Morpholine Derivatives Research Articles

Overview of Piperidine and Morpholine Derivatives as Promising Sources of Biologically Active Compounds (Review)

Introduction. The search for new, effective and safe pharmacologically active substances remains an urgent task in the field of pharmacy. Many compounds of the piperidine and morpholine series are widely used in medical practice and belong to an important group of biologically active compounds. An informational, literature search on the synthesis of new derivatives of piperidine and morpholine was carried out. The article summarizes the results of studies of new derivatives of piperidine and morpholine as potential sources of biologically active substances.Text. The review is devoted to the relationship between the pharmacological activity of the N-derivatives of piperidine and morpholine in relation to various biological targets and the structure of the substance, the importance of the piperidine and morpholine rings in the design and development of drugs is highlighted. Piperidine and morpholine are considered as prerogative structures not only for increasing activity, but also for obtaining biological substances with desired therapeutic properties and improved pharmacokinetics.Conclusion. The literature review shows the current trend towards the study of morpholine and piperidine derivatives, reveals their high pharmacophore activity. The review will provide researchers with the necessary knowledge base to make chemical structural changes to the structures of drug leaders to enhance pharmacological activities.

Homology modeling, virtual screening, molecular docking, and dynamics studies for discovering Staphylococcus epidermidis FtsZ inhibitors.

Staphylococcus epidermidis is the most common cause of medical device-associated infections and is an opportunistic biofilm former. Among hospitalized patients, S. epidermidis infections are the most prevalent, and resistant to most antibiotics. In order to overcome this resistance, it is imperative to treat the infection at a cellular level. The present study aims to identify inhibitors of the prokaryotic cell division protein FtsZ a widely conserved component of bacterial cytokinesis. Two substrate binding sites are present on the FtsZ protein; the nucleotide-binding domain and the inter-domain binding sites. Molecular modeling was used to identify potential inhibitors against the binding sites of the FtsZ protein. One hundred thirty-eight chemical entities were virtually screened for the binding sites and revealed ten molecules, each with good binding affinities (docking score range -9.549 to -4.290kcal/mol) compared to the reference control drug, i.e., Dacomitinib (-4.450kcal/mol) and PC190723 (-4.694kcal/mol) at nucleotide and inter-domain binding sites respectively. These top 10 hits were further analyzed for their ADMET properties and molecular dynamics simulations. The Chloro-derivative of GTP, naphthalene-1,3-diyl bis(3,4,5-trihydroxybenzoate), Guanosine triphosphate (GTP), morpholine and methylpiperazine derivative of GTP were identified as the lead molecules for nucleotide binding site whereas for inter-domain binding site, 1-(((amino(iminio)methyl)amino)methyl)-3-(3-(tert-butyl)phenyl)-6,7-dimethoxyisoquinolin-2-ium, and Chlorogenic acidwere identified as lead molecules. Molecular dynamics simulation and post MM/GBSA analysis of the complexes revealed good protein-ligand stability predicting them as potential inhibitors of FtsZ (Figure 1). Thus, identified FtsZ inhibitors are a promising lead compounds for S. epidermidis related infections.

AMINO DERIVATIVES OF ACRIDINE: SYNTHESIS, STUDY OF ANTICHOLINESTERASE AND ANTIOXIDANT ACTIVITIES

A simple and accessible approach to the synthesis of new amine derivatives of acridine based on the direct C–H functionalization methodology was developed. The inhibitory effect of the synthesized compounds on cholinesterases and carboxylesterases, as well as their antioxidant activity, was studied. A moderate inhibition of BChE by the morpholine and pyrazole derivatives of acridine and a high anti-BChE activity of the N-methyl-piperazine one were shown.

N-Tosyl-1,2,3-triazoles as Scaffolds for Morpholines: The Total Synthesis of (–)-Chelonin A

AbstractSubstituted morpholine derivatives appear frequently in biologically active compounds and thus novel routes towards such structures are of great synthetic interest. Herein, we report the total syntheses of chelonin A, a morpholine-derived marine natural product with reported antibacterial and anti-inflammatory activity. The key step in this process was a rhodium carbenoid 1,3-insertion into a bromohydrin O–H bond, followed by annulation, leading to a 2,6-disubstituted-3,4-dihydro-2H-1,4-oxazine core. This work was then extended to deliver the first asymmetric total synthesis of (–)-chelonin A using an enantioenriched bromohydrin, prepared in turn via asymmetric transfer hydrogenation of an α-bromoketone.

Gold(i)-catalyzed cycloisomerization of alcohol or amine tethered-vinylidenecyclopropanes providing access to morpholine, piperazine or oxazepane derivatives: a carbene versus non-carbene process

A gold(i)-catalyzed adjustable intramolecular cyclization of alcohol or amine tethered-vinylidenecyclopropanes (VDCPs).

Synthesis and Anticancer Evaluation of Novel Indole Based Arylsulfonylhydrazides against Human Breast Cancer Cells.

A series of novel indole based sulfonohydrazide derivatives (5a-k) containing morpholine heterocyclic ring were synthesized through multistep chemical reactions. The target compounds (5a-k) were prepared by the reaction of substituted phenyl sulfonylhydrazides (2a-k) with morpholine derivative of indole 3-carboxaldehyde. All the target compounds were screened for their anticancer activity in vitro against the estrogen receptor-positive breast cancer line MCF-7 and triple-negative breast cancer cell line, MDA-MB-468. It was found that among all the evaluated compounds, the chemotype 4-chloro-N'-((1-(2-morpholinoethyl)-1H-indol-3-yl)methylene)benzenesulfonohydrazide (5f) showed promising inhibition of both MCF-7 and MDA-MB-468 cancer cells with the respective IC50 values of 13.2 μM and 8.2 μM. Compound 5f was found to be nontoxic against HEK 293 noncancerous cells in the studied concentration range, therefore indicating that such chemotypes inhibit the proliferation of cancerous cells selectively and significantly.

Discovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor

Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure and renal function and hence is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. However, the development of direct renin inhibitors (DRIs) with favorable oral bioavailability has been a longstanding challenge for many years. This problem was thought to be because most of the reported DRIs were peptide-like structures or nonpeptide-like structures with a molecular weight (MW) of > 600. Therefore, we tried to find nonpeptidomimetic DRIs with a MW of < 500 and discovered the promising 2-carbamoyl morpholine derivative 4. In our efforts to improve the pharmacokinetic profile of 4 without a significant increase in the MW, we discovered compound 18 (SPH3127), which demonstrated higher bioavailability and a more potent antihypertensive effect in preclinical models than aliskiren and has completed a phase II clinical trial for essential hypertension.

Discovery of Novel 2-Carbamoyl Morpholine Derivatives as Highly Potent and Orally Active Direct Renin Inhibitors.

The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin, the first and rate-limiting enzyme of the RAAS, is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. Therefore, various direct renin inhibitors (DRIs) have been researched over recent decades; however, most exhibited poor pharmacokinetics and oral bioavailability due to the peptidomimetic or nonpeptidomimetic structures with a molecular weight (MW) of >600, and only aliskiren is approved. This study introduces a novel class of DRIs comprised of a 2-carbamoyl morpholine scaffold. These compounds have a nonpeptidomimetic structure and a MW of <500. The representative compound 26 was highly potent despite not occupying S1'-S2' sites or the opened flap region used by other DRIs and exerted a significant antihypertensive efficacy via oral administration on double transgenic mice carrying both the human angiotensinogen and the human renin genes.

Five compounds based on [Mo12O40]8− and [β-Mo8O26]4− anions: Electrochemical sensing, photocatalytic and supercapacitor properties

In this paper, five compounds were synthesized by hydrothermal method by employing morpholine derivatives with different N sites and numbers. These five compounds are [MII(HL1)(H2O)2][(H2Mo12O40)0.5] (M = Co(1), Ni(2)), [MII(HL2)2(H2O)2](β-Mo8O26)] (M = Cu(3), Ni(4), Zn(5)), respectively (L1 = 4-[2-(5-Pyridin-2-yl-[1,2,4]triazol-1-yl)-ethyl]-morpholine, L2 = 4-[2-(5-Pyrazin-2-yl-[1,2,4]triazol-1-yl)-ethyl]-morpholine). These compounds were characterized through single crystal X-ray diffraction, FT-IR and PXRD. Compounds 1 and 2 are isomorphic and have a rare [Mo12O40]8- unit. The adjacent [Mo12O40]8- units are connected by bi-nuclear subunits [M2II(L1)2]4+ (M = Co/Ni) to form a 1D structure. Compounds 3–5 are isostructural owning 1D metal–organic chains. The [β-Mo8O26]4- anions are dissociative. Compounds 1–5 can be employed as electrochemical sensors to identify NO2− anions, Cr(VI) cations. In addition, compound 4 has larger capacitance and can be used as a super capacitor. Compounds 1–5 can not only be employed as catalysts for photodegradation of organic dyes, but also as catalysts for photoreduction of Cr(VI), which owns good selectivity.

ПРОИЗВОДНЫЕ МОРФОЛИНА В ПСИХОФАРМАКОЛОГИИ

Morpholine derivatives are nitrogen-containing compounds which are of great interest for psychopharmacology. In particular, among them there are medicines used in clinical practice for the treatment of psychiatric diseases and syndromes: the anxiolytic fabomotizol (afobazole), the antidepressants reboxetine and moclobemide; reboxetine and viloxazine are also used for attention deficit hyperactivity disorder. In addition, this article provides information on a number of other morpholine derivatives with anxiolytic, nootropic and antipsychotic activity.

Laboratory Diagnosis and In Vitro Antifungal Susceptibility of Trichophyton quinckeanum from Human Zoonoses and Cats.

The “One Health” concept increasingly demonstrates the global spread of pathogenic (also eukaryotic) microorganisms and their zoonotic potential. Dermatophytes can cause superficial mycoses in humans and animals. Furthermore, the number of transmissions from asymptomatic carriers to humans has been on the rise over the last few years. This study was focused on the detailed characterisation of clinical isolates of Trichophyton quinckeanum with epidemiological analyses and characterisation of their in vitro antifungal susceptibility patterns. The isolated dermatophytes were identified with a combination of conventional and molecular methods. In turn, their susceptibility in vitro was tested according to the Clinical and Laboratory Standards Institute (CLSI) M38 ed.3 protocol. A total of 36 strains were isolated, with 21 cases of T. quinckeanum zoonoses resulting from direct contact with symptomatic cats (58.3%). The other 15 strains (41.7%) were isolated simultaneously from healthy cats and their owners. All strains showed high susceptibility to allylamine, pyridinone, and phenyl morpholine derivatives but were resistant to fluconazole and ketoconazole. In conclusion, our study shows the frequency of zoonoses contracted from asymptomatic cats. Moreover, the antifungal susceptibility profiles indicate the serious risk posed to animal owners by resistant strains of T. quinckeanum, which are often responsible for recalcitrant-to-treatment cases.

Electrochemical Syntheses of Substituted Morpholine Derivatives

Electrochemical Syntheses of Substituted Morpholine Derivatives

An updated review on morpholine derivatives with their pharmacological actions

The invention of newer chemical entities, which have some therapeutically worth is always a great challenge. It is no doubt that it is a lengthier process. We have several drugs in the market for treatment of wide variety of diseases. The marketed drugs available may be heterocyclic or non-heterocyclic derivatives. Always it was found that heterocyclic derivatives have wide variety of pharmacological activity. The intension of this review is to highlight one of the important heterocyclic rings i.e.: Morpholine. Several works have been done on this nucleus, which should be enlighten for more and more applicability.

Design and synthesis of novel s-triazine based coumarin, quinoline, morpholine and isoniazid derivatives and their antitubercular and antimicrobial evaluation

This study presents the synthesis of novel s-triazine derivatives. The synthetic route to final s-triazines consists of two nucleophilic substitution reactions of 4-hydroxy benzonitrile and 8-hydroxyquinoline or 8-hydroxy-7-methyl coumarin or isoniazid or morpholine with 2,4,6-trichloro-1,3,5-triazine resulting in 2,4-disubstituted-6-chloro-1,3,5-triazine derivatives to introduce the various amines functionality. The structures of the compounds have been elucidated with the aid of IR, 1H and 13C NMR, mass spectroscopy and elemental analysis. The title compounds have then been investigated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain by using BACTEC MGIT and Lowenstein-Jensen MIC method and antimicrobial evaluation.

Electrochemical Synthesis of Substituted Morpholines via a Decarboxylative Intramolecular Etherification.

An efficient method for the synthesis of 2,6-multisubstituted morpholines via an electrochemical intramolecular etherification has been developed. The method, which is operationally simple and easy to scale up, provides various substituted morpholine derivatives in high yields. The utility of this method is showcased by the synthesis of 2,2,6,6-tetrasubstituted morpholines, which are difficult to synthesize efficiently using previously reported strategies.

Nucleophilic substitution reactions of unbranched alkyl amines using triazine reagents

Since amines are present in many organic, biological, and drug molecules, a strategy of synthesizing desired compounds by nucleophilic substitution reactions of these amines is very attractive. By using triazine reagents, we have found that nucleophilic substitution reactions of unbranched alkyl amines via morpholine derivatives are feasible. This method can be performed under milder reaction conditions than those in previously reported methods.

A series of polyoxometalate compounds by tuning N sites and numbers of ligands: syntheses, characterization and electrochemical sensing, and photocatalytic and supercapacitor properties

Using morpholine derivatives with different N sites and numbers, we synthesized seven compounds by a hydrothermal method. They can photocatalytically degrade organic dyes and reduce Cr(vi) and can be used as electrochemical sensors.4has capacitor performance.

Development of next-generation formulation against Fusarium oxysporum and unraveling bioactive antifungal metabolites of biocontrol agents

Biocontrol agents serve as a sustainable means of controlling wilt caused by the widespread plant pathogen, Fusarium oxysporum f. sp. lycopersici. The present study aimed to develop water dispersible granules (WDG) using response surface methodology (RSM) for Bacillus subtilis MTCC 2274 and Trichoderma harzianum MTCC 3928, and to compare their antifungal efficacy with other formulations. Further, characterization of the bioactive metabolites responsible for biocontrol was performed. A new microbial formulation, WDG, was developed in the present study with talcum powder (substrate), alginic acid (dispersing agent) and acacia gum (wetting agent) (suspensibility 82.23%; wetting time 2.5 min; dispersion time 10.08 min) that fulfilled the guidelines of Collaborative International Pesticides Analytical Council (CIPAC). In planta study demonstrated that WDG of B. subtilis showed maximum reduction in disease incidence (48%) followed by talc formulation of B. subtilis (44%) and WDG of T. harzianum (42%) with profound effect on plant growth promotion. B. subtilis and T. harzianum demonstrated protease (929 and 846 U ml−1 min−1), chitinase (33.69 and 154 U ml−1 min−1), and β-1,3-glucanase (12.69 and 21.47 U ml−1 min−1) activities. Culture filtrates of B. subtilis and T. harzianum exhibited significant inhibition against mycelial growth of pathogen. The compounds present in the culture filtrates were identified with GC–MS as fatty acids, alkanes, phenols, benzene, pyran derivatives etc. The major non-volatile compounds in bioactive antifungal fraction were identified as derivatives of morpholine and piperdine for T. harzianum and B. subtilis, respectively. The findings propose a multivariate biocontrol mechanism against phytopathogen by production of hydrolytic enzymes, volatile and non-volatile compounds, together with development of an efficient next-generation formulation.

Design, synthesis, and biological evaluation of novel morpholinated isatin-quinoline hybrids as potent anti-breast cancer agents.

Keeping in view the emerging need for potent and safer anti-breast cancer agents as well as the pharmacological attributes of isatin, quinolone, and morpholine derivatives, novel hydrazine-linked morpholinated isatin-quinoline hybrids were designed, synthesized, and evaluated as anti-breast cancer agents. The synthesized hybrid compounds were preliminarily 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 being inactive against hormone-negative MDA-MB-231 cells. Potent compounds were further evaluated against the L929 (noncancerous skin fibroblast) cell line and found to be highly selective for MCF-7 cells over L929 cells. Cell cycle analysis confirmed that the most potent compound AS-4 (MCF-7: GI50 = 4.36 µM) causes mitotic arrest at the 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 to completely block ERα. Overall, the study suggests that AS-4 can act as a potential lead for further development of potent and safer anti-breast cancer agents.

Synthesis and In Vitro Antibacterial Activity of Morpholine Derived Benzenesulphonamides

This study investigated the synthesis of sulphonamide substituted derivatives of morpholine from appropriate benzenesuphonyl chlorides obtaining excellent yields of oily products. The structural elucidation was confirmed by 1H and 13C NMR spectral analysis. The synthesized compounds; 4(-phenylsulonphonyl)morpholine and N-(4-(4-Methylbenzene-1-sulphonyl)morpholine) were evaluated for their in vitro antibacterial activity against bacteria; B. subtilus, S. typhi and E. coli. Both compounds were moderately active against B. Subtilis, but had no inhibitive activity against E. coli. Whereas, N-(4-(4-Methylbenzene-1-sulphonyl)morpholine) was moderately active against S. typhi. The physiochemical properties of the synthesized compounds evaluated, revealed its’ potential for drugs.