Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations

Sasidharan, Rani; Eom, Bo Hyun; Heo, Jeong Hyun; Park, Jong Eun; Abdelgawad, Mohamed A.; Musa, Arafa; Gambacorta, Nicola; Nicolotti, Orazio; Manju, S. L.; Mathew, Bijo; Kim, Hoon

doi:10.1080/14756366.2020.1842390

Cited by 29 publications

(13 citation statements)

References 51 publications

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“…The modification of a simple amino to the denser cyclic functionalities has been reported by various groups. The ChEs inhibitory potential of various morpholine-based chalcone analogs was reported by Sasidharan et al, ( Figure 12 ) [ 46 ]. Among the screened analogs, compound 7 exerted the maximum inhibitory potential (IC 50 ; AChE = 6.1 μM, BChE = 18.09 μM).…”

Section: Structural Attachment Of Various Chemical Functionalities On...mentioning

confidence: 88%

“…Further, these analogs exhibited weaker BChE inhibition (>40 µM). PAMPA-BBB assay suggested their higher membrane permeability to brain (Pe-14.44 to 16.34 × 10 −6 cm/s) [46]. In another study, a series of piperazine-substituted chalcone was synthesized and their AChE inhibitory potential evaluated by Mathew et al, (Figure 13) [47].…”

Section: Chalcone Derivatives With Amine Substituent Modificationmentioning

confidence: 99%

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Structural Modifications on Chalcone Framework for Developing New Class of Cholinesterase Inhibitors

George

Koyiparambath

Sunitha

et al. 2022

IJMS

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Due to the multifaceted pharmacological activities of chalcones, these scaffolds have been considered one of the most privileged frameworks in the drug discovery process. Structurally, chalcones are α, β-unsaturated carbonyl functionalities with two aryl or heteroaryl units. Amongst the numerous pharmacological activities explored for chalcone derivatives, the development of novel chalcone analogs for the treatment of Alzheimer’s disease (AD) is among the research topics of most interest. Chalcones possess numerous advantages, such as smaller molecular size, opportunities for further structural modification thereby altering the physicochemical properties, cost-effectiveness, and convenient synthetic methodology. The present review highlights the recent evidence of chalcones as a privileged structure in AD drug development processes. Different classes of chalcone-derived analogs are summarized for the easy understanding of the previously reported analogs as well as the importance of certain functionalities in exhibiting cholinesterase inhibition. In this way, this review will shed light on the medicinal chemistry fraternity for the design and development of novel promising chalcone candidates for the treatment of AD.

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Section: Structural Attachment Of Various Chemical Functionalities On...mentioning

confidence: 88%

Section: Chalcone Derivatives With Amine Substituent Modificationmentioning

confidence: 99%

Structural Modifications on Chalcone Framework for Developing New Class of Cholinesterase Inhibitors

George

Koyiparambath

Sunitha

et al. 2022

IJMS

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“…Therefore, development of such drugs to act as both kinase and COX inhibitors is predicted to be very effective and selective in treating cancer [14][15][16][17][18][19]. Among the highly effective and reactive organic scaffolds is the chalcone nucleus, which has anticancer, antioxidant, anti-inflammatory, and analgesic effects [20][21][22][23]. It can be used to synthesize and develop certain lead compounds that have reasonable plasma concentrations and low toxicity.…”

Section: Introductionmentioning

confidence: 99%

EGFR and COX-2 Dual Inhibitor: The Design, Synthesis, and Biological Evaluation of Novel Chalcones

et al. 2022

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For most researchers, discovering new anticancer drugs to avoid the adverse effects of current ones, to improve therapeutic benefits and to reduce resistance is essential. Because the COX-2 enzyme plays an important role in various types of cancer leading to malignancy enhancement, inhibition of apoptosis, and tumor-cell metastasis, an indispensable objective is to design new scaffolds or drugs that possess combined action or dual effect, such as kinase and COX-2 inhibition. The start compounds A1 to A6 were prepared through the diazo coupling of 3-aminoacetophenone with a corresponding phenol and then condensed with two new chalcone series, C7–18. The newly synthesized compounds were assessed against both COX-2 and epidermal growth factor receptor (EGFR) for their inhibitory effect. All novel compounds were screened for cytotoxicity against five cancer cell lines. Compounds C9 and G10 exhibited potent EGFR inhibition with IC50 values of 0.8 and 1.1 µM, respectively. Additionally, they also displayed great COX-2 inhibition with IC50 values of 1.27 and 1.88 µM, respectively. Furthermore, the target compounds were assessed for their cytotoxicity against pancreatic ductal cancer (Panc-1), lung cancer (H-460), human colon cancer (HT-29), human malignant melanoma (A375) and pancreatic cancer (PaCa-2) cell lines. Interestingly, compounds C10 and G12 exhibited the strongest cytotoxic effect against PaCa-2 with average IC50 values of 0.9 and 0.8 µM, respectively. To understand the possible binding modes of the compounds under investigation with the receptor cites of EGFR and COX-2, a virtual docking study was conducted.

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“…Based on the previous studies, in the simple framework of non-nitrogenous based chalcones, the selective and potent candidates against the MAO-B isoform were characterized by the presence of methoxyl or methyl substituents at the para or ortho positions of phenyl ring A [26][27][28][29][30][31]. At the same time, the presence of halogens and electron-releasing substituents, preferably methoxy, dimethylamino, ethyl acetohydroxamate, and ethoxy on the para position of phenyl ring B, are well tolerated in the MAO-B inhibition [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]. Based upon the existing literature, it is clearly proved that 99% of chalcone derived compounds are a selective and reversible type of MAO-B inhibitors [51][52][53].…”

Section: Introductionmentioning

confidence: 99%

Trimethoxylated Halogenated Chalcones as Dual Inhibitors of MAO-B and BACE-1 for the Treatment of Neurodegenerative Disorders

Vishal

Khames

et al. 2021

Pharmaceutics

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Six halogenated trimethoxy chalcone derivatives (CH1–CH6) were synthesized and spectrally characterized. The compounds were further evaluated for their inhibitory potential against monoamine oxidases (MAOs) and β-secretase (BACE-1). Six compounds inhibited MAO-B more effectively than MAO-A, and the 2′,3′,4′-methoxy moiety in CH4–CH6 was more effective for MAO-B inhibition than the 2′,4′,6′-methoxy moiety in CH1–CH3. Compound CH5 most potently inhibited MAO-B, with an IC50 value of 0.46 µM, followed by CH4 (IC50 = 0.84 µM). In 2′,3′,4′-methoxy derivatives (CH4-CH6), the order of inhibition was –Br in CH5 > -Cl in CH4 > -F in CH6 at the para-position in ring B of chalcone. CH4 and CH5 were selective for MAO-B, with selectivity index (SI) values of 15.1 and 31.3, respectively, over MAO-A. CH4 and CH5 moderately inhibited BACE-1 with IC50 values of 13.6 and 19.8 µM, respectively. When CH4 and CH5 were assessed for their cell viability studies on the normal African Green Monkey kidney cell line (VERO) using MTT assays, it was noted that both compounds were found to be safe, and only a slightly toxic effect was observed in concentrations above 200 µg/mL. CH4 and CH5 decreased reactive oxygen species (ROS) levels of VERO cells treated with H2O2, indicating both compounds retained protective effects on the cells by antioxidant activities. All compounds showed high blood brain barrier permeabilities analyzed by a parallel artificial membrane permeability assay (PAMPA). Molecular docking and ADME prediction of the lead compounds provided more insights into the rationale behind the binding and the CNS drug likeness. From non-test mutagenicity and cardiotoxicity studies, CH4 and CH5 were non-mutagenic and non-/weak-cardiotoxic. These results suggest that CH4 and CH5 could be considered candidates for the cure of neurological dysfunctions.

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Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations

Cited by 29 publications

References 51 publications

Structural Modifications on Chalcone Framework for Developing New Class of Cholinesterase Inhibitors

Structural Modifications on Chalcone Framework for Developing New Class of Cholinesterase Inhibitors

EGFR and COX-2 Dual Inhibitor: The Design, Synthesis, and Biological Evaluation of Novel Chalcones

Trimethoxylated Halogenated Chalcones as Dual Inhibitors of MAO-B and BACE-1 for the Treatment of Neurodegenerative Disorders

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