RESUMEN
Four novel scaffolds consisting of total 24 compounds (1a-1o, 2a-2c, 3a-3c and 4a-4c) bearing aromatic sulfonamide and coumarin moieties connected through various linkers were synthesized in order to synergize the inhibition potential of both the moieties against four selected human carbonic anhydrase isoforms (hCA I, II, IX & XII). All compounds were found to be potent inhibitors of tumor associated hCA IX & XII while at the same time required large amounts to inhibit off-targeted housekeeping hCA I & II. Selectivity was more pronounced against hCA II over I, and hCA XII over IX. Results were compared with antitumor drug acetazolamide. One derivative 2b of series 2 was found to be a better selective inhibitor of hCA IX and XII.
Asunto(s)
Anhidrasa Carbónica IX/antagonistas & inhibidores , Anhidrasa Carbónica IX/metabolismo , Inhibidores de Anhidrasa Carbónica/síntesis química , Anhidrasas Carbónicas/metabolismo , Cumarinas/química , Sulfonamidas/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Anhidrasa Carbónica IX/química , Inhibidores de Anhidrasa Carbónica/química , Anhidrasas Carbónicas/química , Cumarinas/síntesis química , Activación Enzimática/efectos de los fármacos , Humanos , Isoenzimas/química , Isoenzimas/metabolismo , Estructura Molecular , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
Some of the environmental toxicants acting as endocrine disruptors have been associated with health hazards in human and wildlife by modulating hormonal actions. Atrazine, a strong endocrine disruptor, induces detrimental effects on gonads in male and female, and causes impairment of fertility and developmental problems as well as sex alterations. Atrazine decreases the activities of antioxidant enzymes and thus responsible for oxidative stress. Natural antioxidants have shown ability to reduce/slow down the apoptotic effect of atrazine on testicular tissue. In the present study, some N-phenyl-4-aryl-polyhydroquinolines bearing phenolic or/and alkoxy group(s) (6a-6g) were synthesized and evaluated for antioxidant activity in four different assays. Three best compounds (6e-6g) were studied for their ameliorative effect on testicular tissue supplemented with atrazine in vitro.
Asunto(s)
Antioxidantes/farmacología , Atrazina/antagonistas & inhibidores , Polímeros/farmacología , Quinolinas/farmacología , Testículo/efectos de los fármacos , Animales , Antioxidantes/síntesis química , Antioxidantes/química , Atrazina/farmacología , Relación Dosis-Respuesta a Droga , Cabras , Masculino , Estructura Molecular , Polímeros/síntesis química , Polímeros/química , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-Actividad , Testículo/patologíaRESUMEN
Synthesis of total eighteen 2-amino-substituted 4-coumarinylthiazoles including sixteen new compounds (3a-o and 5b) bearing the benzenesulfonamide moiety is described in the present report. All the synthesized target compounds were examined for their in vivo anti-inflammatory (AI) activity and in vitro antimicrobial activity. Results revealed that six compounds (3 d, 3 f, 3 g, 3 h, 3 j and 3 n) exhibited pronounced anti-inflammatory activity comparable to the standard drug indomethacin. AI results were further confirmed by the docking studies of the most active (3n) and the least active compound (3a) with COX-1 and COX-2 active sites. In addition, most of the compounds exhibited moderate antimicrobial activity against Gram-positive bacteria as well as fungal yeast, S. cervisiae. Comparison between 3 and 5 indicated that incorporation of additional substituted pyrazole nucleus into the scaffold significantly enhanced AI activity.
Asunto(s)
Antibacterianos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antifúngicos/farmacología , Dominio Catalítico/efectos de los fármacos , Cumarinas/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Edema/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Tiazoles/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antifúngicos/síntesis química , Antifúngicos/química , Candida albicans/efectos de los fármacos , Carragenina , Cumarinas/síntesis química , Cumarinas/química , Ciclooxigenasa 1/química , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/química , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Masculino , Estructura Molecular , Ratas , Ratas Wistar , Saccharomyces cerevisiae/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
Pifithrin-α, a known p53 inactivator, inhibits p53-dependant mitochondrial cell death induced by toxins or γ-radiation. It has been found that aromatic IBT analogues of PFT-α are more cytoprotective and nonpeptide-based, isatin sulfonamides selectively inhibit caspases 3 and 7, responsible for mitochondrial mediated apoptosis. Therefore, we envisioned the synthesis of novel IBTs 4 and 5 bearing sulfonamide moiety and observed the mitigating effects of these IBTs in rescue of malathion induced apoptosis in testicular germ cells of goat. Two IBTs (4b; R = CH(3), 5b; R(1) = Cl) showed very high survival rate of cells whereas IBT 4f (R = NO(2)) showed some exceptional behaviour by increasing the apoptosis. These IBTs nullify the cytotoxic effect of malathion on mitochondria, following p53-independent pathway.
Asunto(s)
Apoptosis/efectos de los fármacos , Células Germinativas/efectos de los fármacos , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Testículo/citología , Animales , Supervivencia Celular/efectos de los fármacos , Células Germinativas/citología , Cabras , Humanos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacología , Masculino , Sulfonamidas/química , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
Four pyrimidine nucleosides wherein a benzensulfonamide group is linked to the C-5 position of the uracil nucleobase through a triazolyl or an alkynyl linker were prepared by Cu(I)-assisted azide-alkyne cycloadditions (CuAAC) or Sonogashira reactions, respectively, and incorporated into oligonucleotides. Efficient π-π-stacking between two or more phenyltriazoles in the major groove was found to increase the thermal stability of a DNA:RNA duplex significantly. On the other hand, the alkynyl group was not as efficient in stacking as the triazolyl group. No effect of positional orientation of the sulfonamide group on the stacking efficiency was observed, and the most stable DNA:RNA duplex contained four consecutive sulfonamide substituted phenyltriazole moieties in the major groove.
Asunto(s)
Oligonucleótidos/química , Oligonucleótidos/síntesis química , ARN/química , Sulfonamidas/química , Disparidad de Par Base , TemperaturaRESUMEN
1,3-Diaryl-4-formylpyrazoles 8 bearing benzenesulfonamide moiety at position-1 were synthesized as important intermediates following Vilsmeier-Haack strategy. Aldehyde moiety of 4-formylpyrazole was then converted into carboxylic acid 9, cyano 10 and carbothioamide 11 using established procedures. Out of these 4-functionalized pyrazoles, pyrazole-4-carboxylic acids 9 and carbothioamides 11 were evaluated for their in vitro antibacterial activity against four pathogenic bacterial strains namely, Staphylococcus aureus, Bacillus subtilis (Gram-positive), Escherichia coli, Pseudomonas aeruginosa (Gram-negative), and in vitro antifungal activity against two pathogenic fungal strains namely, Aspergillus niger and Aspergillus flavus. Three tested compounds, 9e, 11b and 11f exhibited moderate antibacterial activity against Gram-positive bacteria and 9g showed moderate antifungal activity against the tested fungi. However, none of the compounds showed any activity against Gram-negative bacteria.
Asunto(s)
Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Hongos/efectos de los fármacos , Pirazoles/síntesis química , Pirazoles/farmacología , Antiinfecciosos/química , Ácidos Carboxílicos/química , Pruebas de Sensibilidad Microbiana , Pirazoles/química , Sulfonamidas/química , BencenosulfonamidasRESUMEN
Three pyrimidine nucleosides with differently substituted phenyltriazoles attached to the 5-position were prepared by Cu(I)-assisted azide-alkyne cycloadditions (CuAAC) and incorporated into oligonucleotides. Efficient π-π-stacking between two or more phenyltriazoles in the major groove was found to increase the thermal stability of a DNA:RNA duplex significantly. The best stacking, and most stable duplex, was obtained by a sulfonamide substituted derivative.