Diastereoselective Synthesis of Morpholine Derivatives from Grignard Reagents and N-Sulfinyl Imines

The stereoselective synthesis of C3-substituted morpholine derivatives has been achieved through a two-step process involving diastereoselective addition of a Grignard reagent to a sulfinyl imine, followed by cyclization.

Design, Synthesis and Biological Evaluation of Morpholinated Isatin-Quinoline Hybrids as Potential Anti-Breast Cancer Agents.

Keeping in view the emerging need of potent and safer anti-breast cancer agents as well as pharmacological attributes of isatin, quinoline and morpholine derivatives, novel hydrazone linked morpholinated isatin-quinoline hybrids has been designed, synthesized and evaluated as anti-breast cancer agents. Synthesized hybrid compounds were preliminary screened against two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all synthetics showed potent inhibitory potential against hormone positive MCF-7 cells while inactive against hormone negative MDA-MB-231 cells. Potent compounds were further evaluated against L929 (noncancerous skin fibroblast) cell line and found highly selective for MCF-7 cells over L929 cells. Cell cycle analysis confirmed that most potent compound AS-4 (MCF-7: GI50 = 4.36 µM) cause mitotic arrest at G2/M-phase. Due to higher selectivity toward estrogen receptor alpha (ERα) dependent MCF-7 cells various binding interactions of AS-4 with ERα are also streamlined, suggesting the capability of AS-4 in completely blocking ERα. Overall study suggest that, AS-4 can act as a potential lead for further development of potent and safer anti-breast cancer agents.

An acidic morpholine derivative containing glyceride from thraustochytrid, Aurantiochytrium

A novel acidic morpholine-derivative containing glyceride (M-glyceride) was isolated from the cells of two strains of the thraustochytrid, Aurantiochytrium. The glyceride accounted for approximately 0.1 -0.4% of the lyophilized cells. The glyceride consisted of peaks I (85%) and II (15%). The structures of the intact and acetylated glycerides were elucidated by liquid chromatography-quadrupole time-of-flight chromatograph mass spectrometer (LC–Q/TOF) and NMR spectroscopy. The hydrate type of M-glyceride was detected as a minor component by LC–MS/MS. By 2D-NMR experiments, peaks I of the intact M-glyceride were elucidated as 1,2-didocosapentaenoyl-glyceryl-2′-oxy-3′-oxomorpholino propionic acid, and peak II was estimated 1,2-palmitoyldocosapentaenoyl- and/or 1,2-docosapentaenoylpalmitoyl-glyceryl-2′-oxy-3′-oxomorpholino propionic acid. The double bond position of docosapentaenoic acid was of the ω − 6 type (C22 = 5.ω − 6). The M-glyceride content varied by the cell cycle. The content was 0.4% of lyophilized cells at the mid logarithmic phase, and decreased to 0.1% at the mid stationary phase. When cells were grown in 1.0 µM M-glyceride-containing growth media, cell growth was stimulated to 110% of the control. With 0.1 µM acetyl M-glyceride, stimulation of 113% of the control was observed. Finding morpholine derivatives in biological components is rare, and 2-hydroxy-3-oxomorpholino propionic acid (auranic acid) is a novel morpholine derivative.

SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF MANNICH BASES CONTAINING MORPHOLINE MOIETY

A variety of morpholine derivatives as mannich bases were prepared through mannich reaction by reacting 4-nitro acetophenone as compound containing active hydrogen, substituted benzaldehyde and morpholine as secondary amine compound. All the synthesized compounds structures were characterized by physical analysis data and spectral analysis data (IR and 1H-NMR spectral analysis). The newly synthesized compounds were evaluated for their antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa in comparision with standard drug Streptomycin. However the antibacterial activity of the synthesized compounds against the tested organisms was found to possess good to moderate activity.

Synthesis, In vitro and In silico Evaluation of a Series of Pyrazolines as New Anticholinesterase Agents

Background: Pyrazolines, electron-rich nitrogen carriers, are of great importance due to their potential applications for the treatment of many diseases including inflammation, infectious diseases and neurodegenerative disorders. Objectives: The purpose of this work was to synthesize new pyrazoline derivatives and evaluate their anticholinesterase effects. Methods: 1-Aryl-5-[4-(piperidin-1-yl)phenyl]-3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazoles (1-7) were synthesized via the treatment of 1-(3,4-dimethoxyphenyl)-3-[4-(piperidin-1-yl)phenyl]prop-2- en-1-one with arylhydrazine hydrochloride derivatives in acetic acid, whereas 1-aryl-5-[4- (morpholin-4-yl)phenyl]-3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazoles (8-14) were obtained by the treatment of 1-(3,4-dimethoxyphenyl)-3-[4-(morpholin-4-yl)phenyl]prop-2-en-1-one with arylhydrazine hydrochloride derivatives in acetic acid. Their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were determined using a modification of Ellman’s spectrophotometric method. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were performed using Schrödinger’s Maestro molecular modeling package. Results: In general, piperidine derivatives were found to be more effective than morpholine derivatives on cholinesterases (ChEs). 1-Phenyl-5-[4-(piperidin-1-yl)phenyl]-3-(3,4-dimethoxyphenyl)- 4,5-dihydro-1H-pyrazole (1) and 1-(4-cyanophenyl)-5-[4-(piperidin-1-yl)phenyl]-3-(3,4- dimethoxyphenyl)-4,5-dihydro-1H-pyrazole (7) were identified as the most effective AChE inhibitors in this series with 40.92% and 38.98%, respectively. Compounds 1 and 7 were docked into the active site of human AChE (PDB code: 4EY7). Both the compounds were found to be capable of forming π-π stacking interactions with Trp286. Based on in silico ADME studies, these compounds are expected to have reasonable oral bioavailability. Conclusion: In the view of this work, the structural modification of the identified agents is going on for the generation of new anticholinesterase agents with enhanced efficacy.