in drug design and discovery and potential role in medicinal chemistry.
Asunto(s)
Química Farmacéutica , Productos Biológicos , Carbohidratos , Diseño de Fármacos , Compuestos MacrocíclicosRESUMEN
The histamine 3 receptor (H3R) is a presynaptic receptor, which modulates several neurotransmitters including histamine and various essential physiological processes, such as feeding, arousal, cognition, and pain. The H3R is considered as a drug target for the treatment of several central nervous system disorders. We have synthesized and identified a novel series of 4-aryl-6-methyl-5,6,7,8-tetrahydroquinazolinamines that act as selective H3R antagonists. Among all the synthesized compounds, in vitro and docking studies suggested that the 4-methoxy-phenyl-substituted tetrahydroquinazolinamine compound 4c has potent and selective H3R antagonist activity (IC50 < 0.04 µM). Compound 4c did not exhibit any activity on the hERG ion channel and pan-assay interference compounds liability. Pharmacokinetic studies showed that 4c crosses the blood brain barrier, and in vivo studies demonstrated that 4c induces anorexia and weight loss in obese, but not in lean mice. These data reveal the therapeutic potential of 4c as an anti-obesity candidate drug via antagonizing the H3R.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Obesidad/tratamiento farmacológico , Quinazolinas/uso terapéutico , Receptores Histamínicos H3/metabolismo , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacocinética , Glucemia/metabolismo , Dieta Alta en Grasa , Células HEK293 , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Proteínas Proto-Oncogénicas c-fos/metabolismo , Quinazolinas/síntesis química , Quinazolinas/farmacocinética , Estereoisomerismo , Relación Estructura-Actividad , Pérdida de Peso/efectos de los fármacosRESUMEN
In an attempt to develop new antimalarial drugs, we have synthesized a new class of N-alkylated 3-glycoconjugated-oxopropylidene oxindoles starting from substituted isatins and glucopyranosyl propanone via a well-known cross-aldol reaction followed by dehydration. The newly synthesized compounds were screened for their in vitro antiplasmodial activity, and among all the compounds 9g, 9f, 9b, 8d, 9d, 9c, and 9e displayed potent activity with the IC50 values in the range of 0.1-0.3⯵M against Chloroquine (CQ) sensitive Pf3D7 strain, while compounds 9d, 9b, 9e, 8c, 8f, 9c, and 9a have shown promising activity having IC50 values in 0.1-0.4⯵M range against CQ resistant PfK1 strain, which is even better than the standard drug chloroquine with IC50 value of 0.5⯵M.
Asunto(s)
Antiprotozoarios/síntesis química , Isatina/química , Oxindoles/síntesis química , Antimaláricos/síntesis química , Antiprotozoarios/farmacología , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
A series of homologous C-nucleoside mimics have been synthesized via an efficient and facile synthetic protocol involving the conjugate addition of purine to sugar derived olefinic ester in good yields. The synthesized compounds were evaluated for their antiplasmodial activity in vitro against both the CQ-sensitive and resistant strains of P. falciparum. Interestingly, all the synthesized nucleoside analogs exhibited an IC50 of <5 µM, while compounds 22a, 23a, and 23b showed promising antiplasmodial activity with an IC50 of 1.61, 0.88, and 1.01 µM against the CQ-sensitive Pf3D7 strain and 1.14, 1.01, and 2.57 µM against the CQ-resistant PfK1 strain, respectively.
RESUMEN
Tuberculosis (TB) is a contagious infection that usually attacks not only the lungs, but also brain and spine. More than twenty drugs have been developed for the treatment of TB, but most of them were developed some years ago. They are used in different combinations. Isoniazid and Rifampicin are examples of the five first line TB drugs, whereas, for instance, Levofloxacin, Kanamycin and Linezolid belong to the second line drugs that are used for the treatment of drug resistant TB. Several new bicyclic nitroimidazoles (e.g., Delamanid) without mutagenic effects were developed. New TB drugs need to provide several main issues such as more effective, less toxic, and less expensive for drug resistant TB. Besides polymeric, metal-based nanoparticles, polymeric micelles and polymers, dendrimer nanostructures represent ideal delivery vehicles and offer high hopes for the future of nanomedicine. In this original review, we present and analyze the development of anti-TB drugs in combination with dendrimers. Few articles have highlighted the encapsulation of anti-TB drugs with dendrimers. Due to their unique structure, dendrimers represent attractive candidates for the encapsulation and conjugation of other anti-TB drugs presenting important drawbacks (e.g., solubility, toxicity, low bioavailability) that hinder their development, including clinic trials.
RESUMEN
A small library of 36 new glycohybrids of phenylhydrazono-indolinones was synthesized employing glycosylated 1,2,3-triazolyl-methyl-indoline-2,3-diones and different phenylhydrazines via acid catalyzed reaction. All the compounds were screened for their antiplasmodial activity in vitro. Compounds 6c, 7c, and 7b showed significant activity with the IC50 values 1.27, 1.64 and 1.96⯵M, respectively against CQ sensitive Pf3D7 strain while compounds 7b and 6f showed good activity with IC50 1.61 and 1.93⯵M, respectively against CQ resistant PfK1 strain.
Asunto(s)
Antimaláricos/farmacología , Hidrazonas/farmacología , Indoles/farmacología , Plasmodium falciparum/efectos de los fármacos , Triazoles/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Relación Dosis-Respuesta a Droga , Glicosilación , Hidrazonas/química , Indoles/química , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
Due to the recent reports of growing parasite resistance to artemisinins and other antimalarial drugs, development of new antimalarial chemotypes is an urgent priority. Here in, we report a novel series of adamantyl/cycloheptyl indoleamide derivatives bearing sulfonamide and triazole pharmacophores adopting different chemical modifications and evaluated them for antiplasmodial activity in vitro. Among all the indoleamides, compounds 22, 24, 26 and 30 with sulfonamide pharmacophore showed promising activity with IC50 of 1.87, 1.93, 2.00, 2.17 µM against CQ sensitive Pf3D7 strain and 1.69, 2.12, 1.60, 2.19 µM against CQ resistant PfK1 strain, respectively.
Asunto(s)
Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Sulfanilamidas/farmacología , Triazoles/farmacología , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Sulfanilamida , Sulfanilamidas/química , Triazoles/química , Células VeroRESUMEN
A novel and efficient Cu(I)-catalyzed ligand- and base-free multipathway domino strategy has been developed for the synthesis of 2-substituted quinazolinones. The reaction utilizes 2-bromobenzamide and multiform substrates such as aldehydes, alcohols, and methyl arenes for a one-pot protocol, whereas TMSN3 is used as a nitrogen source. A wide range of substrate scope, functional group tolerance, and operational simplicity are synthetically useful features.
RESUMEN
Here we report the crystal structure of M. tuberculosis AldR (Rv2779c) showing that the N-terminal DNA-binding domains are swapped, forming a dimer, and four dimers are assembled into an octamer through crystal symmetry. The C-terminal domain is involved in oligomeric interactions that stabilize the oligomer, and it contains the effector-binding sites. The latter sites are 30-60% larger compared with homologs like MtbFFRP (Rv3291c) and can consequently accommodate larger molecules. MtbAldR binds to the region upstream to the ald gene that is highly up-regulated in nutrient-starved tuberculosis models and codes for l-alanine dehydrogenase (MtbAld; Rv2780). Further, the MtbAldR-DNA complex is inhibited upon binding of Ala, Tyr, Trp and Asp to the protein. Studies involving a ligand-binding site G131T mutant show that the mutant forms a DNA complex that cannot be inhibited by adding the amino acids. Comparative studies suggest that binding of the amino acids changes the relative spatial disposition of the DNA-binding domains and thereby disrupt the protein-DNA complex. Finally, we identified small molecules, including a tetrahydroquinoline carbonitrile derivative (S010-0261), that inhibit the MtbAldR-DNA complex. The latter molecules represent the very first inhibitors of a feast/famine regulatory protein from any source and set the stage for exploring MtbAldR as a potential anti-tuberculosis target.
Asunto(s)
Alanina-Deshidrogenasa/genética , Proteínas Bacterianas/genética , Regulación Bacteriana de la Expresión Génica/genética , Factores de Transcripción/genética , Alanina-Deshidrogenasa/química , Alanina-Deshidrogenasa/metabolismo , Aminoácidos/química , Aminoácidos/genética , Aminoácidos/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Sitios de Unión/genética , Dicroismo Circular , Cristalografía por Rayos X , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Modelos Moleculares , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Unión Proteica , Dominios Proteicos , Estructura Secundaria de Proteína , Secuencias Reguladoras de Ácidos Nucleicos/genética , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Factores de Transcripción/química , Factores de Transcripción/metabolismoRESUMEN
In a quest to discover new drugs, we have synthesized a series of novel ß-amino alcohol grafted 1,2,3-triazoles and screened them for their in vitro antiplasmodial and in vivo antimalarial activity. Among them, compounds 16 and 25 showed potent activity against chloroquine-sensitive (Pf3D7) strain with IC50 of 0.87 and 0.3 µM respectively, while compounds 7 and 13 exhibited better activity in vitro than the reference drug against chloroquine-resistance strain (PfK1) with IC50 of 0.5 µM each. Compound 25 showed 86.8% in vivo antimalarial efficacy with favorable pharmacokinetic parameters. Mechanistic studies divulged that potent compounds significantly boosted p53 protein levels to exhibit the antimalarial activity.
Asunto(s)
Antimaláricos/química , Antimaláricos/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Triazoles/química , Triazoles/uso terapéutico , Amino Alcoholes/química , Amino Alcoholes/farmacocinética , Amino Alcoholes/farmacología , Amino Alcoholes/uso terapéutico , Animales , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Chlorocebus aethiops , Humanos , Células MCF-7 , Malaria Falciparum/metabolismo , Masculino , Ratones , Ratas Sprague-Dawley , Triazoles/farmacocinética , Triazoles/farmacología , Proteína p53 Supresora de Tumor/genética , Regulación hacia Arriba/efectos de los fármacos , Células VeroRESUMEN
A novel class of gallic acid based glycoconjugates were designed and synthesized as potential anticancer agents. Among all the compounds screened, compound 2a showed potent anticancer activity against breast cancer cells. The latter resulted in tubulin polymerization inhibition and induced G2/M cell cycle arrest, generation of reactive oxygen species, mitochondrial depolarization and subsequent apoptosis in breast cancer cells. In addition, ultraviolet-visible spectroscopy and fluorescence quenching studies of the compound with tubulin confirmed direct interaction of compounds with tubulin. Molecular modeling studies revealed that it binds at the colchicine binding site in tubulin. Further, 2a also exhibited potent in vivo anticancer activity in LA-7 syngeneic rat mammary tumor model. Current data projects its strong candidature to be developed as anticancer agent.
Asunto(s)
Antineoplásicos/farmacología , Ácido Gálico/farmacología , Glicoconjugados/farmacología , Polimerizacion/efectos de los fármacos , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Ácido Gálico/química , Glicoconjugados/síntesis química , Glicoconjugados/química , Humanos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones , Ratas , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Moduladores de Tubulina/síntesis química , Células Tumorales CultivadasRESUMEN
Autophagy is considered as an important cell death mechanism that closely interacts with other common cell death programs like apoptosis. Critical role of autophagy in cell death makes it a promising, yet challenging therapeutic target for cancer. We identified a series of 1,2,3-triazole analogs having significant breast cancer inhibition property. Therefore, we attempted to study whether autophagy and apoptosis were involved in the process of cancer cell inhibition. The lead molecule, 1-(1-benzyl-5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(4-bromophenylamino)-1-(4-chlorophenyl)ethanol (T-12) induced significant cell cycle arrest, mitochondrial membrane depolarization, apoptosis and autophagy in MCF-7 and MDA-MB-231 cells. T-12 increased reactive oxygen species and its inhibition by N-acetyl-L-cysteine protected breast cancer cells from autophagy and apoptosis. Autophagy inhibitor, 3-methyladenine abolished T-12 induced apoptosis, mitochondrial membrane depolarization and reactive oxygen species generation. This suggested that T-12 induced autophagy facilitated cell death rather than cell survival. Pan-caspase inhibition did not abrogate T-12 induced autophagy, suggesting that autophagy precedes apoptosis. In addition, T-12 inhibited cell survival pathway signaling proteins, Akt, mTOR and Erk1/2. T-12 also induced significant regression of tumor with oral dose of as low as 10mg/kg bodyweight in rat mammary tumor model without any apparent toxicity. In presence of reactive oxygen species inhibitor (N-acetyl-L-cysteine) and autophagy inhibitor (chloroquine), T-12 induced tumor regression was significantly decreased. In conclusion, T-12 is a potent inducer of autophagy-dependent apoptosis in breast cancer cells both in vitro and in vivo and can serve as an important lead in development of new anti-tumor therapy.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Etanol/análogos & derivados , Especies Reactivas de Oxígeno/metabolismo , Triazoles/farmacología , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Etanol/farmacología , Femenino , Células HEK293 , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratas , Ratas Sprague-DawleyRESUMEN
Lymphatic filarial nematodes maintain a mutualistic relationship with the endosymbiont Wolbachia. Depletion of Wolbachia produces profound defects in nematode development, fertility, and viability and thus has great promise as a novel approach for treating filarial diseases. NAD(+)-dependent DNA ligase is an essential enzyme of DNA replication, repair, and recombination. Therefore, in the present study, the antifilarial drug target potential of the NAD(+)-dependent DNA ligase of the Wolbachia symbiont of Brugia malayi (wBm-LigA) was investigated using dispiro-cycloalkanone compounds. Dispiro-cycloalkanone specifically inhibited the nick-closing and cohesive-end ligation activities of the enzyme without inhibiting human or T4 DNA ligase. The mode of inhibition was competitive with the NAD(+) cofactor. Docking studies also revealed the interaction of these compounds with the active site of the target enzyme. The adverse effects of these inhibitors were observed on adult and microfilarial stages of B. malayi in vitro, and the most active compounds were further monitored in vivo in jirds and mastomys rodent models. Compounds 1, 2, and 5 had severe adverse effects in vitro on the motility of both adult worms and microfilariae at low concentrations. Compound 2 was the best inhibitor, with the lowest 50% inhibitory concentration (IC50) (1.02 µM), followed by compound 5 (IC50, 2.3 µM) and compound 1 (IC50, 2.9 µM). These compounds also exhibited the same adverse effect on adult worms and microfilariae in vivo (P < 0.05). These compounds also tremendously reduced the wolbachial load, as evident by quantitative real-time PCR (P < 0.05). wBm-LigA thus shows great promise as an antifilarial drug target, and dispiro-cycloalkanone compounds show great promise as antifilarial lead candidates.
Asunto(s)
Brugia Malayi/microbiología , ADN Ligasas/antagonistas & inhibidores , Filaricidas/farmacología , Cetonas/farmacología , Compuestos de Espiro/farmacología , Wolbachia/efectos de los fármacos , Animales , Antibacterianos/farmacología , ADN Ligasa (ATP) , ADN Ligasas/efectos de los fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Gerbillinae , Cetonas/síntesis química , Masculino , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Simulación del Acoplamiento Molecular , Murinae/parasitología , Compuestos de Espiro/síntesis química , Simbiosis , Wolbachia/enzimologíaRESUMEN
Tyrosine phosphorylation is one of the most common means of posttranslational modifications which can generate novel recognition motifs for protein interactions and thereafter affecting cellular localization, protein stability, and enzyme activity. Mycobacterium tuberculosis (Mtb) possesses a wide range of signal transduction systems, including two protein tyrosine phosphatases (PtpA and PtpB). Since functional diversities between protein tyrosine phosphatases (PTPases) are illustrated by regulatory domains and subunits, we have characterized the nature of tyrosine phosphatases from slow-grower pathogenic species Mtb and from fast-grower nonpathogenic species Mycobacterium smegmatis (MS). The findings delineate that the enzymes present in MS have significantly lesser phosphatase activity than PTPases of Mtb as evidenced by low K cat/K m of recombinantly expressed proteins. The K cat/K m for Mtb PtpA was 500-1000-fold higher than MS PTPases. We have designed and synthesized phenyl cyclopropyl methyl-/phenyl butenyl azoles which inhibit growth of mycobacteria, in culture and in macrophages. The mechanism of efficacy of these compounds against mycobacteria was identified and suggested that the inhibition may possibly be mediated via the targeting of Mtb tyrosine phosphatase. The results further added that these compounds exclusively inhibit PtpA of Mtb.
Asunto(s)
Antituberculosos/metabolismo , Azoles/metabolismo , Inhibidores Enzimáticos/metabolismo , Mycobacterium smegmatis/enzimología , Mycobacterium tuberculosis/enzimología , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas/metabolismo , CinéticaRESUMEN
A new series of C-linked phenyl butenonyl glycosides bearing ureidyl(thioureidyl) and sulfonamidyl moieties in the phenyl rings were designed, synthesized, and evaluated for their in vitro antimalarial activities against Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains. Among all the compounds screened the C-linked phenyl butenonyl glycosides bearing sulfonamidyl moiety (5a) and ureidyl moiety in the phenyl ring (7d and 8c) showed promising antimalarial activities against both 3D7 and K1 strains with IC50 values in micromolar range and low cytotoxicity offering new HITS for further exploration.
RESUMEN
An efficient and simple strategy for the synthesis of a diverse range of anthraquinone-based aryl-C-glycosides has been developed. It involves the sequential Diels-Alder reaction and oxidative aromatization with the preformed glycosyl diene and dienophiles. The glycosyl dienes were obtained from simple sugars by tandem one-pot substitution and elimination reaction.
Asunto(s)
Antraquinonas/química , Glicósidos/síntesis química , Glicósidos/química , Estructura MolecularRESUMEN
A series of 1-[(4-benzyloxyphenyl)-but-3-enyl]-1H-azoles has been identified as potent antitubercular agents against Mycobacterium tuberculosis. Synthesis of compounds involved acid catalyzed ring-opening of cyclopropyl ring of phenyl cyclopropyl methanols followed by nucleophilic attack of the azoles on the carbocation intermediates. Several of the compounds 26, 34, and 36 exhibited significant antitubercular activities with MIC value as low as 1.56, 1.56, and 0.61 µg/mL, respectively, comparable to many standard drugs. These compounds were also screened against other strains of bacteria and fungi, and few of them showed good antifungal activity against A. fumigatus, responsible for lung infection.
RESUMEN
A new approach to synthesize a homologous series of 14-, 15-, and 16-membered drug-like, macrocyclic glycoconjugates involving TBAHS promoted azide-propenone intramolecular cycloaddition in designed C-glycopyranosyl butenones from a simple sugar d-glucose and d-mannose is reported.