[show abstract][hide abstract] ABSTRACT: A series of 1,3-disubstituted pyrrolo[2,3-b]quinoxalines has been designed for the potential inhibition of PDE4 without inhibiting luciferase. A ligand/PTC (phase transfer catalyst) free intramolecular Heck cyclization strategy was used to prepare these compounds, some of which showed significant inhibition of PDE4B (IC50 ≈ 5-14 μM) and growth inhibition of oral cancer cells (CAL 27) but not inhibition of luciferase in vitro. They also showed acceptable safety profiles but no apoptosis in zebrafish embryos.
[show abstract][hide abstract] ABSTRACT: Ligand/PTC-free intramolecular Heck reaction: synthesis of pyrroloquinoxalines and their evaluation against PDE4/luciferase/oral cancer cell growth in vitro and zebrafish in vivo a A series of 1,3-disubstituted pyrrolo[2,3-b]quinoxalines has been designed for the potential inhibition of PDE4 without inhibiting luciferase. A ligand/PTC (phase transfer catalyst) free intramolecu-lar Heck cyclization strategy was used to prepare these com-pounds, some of which showed significant inhibition of PDE4B (IC 50 ≈ 5–14 μM) and growth inhibition of oral cancer cells (CAL 27) but not inhibition of luciferase in vitro. They also showed acceptable safety profiles but no apoptosis in zebrafish embryos. Phosphodiesterases (PDEs), a superfamily of enzymes that degrade cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), are classified into 11 families e.g. PDE1–PDE11. 1 One of them, e.g. the cAMP-specific enzyme PDE4 has been targeted to treat several inflammatory diseases including COPD, asthma and CNS related disorders. However, recent literature has indicated that PDE4 is widely expressed in tumour cells and thus inhibition of PDE4 in cancerous cells could be a new therapeutic target for cancer. For example, PDE4 inhibitors have been reported to inhibit brain tumor cell growth, 2,3 reduce proliferation and angiogenesis of lung cancer cell lines 4 and display the ability for selective apoptosis of malignant cells without affecting normal cells. 5 Thus, targeting PDE4 can be beneficial in treat-ing cancer. Due to our long term interest in PDE4 inhibitors, 6 we now report the design and synthesis of 1,3-disubstituted pyrrolo[2,3-b]quinoxalines as new and potential inhibitors of PDE4. To the best of our knowledge this class of heterocycles has not previously been explored as PDE4/cancer cell growth inhibitors. Recently, we reported the luciferase inhibiting properties of a series of 2-substituted pyrrolo[2,3-b]quinoxalines A (Fig. 1) that were originally designed for potential inhibition of PDE4. 7
[show abstract][hide abstract] ABSTRACT: A new strategy for converting antipsychotic drug olanzapine into PDE4 inhibitors is described via the design and Pd/C mediated synthesis of novel N-indolylmethyl olanzapine derivatives. One compound showed good inhibition (IC 1.1 μM) and >10 fold selectivity towards PDE4B over D that was supported by docking studies. This compound also showed significant inhibition of TNF-α and no major toxicities in cell lines and a zebrafish embryo model except the teratogenic effects to be re-assessed in rodents.
[show abstract][hide abstract] ABSTRACT: Background
The N-acylation of sulfonamides and carbamates with acid anhydrides in the presence of Lewis catalysis has been described. The N-acylation of various sulfonamides and carbamates with carboxylic acid anhydrides were effectively promoted by catalytic amount of CeCl3 under solvent-free conditions to produce the corresponding N-acyl products in good to excellent yields. The synthesized compounds were tested for their antifungal activity.Methods
To a mixture of sulfonamide and anhydride, and anhydrous CeCl3 was added and the reaction was stirred for the given time. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water and brine solution. The combined organic layers were dried over Na2SO4 and evaporated in vacuum. The crude compound was purified by column chromatography to afford the corresponding N-acylated product.ResultsSynthesized compounds were screened for their antifungal activity against two virulent organisms Malassezia furfur and Malassezia pachydermatis. The compounds were tested in different concentrations ranging from 200 uM to 1 uM and taking their growth observations at OD 600 nm at different time intervals. The growth in the treated wells was compared with the growth in the untreated wells. Ketoconazole was used as control, among the compounds screened 2a, 2i and 4a showed activity than the standard antifungal drug i.e. Ketoconazole.Conclusion
Synthesized compounds were evaluated for their antifungal activity and three compounds 2a, 2i, and 4a showed very good activity against both the organisms, for the first time N-acyl sulfonamides and carbamates classes were evaluated as potential anti-Malassezia agents.
Journal of Pharmacy Research. 02/2013; 7(2):195–199.
[show abstract][hide abstract] ABSTRACT: Prompted by the potential of screening strategy in Zebrafish for the identification of valuable pharmacophore a series of triazole substituted mefenamic acid derivatives were designed and synthesized via a CuAAC under green conditions. A variety of terminal alkynes were reacted with the azide obtained from mefenamic acid to give the expected products in good to excellent yields. When screened for apoptosis, teratogenicity and hepatotoxicity in zebrafish embryos one of these compounds showed encouraging apoptotic properties and safety profiles and seemed to have medicinal value.
[show abstract][hide abstract] ABSTRACT: We demonstrate the synthesis of multifunctional 3,4-dihydroquinoxalin-2-amine derivatives 4 through a three-component condensation reactions of a substituted o-phenylenediamines 1 (OPDA), diverse ketones 2 and various isocyanides 3 in the presence of a catalytic amount of p-toluenesulfonic acid (PTSA) affording excellent yields (82–96%) and 10 mol % of silica gel supported sulfuric acid with good yields (85–98%) in ethanol at room temperature (2–4 h). We also carried out the anti-neuroinflammatory activity of 3,4-dihydroquinoxalin-2-amine derivatives and some of the compounds exhibited good activity.
[show abstract][hide abstract] ABSTRACT: Pyranones fused with a pyrazolopyrimidine moiety were prepared via regioselective construction of pyranone ring using (Pd/C-mediated)coupling–iodocyclization followed by Sonogashira/Heck/Suzuki reactions. The pyrazolopyrimidine based reactant required was obtained via a new H3PO3 mediated condensation reaction. This strategy has led to the discovery of a novel and potentially safe PDE4 inhibitor.
Medicinal Chemistry Communication 04/2012; 3:667-672. · 2.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: A regioselective route to novel mono triazolyl substituted quinolines has been developed via copper-catalyzed azide-alkyne cycloaddition (CuAAC) of 2,4-diazidoquinoline with terminal alkynes in DMF. The reaction provided bis triazolyl substituted quinolines when performed in water in the presence of Et(3)N. A number of the compounds synthesized showed promising anti-proliferative properties when tested in vitro especially against breast cancer cells.
[show abstract][hide abstract] ABSTRACT: The design and synthesis of 4-alkynyl pyrazole derivatives has led to the identification of new class of PDE4 inhibitors. All these compounds were accessed for the first time via a facile Pd/C-CuI-PPh(3) mediated C-C bond forming reaction between an appropriate pyrazole iodide and various terminal alkynes. In vitro PDE4B inhibitory properties and molecular modeling studies of some of the compounds synthesized indicated that 4-alkynyl pyrazole could be a promising template for the discovery of novel PDE4 inhibitors.
[show abstract][hide abstract] ABSTRACT: A clean and operationally simple method has been developed for the preparation of mutual prodrug using paracetamol and various nonsteroidal anti-inflammatory drugs. The methodology involves use of TFAA/H3PO4 in acetonitrile and a variety of mutual prodrugs has been prepared in good yields by using this single-step C–O bond forming reaction.
Green Chemistry Letters and Reviews 01/2012; · 1.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: A conceptually new three-component reaction was developed to construct a six-membered fused N-heterocyclic ring affording (pyrazolo)pyrimidines/pyridines as potential inhibitors of PDE4. The reaction is catalyzed by triflic acid in acetic acid in the presence of aerial oxygen.
Chemical Communications 11/2011; 48(3):431-3. · 6.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: A number of novel 1-(3-arylprop-2-ynyl) substituted 1,2-dihydroquinoline derivatives related to nimesulide and their 2-oxo analogues have been designed as potential inhibitors of PDE4. All these compounds were synthesized by using Sonogashira coupling as a key step. In vitro PDE4B inhibitory properties and molecular modeling studies of some of the compounds synthesized are presented.
[show abstract][hide abstract] ABSTRACT: The Pd-mediated alkynylation of N-(3-iodopyridin-2-yl)sulfonamide was investigated in the presence of 2-aminoethanol as a base. The combination of Pd/C–Cu catalysts and 2-aminoethanol facilitated the reaction to proceed via a coupling-cyclization sequence in a single-pot. Unlike earlier Pd-mediated two-step process the present reaction proceeds via a tandem C–C and C–N bond forming reaction affording a direct synthesis of 2-substituted-7-azaindole derivatives. A variety of novel 2-substituted-7-azaindoles were prepared by using this one-pot method. The methodology was explored for a formal synthesis of a Variolin B analogue. When tested in vitro some of the compounds synthesized showed promising sirtuin inhibiting properties in yeast without showing significant cell toxicities. Docking studies using the active molecules were carried out to understand the nature of their interactions with Sir2protein.
Medicinal Chemistry Communication 06/2011; 2(6):478-485. · 2.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: Impurities found in stressed and stability studies of olanzapine (polymorphic form-I) [1-7] in both drug substance and drug product are described. These impurities are identified as 4-(4-methyl-1-piperazinyl)-3-hydroxymethylidene-1H-benzo[b][1,4]diazepine-2(3H)-thione (hydroxymethylidene thione) and (Z)-4-(4-methyl-1-piperazinyl)-3-acetoxymethylidene-1H-benzo[b][1,4]diazapine-2(3H)-thione (acetoxymethylidene thione). An oxidative degradation pathway of olanzapine, for the formation of these impurities, has been proposed.
Journal of pharmaceutical and biomedical analysis 05/2011; 56(2):413-8. · 2.45 Impact Factor
[show abstract][hide abstract] ABSTRACT: A facile two-step method for the construction of fused pyrrole ring leading to 5-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-1-ones via C-C followed by intramolecular C-N bond forming reaction is described. In vitro pharmacological evaluation and molecular modelling studies of some of the compounds synthesized are presented.
[show abstract][hide abstract] ABSTRACT: The Pd/C-CuI-PPh(3) catalytic system facilitated C-C bond formation between 4-chlorothieno[2,3-d]pyrimidines and terminal alkynes in methanol with high selectivity without generating any significant side products arising from C-O bond formation between the chloro compounds and methanol. A variety of novel 4-alkynylthieno[2,3- d]pyrimidines were prepared via alkynylation of 4-chlorothieno[2,3-d]pyrimidines in good to excellent yields. Some of the compounds synthesized were tested for cytotoxic activity in vitro.
[show abstract][hide abstract] ABSTRACT: A new unknown impurity of cefoxitin formed during a gradient reverse phase high performance liquid chromatography (HPLC) analysis of stress stability samples of the drug substance cefoxitin, and the level of this impurity was found at up to 0.9%. This impurity was identified by LC-MS and characterized by (1H NMR, 13C NMR, LC/MS/MS, elemental analysis and FT-IR). Based on the spectral data, the impurity was named as, 3-[[(2R,3S)-[3-methoxy-3-N-[2-(thiophen-2-yl)acetamido]]-4-oxoazetidin-2-ylthio]-2-[(carbamoyloxy)methyl]]-acrylic acid. The structure of this impurity was also established unambiguously, prepared by isolation and co-injected into HPLC to confirm the retention time. To the best of our knowledge, this impurity has not been reported elsewhere. Structural elucidation of the impurity by spectral data is discussed in detail.