Synthesis and Antifungal Activity of 1‐Aryl‐3‐phenethylamino‐1‐propanone Hydrochlorides and 3‐Aroyl‐4‐aryl‐1‐phenethyl‐4‐piperidinols

Mono‐Mannich bases, 1‐aryl‐3‐phenethylamino‐1‐propanone hydrochlorides, 1a, 2a , 3a , 4a , 5a , 6a , 7a , 8a , 9a , and semi‐cyclic mono‐Mannich bases, 3‐aroyl‐4‐aryl‐1‐phenethyl‐4‐piperidinols, 1b , 2b , 3b , 4b , 5b , 6b , 7b , 8b , 9b , were synthesized by a non‐classical Mannich reaction. The aryl part was: C₆H₅ for 1a , 1b ; 4‐CH₃C₆H₄ for 2a , 2b ; 4‐CH₃OC₆H₄ for 3a , 3b ; 4‐ClC₆H₄ for 4a , 4b ; 4‐FC₆H₄ for 5a , 5b ; 4‐BrC₆H₄ for 6a , 6b ; 2,4‐(Cl)₂C₆H₃ for 7a , 7b ; 4‐NO₂C₆H₄ for 8a , 8b ; and C₄H₃S(2‐yl) i. e., 2‐thienyl for 9a , 9b . Piperidinol compounds 2b , 3b , 4b , 5b , 7b , 8b , and 9b are reported here for the first time. The synthesized compounds were tested against seven types of plant pathogenic fungi and three types of human pathogenic fungi using the agar dilution assay. Itraconazole was tested against Candida parapsilosis as the reference compound, while Nystatin was tested as the reference compound against the other fungi. Compounds 1a , 1b , 2a , 4a , 4b , 5a , 5b , 6a , 7a , 8a , 9a , and 9b can be selected as model compounds to develop new antifungal agents against the human pathogen Microsporum canis. Compounds 8a and 8b , which had a similar antifungal activity compared with the reference compound Nystatin against the plant pathogen Aspergillus flavus, can serve as model compounds to develop new antifungal agents to solve agricultural problems.     

The synthesis of (S)‐di‐n‐propyl‐(8‐isoxazol‐5‐yl‐1,2,3,4‐tetrahydronaphthalen‐2‐yl)amine hydrochloride and its C‐14‐labeled isotopomer

The partial ergoline LY228729 (1) which was a potent 5HT_1A agonist has been studied clinically. Somewhat later, a related analog, (S)‐di‐n‐propyl‐(8‐isoxazol‐5‐yl‐1,2,3,4‐tetrahydronaphthalen‐2‐yl)amine (2a) which in addition to potent 5HT_1A agonist activity was a muscarinic antagonist, was chosen for clinical development for use in the treatment of irritable bowel syndrome. In the course of pre‐clinical evaluation of 2a , radiolabeled material was required for ADME studies. In this paper, we have discussed the preparation of 2a and 2b (the C‐14‐labeled isotopomer of 2a ). Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis and mycobacterial evaluation of 5‐substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido‐[2,3‐d]pyrimidin‐4(3H)‐one derivatives

5‐Substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido[2,3‐d]pyrimidin‐4(3H)‐one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus as well as a human monocyte‐derived macrophage (THP‐1), and murine macrophage (RAW 264.7) cell lines to assess their antibacterial and cytotoxic potential, respectively. The compounds showed activity in the range of 1.95–125 µg/ml against M. tuberculosis but showed no activity against M. aurum, E. coli, and S. aureus, indicating selectivity towards slow‐growing mycobacterial pathogens. The compounds exhibited very low to no cytotoxicity up to 500 µg/ml concentration against eukaryotic cell lines. The most potent molecule, 2l , showed a minimum inhibitory concentration of 1.95 µg/ml against M. tuberculosis H37Rv and a selectivity index of >250 against both the eukaryotic cell lines. Furthermore, 2l showed moderate inhibition of whole‐cell mycobacterial drug‐efflux pumps when compared to verapamil, a known potent inhibitor of efflux pumps. Thus, derivative 2l was identified as an antituberculosis hit molecule, which could be used to yield more potent lead molecules.     

Preparation of 1,2,3,4,6‐penta‐O‐galloyl‐[U‐14C]‐D‐glucopyranose

The synthesis of 1,2,3,4,6‐penta‐O‐galloyl‐[U‐¹⁴C]‐D‐glucopyranose is described. [U‐¹⁴C] glucopyranose was reacted with tri‐O‐benzylgallic acid forming 1,2,3,4,6‐penta(tri‐O‐benzylgalloyl)‐[U‐¹⁴C]‐D‐glucopyranose as chromatograpically separable anomers. Removal of the benzyl group by catalytic hydrogenation afforded 1,2,3,4,6‐penta‐O‐galloyl‐[U‐¹⁴C]‐D‐glucopyranose in 54% overall yield. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis and characterization of tritium labeled N‐((R)‐1‐((S)‐4‐(4‐chlorophenyl)‐4‐hydroxy‐3,3‐dimethylpiperidin‐1‐yl)‐3‐methyl‐1‐oxobutan‐2‐yl)‐3‐sulfamoylbenzamide

N‐((R)‐1‐((S)‐4‐(4‐chlorophenyl)‐4‐hydroxy‐3,3‐dimethylpiperidin‐1‐yl)‐3‐methyl‐1‐oxobutan‐2‐yl)‐3‐sulfamoylbenzamide is a potent C‐C chemokine receptor 1 (CCR1) antagonist. The compound, possessing benzamide functionality, successfully underwent tritium/hydrogen (T/H) exchange with an organoiridium catalyst (Crabtree's catalyst). The labeling pattern in the product was studied with liquid chromatography–mass spectrometry, time‐of‐flight mass spectrometry, and ³H‐NMR. Overall, multiple labeled species were identified. In addition to the anticipated incorporation of tritium in the benzamide moiety, tritium labeling was observed in the valine portion of the molecule including substitution at its chiral carbon. Using authentic standards, liquid chromatography analysis of the labeled compound showed complete retention of stereochemical configuration.     

Antithrombotic Activity of a Newly Synthesized Coumarin Derivative 3‐(5‐Hydroxy‐2,2‐dimethyl‐chroman‐6‐yl)‐N‐{2‐[3‐(5‐hydroxy‐2,2‐dimethyl‐chroman‐6‐yl)‐propionylamino]‐ethyl}‐propionamide

Anti‐platelet therapy is a useful strategy to prevent acute thromboembolic artery occlusions. This study was designed to assess the efficacy of seselin derivatives against murine pulmonary thromboembolism, bleeding time, platelet activation and thrombosis. Administration of C3 (16 mg/kg) offered 70% protection against collagen‐ and epinephrine‐induced pulmonary thromboembolism and 30% protection against arachidonic acid‐induced death in mice, without adversely affecting bleeding time. No significant difference was observed by C3 in ferric chloride‐induced arterial thrombosis in rats. Significant reduction in thrombus weight was observed in arteriovenous shunt model. In rat PRP, C3 reduced ADP and collagen‐induced platelet aggregation. In chronic hamster model of dyslipidemia, administration of C3 (16 mg/kg p.o. for 90 days) had no effect on plasma lipids, vasoreactivity and platelet adhesion. C3 fed hamsters showed reduced whole‐blood aggregation response to ADP and collagen compared to HC‐fed hamsters. In addition, C3 augmented thrombin time; however, time to occlusion was not increased. These results convincingly demonstrated that C3 is a novel molecule that reduces the risk of thrombosis and alleviates prothrombotic state associated with hyperlipidemia without any adverse effect on bleeding time. The high benefit/risk ratio of this compound makes it a suitable candidate for future valid studies.     

New biological investigations on 3‐bromophenyl 6‐acetoxymethyl‐2‐oxo‐2H‐1‐benzopyran‐3‐carboxylate as anti‐angiogenic agent

The development of blood vessels inside tumors is required to provide the nutrients and oxygen needed for tumor growth and to allow the spread of cancer cells at a distance to form metastasis. Angiogenesis is also implicated in ocular diseases like age‐related macular degeneration. The present work describes the potential anti‐angiogenic properties of a coumarinic derivative, 3‐bromophenyl 6‐acetoxymethyl‐2‐oxo‐2H‐1‐benzopyran‐3‐carboxylate (IK9), previously described as a potent inhibitor of HT 1080 fibrosarcoma cell invasion in vitro and tumor growth in vivo. In vivo, ex vivo, and in vitro models were used to delineate the anti‐angiogenic properties of IK9. The anti‐angiogenic effect of IK9 was demonstrated in vivo in a choroidal neovascularization mice model and additionally ex vivo in a rat aortic ring assay where it was more active than the known matrix metalloproteinase inhibitor Ro 28‐2653. IK9 did not affect apoptosis, proliferation, or endothelial cell invasiveness in vitro. These findings suggest a complex mechanism of action of the compound via direct or indirect effects on endothelial cell properties. This study identifies IK9 as a new potent inhibitor of angiogenesis and suggests its potential use as a therapeutic agent. Drug Dev Res 71, 2010. © 2010 Wiley‐Liss, Inc.     

Solid‐phase synthesis of peptides containing the spin‐labeled 2,2,6,6‐tetramethylpiperidine‐1‐oxyl‐4‐amino‐4‐carboxylic acid (TOAC)

Abstract: 2,2,6,6‐Tetramethylpiperidine‐1‐oxyl‐4‐amino‐4‐carboxylic acid (TOAC) is a nitroxide spin‐labeled, achiral C^α‐tetrasubstituted amino acid recently shown to be not only an effective β‐turn and 3₁₀/α‐helix promoter in peptides, but also an excellent rigid electron paramagnetic resonance probe and fluorescence quencher. Here, we demonstrate that TOAC can be effectively incorporated into internal positions of peptide sequences using Fmoc chemistry and solid‐phase synthesis in an automated apparatus.     

Synthesis of carbon‐14 analogue of N‐(1‐methyl‐2‐oxo‐5‐phenyl‐2,3‐dihydro‐1H‐benzo[e][1,4]diazepin‐3‐yl)‐benzamide‐[carboxyl‐14C] as CCK‐A antagonist

N‐(1‐methyl‐2‐oxo‐5‐phenyl‐2,3‐dihydro‐1H‐benzo[e][1,4]diazepin‐3‐yl)‐benzamide‐[carboxyl‐¹⁴C] has been synthesized from benzonitrile‐[cyano‐¹⁴C]. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of 2H‐ and 3H‐labeled N‐cyclopropylmethyl‐7α‐[(R)‐1‐hydroxy‐1‐methyl‐3‐(2thienyl)‐propyl]‐6,14‐endoethano‐6,7,8,14‐tetrahydro nororipavine

A procedure for deuterium and tritium labeling of the titled compound, an analgesic agent, was developed. A secondary amine intermediate was acylated to an acylamide, then the carbonyl function was reduced by LiAlD₄ to yield the tertiary amine. In the tritium‐labeled synthesis, the process utilized a bromo‐substituted precursor, which was subsequently reduced with ³H₂ in the presence of a Pd/C catalyst. The labeled compounds were successfully applied in pharmacokinetic and pharmacological studies. Copyright © 2005 John Wiley & Sons, Ltd.     

1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine Pretreatment Attenuates Methamphetamine‐Induced Dopamine Toxicity

Abstract: The effects of pretreatment with MPTP (1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine) on the acute and long‐term effects of methamphetamine on striatal dopamine were evaluated in BALB/c mice. Four subcutaneous injections of a non‐toxic dose of MPTP (8 mg/kg, at 2 hr intervals) were followed three days later by a toxic regimen of methamphetamine (four injections of 4 mg/kg, at 2 hr intervals) and mice were sacrificed immediately or three days later. Control mice received saline in place of the MPTP or methamphetamine and mice were observed for acute changes in body temperature, self‐injurious behaviour, and striatal dopamine metabolites, or long‐term changes in striatal dopamine levels, tyrosine hydroxylase immunoreactivity and glial fibrillary acidic protein. It was observed that pretreatment with MPTP protected mice against the acute increase in body temperature caused by the methamphetamine but, at the same time, delayed the occurrence of self‐injurious behaviour following the repeated injections of methamphetamine. Likewise, pretreatment with MPTP attenuated the long‐term depletion of striatal dopamine induced by the methamphetamine as well as the large increase in glial fibrillary acidic protein and the reduction in tyrosine hydroxylase immunoreactivity. The MPTP‐treatment itself did not alter any of these neurotoxic markers. Finally, the acute decrease in 3,4‐dihydroxyphenyacetic acid levels and increased ratio of 3‐methoxytyramine/dopamine observed 60 min. after a single injection of methamphetamine (4 mg/kg) were also attenuated in MPTP‐treated mice. These results are discussed in the context of the hypothesis that the low‐dose treatment with MPTP may modify exchange diffusion across the striatal cell membrane thereby altering the acute and long‐lasting effects of methamphetamine.     

Characterization of the dopamine D3 receptor agonist R(+)‐7‐hydroxy‐N,N‐di‐n‐propyl‐2‐aminotetralin‐induced hypo‐ and hypermotility in mice

The present study was designed to characterize the dopamine D₃ receptor agonist R(+)‐7‐hydroxy‐N,N‐di‐n‐propyl‐2‐aminotetralin (R(+)‐7‐OH‐DPAT)‐induced changes in locomotor activity in mice. Although R(+)‐7‐OH‐DPAT (0·01–10 mg/kg) produced a significant decrease in horizontal and vertical motility within 15 min after the start of behavioural measurements, the dopamine D₁ receptor antagonist R(+)‐SCH23390 (0·05 mg/kg) and the dopamine D₃ receptor antagonist (+)‐UH232 (10 mg/kg) had no antagonistic effects on the R(+)‐7‐OH‐DPAT (3 mg/kg)‐induced hypomotility, while the dopamine D₂ receptor antagonist S(−)‐sulpiride (20 mg/kg) augmented it. Although R(+)‐7‐OH‐DPAT (0·01–1 mg/kg) had no marked effects on horizontal or vertical motility, higher doses (3 and 10 mg/kg) of the drug produced a significant increase in horizontal or vertical motility from 30 to 90 min after the start of the behavioural measurements. S(−)‐sulpiride (20 mg/kg) and (+)‐UH232 (10 mg/kg) almost completely inhibited the R(+)‐7‐OH‐DPAT (3 mg/kg)‐induced hypermotility, whereas the antagonistic effects of R(+)‐SCH23390 (0·05 mg/kg) were partial. These results suggest that the R(+)‐7‐OH‐DPAT‐induced hypermotility is mediated principally via dopamine D₂ and D₃ receptors, whereas it is unlikely that the hypomotility results from the activation of presynaptic dopamine D₂ or D₃ receptors. Copyright © 1999 John Wiley & Sons, Ltd.     

Synthesis of a labeled inhibitor of HIV‐1 attachment: 1‐(4‐benzoylpiperazin‐1‐yl)‐2‐(4,7‐dimethoxy‐1H‐pyrrolo[2,3‐c]pyridinyl‐3‐yl‐[U‐14C]ethane‐1,2‐dione,BMS‐488043‐14C

BMS‐488043 is a potent inhibitor of the interaction between HIV‐1 gp120 and the host cell receptor CD4. We prepared the carbon‐14‐labeled version to support preclinical studies of the compound. It was prepared from ethyl [U‐¹⁴C]oxalyl chloride by a sequence using Friedel–Crafts acylation reaction. The overall radiochemical yield was 82% with a purity of >99.9%. Copyright © 2010 John Wiley & Sons, Ltd.     

In‐vitro and in‐vivo antivenin activity of 2‐[2‐(5,5,8a‐trimethyl‐2‐methylene‐decahydro‐naphthalen‐1‐yl)‐ethylidene]‐succinaldehyde against Ophiophagus hannah venom

Objectives Curcuma zedoaroides A. Chaveerach & T. Tanee, locally known as Wan‐Paya‐Ngoo‐Tua‐Mia, is commonly used in the North‐Eastern part of Thailand as a ‘snakebite antidote’. The aim of this study was to isolate the active compound from the rhizome of C. zedoaroides, to determine its structure and to assess its antagonistic activity in vitro and in vivo against King cobra venom. Methods The active compound was obtained from C. zedoaroides by extraction with acetone followed by purification using column chromatography; its X‐ray structure was determined. Its inhibition of venom lethality was studied in vitro in rat phrenic nerve‐hemidiaphragms and in vivo in mice. Key findings The acetone extract of the Curcuma rhizomes contained a C20 dialdehyde, [2‐(5,5,8a‐trimethyl‐2‐methylene‐decahydro‐naphthalen‐1‐yl)‐ethylidene]‐succinaldehyde, as the major component. The isolated curcuma dialdehyde was found active in vitro and in vivo for antivenin activity against the King cobra venom. Using isolated rat phrenic nerve‐hemidiaphragm preparations, a significant antagonistic effect on the inhibition of neuromuscular transmission was observed in vitro. Inhibition on muscle contraction, produced by the 4 μg/ml venom, was reversed by 2–16 μg/ml of Curcuma dialdehyde in organ bath preparations over a period of 2 h. Mice intraperitoneally injected with 0.75 mg/kg venom and dialdehyde at 100 mg/kg had a significantly increased survival time. Injection of Curcuma dialdehyde (100 mg/kg) 30 min before the subcutaneous injection of the venom resulted in a 100% survival time after 2 h compared with 0% for the control group. Conclusions The in vitro and in vivo evaluation confirmed the medicinal use of traditional snake plants against snakebites. The bioactivity is linked to an isolated molecule and not a result of synergistic effects of a mixture. The active compound was isolated and the structure fully elucidated, including its stereochemistry. This dialdehyde is a versatile chemical building block and can be easily obtained from this plant source.     

Convenient synthesis of 18F‐radiolabeled R‐(−)‐N‐n‐propyl‐2‐(3‐fluoropropanoxy‐11‐hydroxynoraporphine

Aporphines are attractive candidates for imaging D₂ receptor function because, as agonists rather than antagonists, they are selective for the receptor in the high affinity state. In contrast, D₂ antagonists do not distinguish between the high and low affinity states, and in vitro data suggests that this distinction may be important in studying diseases characterized by D₂ dysregulation, such as schizophrenia and Parkinson's disease. Accordingly, MCL‐536 (R‐(?)‐N‐n‐propyl‐2‐(3‐[¹⁸F]fluoropropanoxy‐11‐hydroxynoraporphine) was selected for labeling with ¹⁸F based on in vitro data obtained for the non‐radioactive (¹⁹F) compound. Fluorine‐18‐labeled MCL‐536 was synthesized in 70% radiochemical yield, >99% radiochemical purity, and specific activity of 167 GBq/µmol (4.5 Ci/µmol) using p‐toluenesulfonyl (tosyl) both as a novel protecting group for the phenol and a leaving group for the radiofluorination.     

Design,Synthesis, and Antitumor Activity of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones

A series of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones ( C1 – C35 ) were designed and synthesized, and the structures of compounds (Z)‐ C27 and (Z)‐ C29 were confirmed by single‐crystal X‐ray diffraction. The antitumor activities of these novel compounds against cervical cancer (HeLa), lung cancer (A549), and breast cancer (MCF‐7) cell lines were evaluated in vitro. Majority of the title compounds exhibited strong antitumor activities and were much more promising than the positive control Taxol, which were also accompanied by lower cytotoxicity to normal cells. In particular, compounds (E,Z)‐ C24 exhibited the most consistent potent activities against three neoplastic cells with IC₅₀ values ranging from 3.2 to 7.1 μm . Further researches demonstrated that compounds (E,Z)‐ C24 could induce cell apoptosis and arrest cell cycle at the G2/M and S phases. Meanwhile, the structure–activity relationship between the configurations and cytotoxicity of the compounds was also investigated.     

Synthesis and in‐vitro Antimycobacterial Evaluation of 1‐(Cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐ 8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids

Fifty one newer 1‐(cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids were synthesized from 1,3‐dichloro‐2‐methylbenzene and evaluated for in‐vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi‐drug resistant Mycobacterium tuberculosis (MDR‐TB), and Mycobacterium smegmatis (MC²). Among the synthesized compounds, 1‐cyclopropyl‐1,4‐dihydro‐7‐(3,4‐dihydro‐6,7‐dimethoxyisoquinolin‐2(1H)‐yl)‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9p was found to be the most active compound in vitro with a MIC value of 0.39 μM against MTB. Against MDR‐TB, compound 7‐(2‐carboxy‐5,6‐dihydroimidazo[1,2‐a]pyrazin‐7(8H)‐yl)‐1‐cyclopropyl‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9n was found to be the most active with a MIC value of 0.09 μM.     

Syntheses,calcium channel modulation effects,and nitric oxide release studies of O2‐alkyl‐1‐(pyrrolidin‐1‐yl) diazen‐1‐ium‐1,2‐diolate 4‐aryl(heteroaryl)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates

A group of racemic 4‐aryl(heteroary)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxy‐lates possessing a potential nitric oxide donor C‐5 O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester [alkyl=(CH₂)_n, n=1–4] substituent were synthesized using a modified Hantzsch reaction. Compounds having a C‐4 2‐trifluoromethylphenyl ( 16 ), 2‐pyridyl ( 17 ), or benzofurazan‐4‐yl ( 20 ) substituent generally exhibited more potent smooth‐muscle calcium channel antagonist activity (IC₅₀ values in the 0.55 to 38.6 μM range) than related analogs having a C‐4 3‐pyridyl ( 18 ), or 4‐pyridyl ( 19 ) substituent with IC₅₀ values > 29.91 μM, relative to the reference drug nifedipine (IC₅₀=0.0143 μM). The point of attachment of C‐4 isomeric pyridyl substituents was a determinant of antagonist activity where the relative potency profile was 2‐pyridyl > 3‐pyridyl and 4‐pyridyl. Subgroups of compounds 16a–d , 17a–d , and 20a–d having alkyl spacer groups of variable chain length [–CO₂(CH₂)_nO–, n=1–4] exhibited small differences in calcium channel antagonist potency. Replacement of the ester “methyl” moiety of Bay K 8644 by an O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate group provided the Bay K 8644 group of analogs 16a‐d that retained the desired cardiac positive inotropic effect. The most potent compound in this group, O²‐ethyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2‐trifluoromethylphenyl)pyridine‐5‐carboxylate ( 16b , EC₅₀=0.096 μM) is about eightfold more potent positive inotrope (cardiac calcium channel agonist) than the reference compound Bay K 8644 (EC₅₀=0.77 μM). A similar replacement of the ester “isopropyl” group in the C‐4 benzofurazan‐4‐yl group of compounds by an O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester substituent provided compounds 20 (n=1 and 4) that were approximately equipotent cardiac positive inotropes with the parent reference compound PN 202‐791 ( 3 , EC₅₀=9.40 μM). The O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester moiety present in 1,4‐dihydropyridine calcium channel modulating compounds 16–20 is not a suitable ?NO donor moiety because the percent nitric oxide released upon in vitro incubation with either l ‐cysteine, rat serum, or pig liver esterase was less than 1%. Drug Dev. Res. 60:204–216, 2003. © 2003 Wiley‐Liss, Inc.     

Synthesis and kinetics studies of N′‐(2‐(3,5‐disubstituted‐4H‐1,2,4‐triazol‐4‐yl)acetyl)‐6/7/8‐substituted‐2‐oxo‐2H‐chromen‐3‐carbohydrazide derivatives as potent antidiabetic agents

A novel series of N′‐(2‐(3,5‐disubstituted‐4H‐1,2,4‐triazol‐4‐yl)acetyl)‐6/7/8‐substituted‐2‐oxo‐2H‐chromen‐3‐carbohydrazides were synthesized and studied for their α‐glucosidase inhibition activity. Most of the synthesized compounds exhibited potential α‐glucosidase inhibition activity with IC₅₀ values ranging from 0.96 ± 0.02 to 32.86 ± 0.73 µg/ml. Among them, compounds 3e and 4e , having a methoxy group on the coumarin ring, proved to be the most potent ones, showing an enzyme inhibition activity with IC₅₀ = 0.96 ± 0.02 and 1.44 ± 0.06 µg/ml, respectively. The kinetic study through Lineweaver–Burk plots revealed that the inhibition mechanism of the most active compounds 3d, 3e, 4d , and 4e , on the α‐glucosidase activity, was found to be in the competitive mode.