RESUMEN
The prevalence of tuberculosis (TB) and mutidrug-resistant tuberculosis (MDR-TB) has been increasing, leading to serious infections, high mortality, and a global health threat. Here, we report the identification of a novel class of dideoxy nucleosides as potent and selective inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis, and drug-resistant Mycobacterium tuberculosis. A series of 5-acetylenic derivatives of 2',3'-dideoxyuridine (3-8) and 3'-fluoro-2',3'-dideoxyuridine (22-27) were synthesized and tested for their antimycobacterial activity against M. bovis, M. tuberculosis, and M. avium. 2',3'-Dideoxyuridine possessing 5-decynyl, 5-dodecynyl, 5-tridecynyl, and 5-tetradecynyl substituents (4-7) exhibited the highest antimycobacterial activity against all three mycobacteria. In contrast, in the 3'-fluoro-2',3'-dideoxyuridine series, a 5-tetradecynyl analogue (26) displayed the most potent activity against these mycobacteria. Among other derivatives, 5-bromo-2',3'-dideoxycytidine (11), 5-methyl-2',3'-dideoxycytidine (12), and 5-chloro-4-thio-2',3'-dideoxyuridine (19) exhibited modest inhibition of M. bovis and M. tuberculosis. In the series of dideoxy derivatives of adenosine, guanosine, and purines, 2-amino-6-mercaptoethyl-9-(2,3-dideoxy-beta-d-glyceropentofuranosyl)purine (32) and 2-amino-4-fluoro-7-(2,3-dideoxy-beta-d-glyceropentofuranosyl)pyrrolo[2,3-d]pyrimidine (35) were the most efficacious against M. bovis and M. tuberculosis, and M. avium, respectively.
Asunto(s)
Antibacterianos/síntesis química , Didesoxinucleósidos/síntesis química , Mycobacterium avium/efectos de los fármacos , Mycobacterium bovis/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Nucleósidos de Purina/síntesis química , Adenosina/análogos & derivados , Adenosina/síntesis química , Adenosina/farmacología , Alquinos/síntesis química , Alquinos/farmacología , Animales , Antibacterianos/química , Antibacterianos/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Didesoxinucleósidos/farmacología , Farmacorresistencia Bacteriana , Guanosina/análogos & derivados , Guanosina/síntesis química , Guanosina/farmacología , Pruebas de Sensibilidad Microbiana , Nucleósidos de Purina/farmacología , Relación Estructura-Actividad , Uridina/análogos & derivados , Uridina/síntesis química , Uridina/farmacologíaRESUMEN
The resurgence of tuberculosis and the emergence of multiple-drug-resistant strains of Mycobacteria necessitate the search for new classes of antimycobacterial agents. We synthesized a series of 1-beta-D-2'-arabinofuranosyl and 1-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl) pyrimidine nucleosides possessing diverse sets of alkynyl, alkenyl, alkyl, and halo substituents at the C-5 position of the uracil and investigated their effect on activity against M. tuberculosis, M. bovis, and M. avium. Among these molecules, 5-alkynyl-substituted derivatives emerged as potent inhibitors of M. bovis, M. tuberculosis, and M. avium. Nucleosides 1-beta-D-2'-arabinofuranosyl-5-dodecynyluracil (5), 1-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl)-5-dodecynyluracil (24), and 1-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl)-5-tetradecynyluracil (25) showed the highest antimycobacterial potency against M. bovis and M. tuberculosis. The MIC90 exhibited by compounds 5, 24, and 25 was similar or close to that of the reference drug rifampicin. The most active compounds 5, 24, and 25 were also found to retain sensitivity against a rifampicin-resistant strain of M. tuberculosis H37Rv at similar concentrations. Some of these analogs also revealed in vitro antimicrobial effect against several other gram-positive pathogens.
Asunto(s)
Arabinofuranosil Uracilo/análogos & derivados , Floxuridina/análogos & derivados , Mycobacterium avium/efectos de los fármacos , Mycobacterium bovis/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Nucleósidos de Pirimidina/síntesis química , Animales , Arabinofuranosil Uracilo/síntesis química , Arabinofuranosil Uracilo/química , Arabinofuranosil Uracilo/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Farmacorresistencia Bacteriana , Floxuridina/síntesis química , Floxuridina/química , Floxuridina/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium avium/crecimiento & desarrollo , Mycobacterium bovis/crecimiento & desarrollo , Mycobacterium tuberculosis/crecimiento & desarrollo , Nucleósidos de Pirimidina/química , Nucleósidos de Pirimidina/farmacología , Rifampin/farmacología , Relación Estructura-ActividadRESUMEN
Hepatitis B virus (HBV) is the most common cause of chronic liver disease worldwide. Development of drug resistance against clinical anti-HBV drug lamivudine due to long-term use and rebound of viral DNA after cessation of treatment has been a major setback of the current therapy. We have synthesized a series of pyrimidine nucleosides possessing a variety of substituents at the C-5 position, and a 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] flexible acyclic glycosyl moiety at the N-1 position, that have the ability to mimic the natural 2'-deoxyribosyl moiety. Some of these potential antiviral compounds included variations at both C-5 and C-6 positions of the uracil base. Other variations of the uracil derivatives were the 6-aza congeners. 4-Amino and 4-methoxy pyrimidine derivatives were also made. Compounds in which the base moiety was substituted by 5-chloro- (25), 5-(2-bromovinyl)- (32), or 5-bromo-6-methyl- (37) groups possess significant activity against duck-HBV, wild-type human HBV (2.2.15 cells), and lamivudine-resistant HBV containing single and double mutations. No cytotoxicity was seen in host HepG2 and Vero cells, up to the highest concentration tested. The anti-HBV activity exhibited by compounds 25, 32, and 37 was superior for human HBV and comparable for DHBV to that of the corresponding purine nucleoside, ganciclovir. Further, they were only 10-15-fold less inhibitory against human HBV in 2.2.15 cells than the reference drug, lamivudine. Other compounds in the series were moderately inhibitory against DHBV and wild-type human HBV. The size of the halogen and the electronegativity of the substituents at the 5- and 6-positions are important for antiviral activity toward HBV. These compounds were also evaluated for their antiviral activity for West Nile virus, respiratory syncytial virus, SARS-coronavirus, and hepatitis C virus. They were generally inactive in these antiviral assay systems (at concentrations up to 100 microg/mL). 1-[(2-Hydroxy-1-(hydroxymethyl) ethoxy)methyl]-5-fluorocytosine (34) showed some inhibitory activity against hepatitis C virus. Taken together, these data support our previous observations that the 5-substituted pyrimidine nucleosides containing acyclic glycosyl moieties have potential to serve as a new generation of potent, selective, and nontoxic anti-HBV agents for wild-type and lamivudine-resistant mutant HBV.
Asunto(s)
Antivirales/síntesis química , Desoxirribosa/química , Virus de la Hepatitis B/efectos de los fármacos , Nucleósidos de Pirimidina/síntesis química , Animales , Antivirales/química , Antivirales/farmacología , Línea Celular , Línea Celular Tumoral , Chlorocebus aethiops , Farmacorresistencia Viral , Patos/virología , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/aislamiento & purificación , Humanos , Lamivudine/farmacología , Imitación Molecular , Mutación , Nucleósidos de Pirimidina/química , Nucleósidos de Pirimidina/farmacología , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. The main clinical limitation of a current antiviral drug for HBV, lamivudine, is the emergence of drug-resistant viral strains upon prolonged therapy. A group of 5-, 6-, or 5,6-substituted acyclic pyrimidine nucleosides with a 1-[(2-hydroxyethoxy)methyl] moiety were synthesized and evaluated for antiviral activities. The target compounds were prepared by the reaction of silylated uracils possessing a variety of substituents at the C-5 or C-6 positions or both with 1,3-dioxolane in the presence of potassium iodide and chlorotrimethylsilane by a convenient and single-step synthesis. Among the compounds tested, 5-chloro and 5-bromo analogues possessing an acyclic glycosyl moiety were the most effective and selective antiviral agents in the in vitro assays against wild-type duck HBV (EC50=0.4-2.2 and 3.7-18.5 microM, respectively) and human HBV-containing 2.2.15 cells (EC50=4.5-45.4 and 18.5-37.7 microM, respectively). These compounds were also found to retain sensitivity against lamivudine-resistant HBV containing a single mutation (M204I) and double mutations (L180M/M204V). The compounds investigated did not show cytotoxicity to host HepG2 and Vero cells, up to the highest concentration tested. The results presented here confirm and accentuate the potential of acyclic pyrimidine nucleosides as anti-HBV agents and extend our previous observations. We herein report the capability of acyclic pyrimidine nucleosides to inhibit the replication of both wild-type and drug-resistant mutant HBV.
Asunto(s)
Antivirales/síntesis química , Virus de la Hepatitis B/efectos de los fármacos , Nucleósidos de Pirimidina/síntesis química , Animales , Antivirales/química , Antivirales/farmacología , Línea Celular , Chlorocebus aethiops , Farmacorresistencia Viral , Patos/virología , Virus de la Hepatitis B/genética , Humanos , Lamivudine/farmacología , Mutación , Nucleósidos de Pirimidina/química , Nucleósidos de Pirimidina/farmacología , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
We herein report a new category of 5-substituted pyrimidine nucleosides as potent inhibitors of mycobacteria. A series of 5-alkynyl derivatives of 2'-deoxyuridine (1-8), 2'-deoxycytidine (9-14), uridine (15-17), and 2'-O-methyluridine (18, 19) were synthesized and evaluated for their antimycobacterial activity in vitro. 5-Decynyl, 5-dodecynyl, and 5-tetradecynyl derivatives showed the highest antimycobacterial potency against M. bovis and M. avium, with the 2'-deoxyribose derivatives being more effective than the ribose analogues. Nucleosides bearing short alkynyl side chains 5-ethynyl, 5-propynyl, 5-pentynyl, and 5-heptynyl were mostly not inhibitory. Incorporation of a phenylethynyl function at the 5-position diminished the antimicrobial effect. Furthermore, related bicyclic analogues (20-24) were devoid of antimycobacterial activity, indicating that an acyclic side chain at the C-5 position of the pyrimidine ring is essential for potent activity. Compounds 1-17 were synthesized by the Pd-catalyzed coupling reactions of respective alkynes with 5-iodo derivatives of 2'-deoxyuridine, 2'-deoxycytidine, and uridine. Intramolecular cyclization of 1 and 3-6 in the presence of Cu afforded the corresponding bicyclic compounds 20-24. The investigated nucleosides are recognized here for the first time to be potent inhibitors of mycobacteria. This class of compounds could be of interest for lead optimization as antimycobacterial agents.
Asunto(s)
Antibacterianos/síntesis química , Mycobacterium avium/efectos de los fármacos , Mycobacterium bovis/efectos de los fármacos , Nucleósidos de Pirimidina/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Diseño de Fármacos , Humanos , Nucleósidos de Pirimidina/química , Nucleósidos de Pirimidina/farmacología , Relación Estructura-ActividadRESUMEN
Mycobacterium tuberculosis and Mycobacterium avium infections cause the two most important mycobacterioses, leading to increased mortality in patients with AIDS. Various 5-substituted 2'-deoxyuridines, uridines, 2'-O-methyluridine, 2'-ribofluoro-2'-deoxyuridines, 3'-substituted-2',3'-dideoxy uridines, 2',3'-dideoxyuridines, and 2',3'-didehydro-2',3'-dideoxyuridines were synthesized and evaluated for their in vitro inhibitory activity against M. bovis and M. avium. 5-(C-1 Substituted)-2'-deoxyuridine derivatives emerged as potent inhibitors of M. avium (MIC90 = 1-5 microg/mL range). The nature of C-5 substituents in the 2'-deoxyuridine series appeared to be a determinant of anti-mycobacterial activity. This new class of inhibitors could serve as useful compounds for the design and study of new anti-tuberculosis agents.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Nucleósidos de Pirimidina/química , Nucleósidos de Pirimidina/farmacología , Antibacterianos/química , Estructura Molecular , Mycobacterium avium/efectos de los fármacos , Mycobacterium bovis/efectos de los fármacos , Nucleósidos de Pirimidina/síntesis química , Relación Estructura-ActividadRESUMEN
3-Aminobenzonitrile and 2-amino-4-phenyl thiazole on condensation with 4-isothiocyanato-4-methyl pentane-2-one gave condensed monocyclic pyrimidine derivatives 1 and 2, 3, respectively. Condensation of 3-aminopropyl imidazole with 3-isothiocyantobutanal gave condensed monocyclic pyrimidine derivative 4. Bicyclic pyrimidine derivatives 5a and 5b have been synthesized by the condensation of diaminomaleonitrile with 4-isothiocyanto-4-methylpentane-2-one and 3-isothiocyanatobutanal, respectively. Condensation of 4-isothiocyanato-4-methyl pentane-2-one with 2,3-diaminopropionic acid hydrochloride yielded another bicyclic compound 7. 4-Isothiocyanato-4-methyl pentane-2-one, 3-isothiocyanatobutanal and 4-isothiocyanatobutan-2-one on condensation with 2-amino-4-nitro phenol gave tricyclic pyrimidine derivatives 8a, 8b and 8c, respectively. Structures of all the synthesized pyrimidine derivatives are supported by correct IR, 1H NMR and mass spectral data. The anti-inflammatory activity evaluation was carried out using carrageenin-induced paw oedema assay, and compounds 1, 3 and 5b exhibited good anti-inflammatory activity, that is, 27.9, 34.5 and 34.3% at 50 mg/kg po, respectively. Analgesic activity evaluation was carried out using phenylquinone writhing assay and compounds 5a, 5b and 8b showed good analgesic activity, that is, 50, 70 and 50% at 50 mg/kg po, respectively.
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Analgésicos/química , Animales , Antiinflamatorios/química , Evaluación Preclínica de Medicamentos , Femenino , Ibuprofeno/farmacología , Ratones , Pirimidinas/clasificación , RatasRESUMEN
(UN) substituted o-phenylenediamines 1a-g reacted with 3-isothiocyanatobutanal to give pyrimidobenzimidazole derivatives, 2a-g, respectively. Products 4, 6 and 8, 10 were obtained by condensation of 3-isothiocyanatobutanal with 2,3-diaminopyridine, 1,4-diaminobutane and 3-isothiocyanatopropanal with 4,5-dimethyl-1,2-phenylenediamine, o-nitroaniline, respectively. S-Methylation of 2f and 11b gave products 12a and 12b, respectively. Anti-inflammatory and analgesic activity evaluations of 2a-g and 12b were carried out at 50 mg kg(-1) p.o. Compound 2c exhibited good anti-inflammatory (46%) and mild analgesic activity (50%). Antiamoebic activity evaluations (using microdilution method) of 2a-g against Entamoeba-histolytica (strain HM1: IMSS) were carried out and compounds 2a, 2b, 2d and 2g exhibited good antiamoebic activity in vitro.
Asunto(s)
Amebicidas/farmacología , Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Bencimidazoles/farmacología , Piridinas/farmacología , Amebicidas/síntesis química , Amebicidas/química , Analgésicos/síntesis química , Analgésicos/química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Carragenina , Edema/inducido químicamente , Edema/patología , Entamoeba histolytica/efectos de los fármacos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Ratones , Dimensión del Dolor/efectos de los fármacos , Piridinas/síntesis química , Piridinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Clinical use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with significant toxicity particularly in the gastrointestinal tract and kidney. Various approaches such as formulation co-administration (of agents to protect the stomach), chemical manipulation and synthesis of new safer anti-inflammatory drugs reported in the literature to overcome the toxicity of NSAIDs have been summarized. As far as synthesis of new more effective and safer anti-inflammatory drugs is concerned, we have reported recent findings in the area of synthesis of heterocyclic compounds such as pyrimidines, imidazole, benzimidazole, thiazole, thiazolidine, acridine, thiourea, alkanoic acid derivatives and other related heterocyclic compounds and their role as inflammation inhibitors.