A green method for the synthesis of isoxazolyl aryl thieno[2,3-d]pyrimidinones using reusable polyethylene glycol as simple solvent catalyst and evaluation of anti-microbial activity

336-347Novel series of isoxazolyl aryl thieno[2,3-d]pyrimidinones 4 have been synthesized from (E)-2-amino-5-(3-methyl-4- nitroisoxazol-5-yl)-N-(3-methyl-5-styrylisoxazol-4-yl)-4-arylthiophene-3-carboxamide synthon 3. Compound 3 is obtained by reaction of 2-(3-methyl-4-nitro-isoxazol-5-yl)-1-aryl-ethanone 1, N1-{3-methyl-5-[(E)-2-aryl-1-ethenyl]-4-isoxazolyl}-2- cyanoacetamide 2 and elemental sulfur in PEG-400. Isoxazolyl aryl thieno[2,3-d]pyrimidinones 4 have been obtained from compounds 3 by tandem N-acetylation and cyclodehydration with acetic anhydride. Compounds 3a-q and 4a-q have been characterized by IR, 1H and 13C NMR, and mass spectral data. The title compounds 4a-q have been evaluated for their antimicrobial activity. Compounds 4b, 4c, 4d, 4e, 4j, 4k, 4l and 4m exhibit significant antimicrobial activity, compared to that of standard drugs

Synthesis and biological evaluation of novel phosphonyl thiazolo pyrazoles

867-876A series of novel dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-8-phenyl-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate 11a-g have been synthesized by the reaction of chalcone derivatives of (E)-5-benzylidene-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-phenylthiazolidin-4-one 10a-g with Bestmen Ohira reagent. The chemical structures of newly synthesized compounds have been elucidated by IR, NMR, MS and elemental analysis. The compounds 11a-g have been evaluated for their nematicidal activity against Dietylenchus myceliophagus and Caenorhabditis elegans. Compound 11b, 11c, 11g and 11f show appreciable nematicidal activity

Synthesis and biological evaluation of novel phosphonyl thiazolo pyrazoles

A series of novel dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-8-phenyl-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate 11a-g have been synthesized by the reaction of chalcone derivatives of (E)-5-benzylidene-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-phenylthiazolidin-4-one 10a-g with Bestmen Ohira reagent. The chemical structures of newly synthesized compounds have been elucidated by IR, NMR, MS and elemental analysis. The compounds 11a-g have been evaluated for their nematicidal activity against Dietylenchus myceliophagus and Caenorhabditis elegans. Compound 11b, 11c, 11g and 11f show appreciable nematicidal activity

Mechanistic insights into apoptosome dependent caspase-9 processing and activation

textDuring stress-induced apoptosis, the initiator caspase-9 is activated by the Apaf-1 apoptosome and must remain bound in order to retain significant catalytic activity. Nevertheless, in apoptotic cells, the vast majority of processed caspase-9 is paradoxically observed outside of the complex. We demonstrate herein that apoptosome-mediated cleavage of procaspase-9 occurs exclusively through a CARD-displacement mechanism, so that unlike the effector procaspase-3, procaspase-9 cannot be processed by the apoptosome as a typical substrate. Indeed, procaspase-9 possessed higher affinity for the apoptosome and could displace processed caspase-9 from the complex, thereby facilitating a continuous cycle of procaspase-9 recruitment/activation, processing, and release from the complex. Due to its rapid autocatalytic cleavage, however, procaspase-9 per se contributed little to the activation of procaspase-3. Thus, the Apaf-1 apoptosome functions as a proteolytic-based “molecular timer”, wherein the intracellular concentration of procaspase-9 sets the overall duration of the timer, procaspase-9 autoprocessing activates the timer, and the rate at which processed caspase-9 dissociates from the complex (and thus loses its capacity to activate procaspase-3) dictates how fast the timer “ticks” over. To understand the physiological relevance of molecular timer in vivo, we are currently generating caspase-9 knock-in mouse models. These mouse models will enhance our understanding of the importance of caspase-9 processing within the apoptosome.Institute for Cellular and Molecular Biolog

Synthesis and evaluation of anti-inflammatory, antioxidant and antimicrobial activities of densely functionalized novel benzo [d] imidazolyl tetrahydropyridine carboxylates

A series of novel benzo[d]imidazolyl tetrahydropyridine carboxylates 7a–n have been synthesized by one-pot multi-component reaction of (E)-5-(benzylidene amino)-1H-benzo[d]imidazole-2-thiol 3, 5-amino-2-mercapto-benzimidazole 4, aromatic aldehyde 5, and ethyl acetoacetate 6 in acetonitrile using ceric ammonium nitrate (CAN) as Lewis acid catalyst, and evaluated for their anti-inflammatory, antioxidant, antibacterial and antifungal activities. All tested compounds showed appreciable activity against the standard drugs

The apaf-1•procaspase-9 apoptosome complex functions as a proteolytic-based molecular timer

During stress-induced apoptosis, the initiator caspase-9 is activated by the Apaf-1 apoptosome and must remain bound to retain significant catalytic activity. Nevertheless, in apoptotic cells the vast majority of processed caspase-9 is paradoxically observed outside the complex. We show herein that apoptosome-mediated cleavage of procaspase-9 occurs exclusively through a CARD-displacement mechanism, so that unlike the effector procaspase-3, procaspase-9 cannot be processed by the apoptosome as a typical substrate. Indeed, procaspase-9 possessed higher affinity for the apoptosome and could displace the processed caspase-9 from the complex, thereby facilitating a continuous cycle of procaspase-9 recruitment/activation, processing, and release from the complex. Owing to its rapid autocatalytic cleavage, however, procaspase-9 per se contributed little to the activation of procaspase-3. Thus, the Apaf-1 apoptosome functions as a proteolytic-based \u27molecular timer\u27, wherein the intracellular concentration of procaspase-9 sets the overall duration of the timer, procaspase-9 auto-processing activates the timer, and the rate at which the processed caspase-9 dissociates from the complex (and thus loses its capacity to activate procaspase-3) dictates how fast the timer \u27ticks\u27 over. The EMBO Journal (2009) 28, 1916-1925. doi:10.1038/emboj.2009.152; Published online 4 June 200

Design, Synthesis, Antibacterial and Antifungal Activity of Novel 2-[(E)-2-aryl-1-ethenyl]-3-(2-sulfanyl-1H-benzo[d]imidazole-5-yl)-3,4- dihydro-4-quinolinones

The novel 2-[(E)-2-aryl-1-ethenyl]-3-(2-sulfanyl-1H-benzo[d]imidazole-5-yl)-3,4- dihydro-4-quinolinones (4a-j) analogs were synthesized by Knoevenagel condensation of a solution of 2-methyl-3-(2-sulfanyl-1H-benzo[d]imidazole-5-yl)-3,4-dihydro-4-quinazolinone (3) with aromatic aldehyde in presence of catalytic amount of piperidine. Compounds (4a-j) showed significant biological activity against all the standard strains. All the synthesized compounds were characterized on the basis of their IR, 1H NMR, MASS spectroscopic data and elemental analyses. All the compounds have been tested for antimicrobial and antifungal activity by the cup-plate method

A green method for the synthesis of isoxazolyl aryl thieno[2,3-d]pyrimidinones using reusable polyethylene glycol as simple solvent catalyst and evaluation of anti-microbial activity

Novel series of isoxazolyl aryl thieno[2,3-d]pyrimidinones 4 have been synthesized from (E)-2-amino-5-(3-methyl-4-nitroisoxazol-5-yl)-N-(3-methyl-5-styrylisoxazol-4-yl)-4-arylthiophene-3-carboxamide synthon 3. Compound 3 is obtained by reaction of 2-(3-methyl-4-nitro-isoxazol-5-yl)-1-aryl-ethanone 1, N1-{3-methyl-5-[(E)-2-aryl-1-ethenyl]-4-isoxazolyl}-2-cyanoacetamide 2 and elemental sulfur in PEG-400. Isoxazolyl aryl thieno[2,3-d]pyrimidinones 4 have been obtained from compounds 3 by tandem N-acetylation and cyclodehydration with acetic anhydride. Compounds 3a-q and 4a-q have been characterized by IR, 1H and 13C NMR, and mass spectral data. The title compounds 4a-q have been evaluated for their antimicrobial activity. Compounds 4b, 4c, 4d, 4e, 4j, 4k, 4l and 4m exhibit significant antimicrobial activity, compared to that of standard drugs.

The Apaf-1•procaspase-9 apoptosome complex functions as a proteolytic-based molecular timer

During stress-induced apoptosis, the initiator caspase-9 is activated by the Apaf-1 apoptosome and must remain bound to retain significant catalytic activity. Nevertheless, in apoptotic cells the vast majority of processed caspase-9 is paradoxically observed outside the complex. We show herein that apoptosome-mediated cleavage of procaspase-9 occurs exclusively through a CARD-displacement mechanism, so that unlike the effector procaspase-3, procaspase-9 cannot be processed by the apoptosome as a typical substrate. Indeed, procaspase-9 possessed higher affinity for the apoptosome and could displace the processed caspase-9 from the complex, thereby facilitating a continuous cycle of procaspase-9 recruitment/activation, processing, and release from the complex. Owing to its rapid autocatalytic cleavage, however, procaspase-9 per se contributed little to the activation of procaspase-3. Thus, the Apaf-1 apoptosome functions as a proteolytic-based ‘molecular timer', wherein the intracellular concentration of procaspase-9 sets the overall duration of the timer, procaspase-9 autoprocessing activates the timer, and the rate at which the processed caspase-9 dissociates from the complex (and thus loses its capacity to activate procaspase-3) dictates how fast the timer ‘ticks' over