TNF-α and IL-6 inhibitors: Conjugates of N-substituted indole and aminophenylmorpholin-3-one as anti-inflammatory agents

Singh, Palwinder; Kaur, Sukhmeet; Sharma, Anuradha; Kaur, Gurcharan; Bhatti, Rajbir

doi:10.1016/j.ejmech.2017.09.003

Cited by 41 publications

(20 citation statements)

References 58 publications

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“…LPS is a main component of Gram-negative bacterial endotoxin and can directly activate macrophages to secrete pro-inflammatory cytokines, such as TNF-and IL-6 (Singh et al, 2017). In our study, (4)-(7) had no significant toxicity at 10 mM on RAW264.7 cells (Fig.…”

Section: Anti-inflammatory Activitymentioning

confidence: 50%

Synthesis, crystal structures and anti-inflammatory activity of four 3,5-bis(arylidene)-N-benzenesulfonyl-4-piperidone derivatives

Bai

Zhang

et al. 2018

Acta Crystallogr C

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of the olefinic double bonds. Molecules of both (4) and (6) are connected by hydrogen bonds into one-dimensional chains. In (5) and (7), pairs of adjacent molecules embrace through intermolecular hydrogen bonds to form a bimolecular combination, which are further extended into a two-dimensional sheet. The anti-inflammatory activity data reveal that (4)-(7) significantly inhibit LPS-induced interleukin (IL-6) and tumour necrosis factor (TNF-) secretion. Most importantly, (6) and (7), with strong electron-withdrawing substituents, display more potential inhibitory effects than (4) and (5).

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Section: Anti-inflammatory Activitymentioning

confidence: 50%

Synthesis, crystal structures and anti-inflammatory activity of four 3,5-bis(arylidene)-N-benzenesulfonyl-4-piperidone derivatives

Bai

Zhang

et al. 2018

Acta Crystallogr C

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“…Recently, Singh et al designed new anti‐inflammatory agents by combining indole and aminophenyl morpholinone moieties and evaluated them for TNF‐α and IL‐6 inhibitory activity in microglial cells. Derivatives 67 ‐ 69 (Figure ), inhibited these inflammatory cytokines (after their induction by LPS) by 51% to 71% and 35% to 53%, respectively.…”

Section: Pharmacological Activity Of Morpholine Derivatives On Varioumentioning

confidence: 99%

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Kourounakis

Xanthopoulos

Tzara

2019

Medicinal Research Reviews

168

114

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Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active‐site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug‐like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.

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“…To rationalize the obtained biological results, a molecular docking study was used to evaluate the potential interaction mechanism between compound 5c and TNF-α, IL-6, JNK1, ERK2. Compound 5c was first docked at the IL-6 (PDB code 1ALU) [ 40 ] and TNF-α (PDB code 2AZ5) [ 41 ] subunit interface. The docking poses of compound 5c were examined and the pose that had the lowest binding energy is shown in Figure 7 .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Evaluation of Thalidomide Derivatives as Potential Anti-Psoriasis Agents

Tang

Lin

Chen

et al. 2018

IJMS

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Several thalidomide derivatives were synthesized and evaluated for their anti-inflammatory activity. Introduction of the benzyl group to the parent thalidomide is unfavorable in which 2-(1-benzyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (4a) was inactivated. However, the inhibitory activities on TNF-α and IL-6 expression in HaCaT cells were improved by the substitution of a chloro- or methoxy- group at the phenyl position of 4a. The IL-6 inhibitory activity decreased in an order of 5c (69.44%) > 4c (48.73%) > 6c (3.19%) indicating the 3-substituted derivative is more active than the 4-substituted counterpart, which in turn is more active than the 2-substituted counterpart. Among them, 2-[1-(3-chlorobenzyl)-2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione (5c) was found to inhibit TNF-α and IL-6 expression in HaCaT cells with a higher potency than thalidomide and no significant cell cytotoxicity was detected at 10 μM. In psoriasis, Compound 5c reduced IL-6, IL-8, IL-1β and IL-24 in imiquimod-stimulated models. Our results indicated that compound 5c is a potential lead of novel anti-psoriasis agents. Structural optimization of compound 5c and its in vivo assay are ongoing.

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TNF-α and IL-6 inhibitors: Conjugates of N-substituted indole and aminophenylmorpholin-3-one as anti-inflammatory agents

Cited by 41 publications

References 58 publications

Synthesis, crystal structures and anti-inflammatory activity of four 3,5-bis(arylidene)-N-benzenesulfonyl-4-piperidone derivatives

Synthesis, crystal structures and anti-inflammatory activity of four 3,5-bis(arylidene)-N-benzenesulfonyl-4-piperidone derivatives

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Synthesis and Biological Evaluation of Thalidomide Derivatives as Potential Anti-Psoriasis Agents

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