Exploration of a library of piperonylic acid-derived hydrazones possessing variable aryl functionalities as potent dual cholinesterase and monoamine oxidase inhibitors

Kumar, Vipin; Sasi, Vishnu Mini; Kumar, Sandeep; Jaiswal, Shivani; Ayyannan, Senthil Raja

doi:10.1007/s11030-022-10564-9

Cited by 4 publications

(3 citation statements)

References 48 publications

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“…In order to assess the extent and effect of the interactions of our lead compound 28 with SHP2 allosteric site, molecular dynamics simulation studies were carried out by Desmond module [49] (Schrodinger Release 2021.1: Desmond Molecular Dynamics System, D. E. Shaw Research, New York, NY, 2021). The simulation was done for 100 ns on Maestro graphical user interface (Maestro, Schrodinger, LLC, New York, NY, 2021) which was also used for the preparation of input files and visualization of results.…”

Section: Resultsmentioning

confidence: 99%

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Design, Synthesis and Evaluation of Thioacetamide‐Tethered Thiadiazole‐1,2,4‐Triazole Hybrids as SHP2 Inhibitors for Cancer Therapy

Mitra,

Kumar,

Chaudhuri

et al. 2024

ChemistrySelect

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Src homology‐2 (SH2) domain‐containing phosphatase‐2 (SHP2), the first protooncogenic phosphatase is a key mediator in the development and progression of various cancers. Several allosteric sites have been identified in SHP2, inhibitors of which are being developed. In the current study, we have designed and synthesized a library of 21 thioacetamide‐tethered thiadiazole‐1,2,4‐triazole hybrids (compounds 16–36) and evaluated their in vitro SHP2 inhibitory potential. Compound 28 (N‐(5‐(benzo[d][1,3]dioxol‐5‐yl)‐1,3,4‐thiadiazol‐2‐yl)‐2‐((5‐(4‐methoxyphenyl)‐4H‐1,2,4‐triazol‐3‐yl)thio)acetamide) emerged as the most potent SHP2 inhibitor (IC50=0.318±0.001 μM) inhibiting the enzyme in a mixed to non‐competitive manner. In silico studies revealed that the lead inhibitor strongly binds to the tunnel allosteric site of SHP2. Further, cytotoxicity studies revealed that compound 28 caused death of SHP2‐driven MCF‐7 (GI50=37.02±0.25 μM) and U87MG cells (GI50=68.69±0.21 μM) in a dose‐dependent manner and inhibited MCF‐7 cell colony formation and migration. Flow cytometric analysis showed that it exerted its antiproliferative effect on U87MG cells by inducing early apoptosis (Q2 phase) and inhibiting cell cycle progression at the G1 and S phase. Compound 28 was shown to increase oxidative stress in the U87 cells by promoting ROS generation and loss of mitochondrial integrity. In summary, the present study produced a potent SHP2 inhibitor (compound 28) with a promising in vitro cytotoxicity profile, thus meriting further investigation.

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Section: Resultsmentioning

confidence: 99%

Section: Molecular Dynamics Simulation Studies For Compound 28mentioning

confidence: 99%

Design, Synthesis and Evaluation of Thioacetamide‐Tethered Thiadiazole‐1,2,4‐Triazole Hybrids as SHP2 Inhibitors for Cancer Therapy

Mitra,

Kumar,

Chaudhuri

et al. 2024

ChemistrySelect

Self Cite

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“…Dual-functional inhibitor is an inhibitor with two or more therapeutic effects and higher therapeutic ability can be expected than single functional inhibitor [21]. Recently, various dual-functional inhibitors have been developed and reported, such as dual-functional inhibitors for MAO, ChE, BACE1, antioxidant, and carbonic anhydrase VII [46][47][48][49][50][51]. However, compound 1 showed weak inhibitory activity against BACE1 as well as MAO-A and AChE.…”

Section: Inhibition Studies Of Mao-a and Mao-bmentioning

confidence: 99%

3-Phenethyl-2-phenylquinazolin-4(3H)-one isolated from marine-derived Acremonium sp. CNQ-049 as a dual- functional inhibitor of monoamine oxidases-B and butyrylcholinesterase

Hillman

Nam

et al. 2023

JABC

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Isolation of the culture broth of a marine-derived Acremonium sp. CNQ-049 guided by HPLC-UV yielded compound 1 (3-phenethyl-2-phenylquinazolin-4(3H)-one), and its inhibitory activities against monoamine oxidases (MAOs), cholinesterases (ChEs), and β-secretase 1 (BACE1) were evaluated. Compound 1 was an effective selective MAO-B inhibitor with an IC 50 value of 9.39 μM and a selectivity index (SI) value of 4.26 versus MAO-A. In addition, compound 1 showed a potent selective butyrylcholinesterase (BChE) inhibition with an IC 50 value of 7.99 μM and an SI value of 5.01 versus acetylcholinesterase (AChE). However, compound 1 showed weak inhibitions against MAO-A, AChE, and BACE1. The K i value of compound 1 for MAO-B was 5.22±1.73 μM with competitive inhibition, and the K i value of compound 1 for BChE was 3.00±1.81 μM with mixed-type inhibition. Inhibitions of MAO-B and BChE by compound 1 were recovered by dialysis experiments. These results suggest that compound 1 is a dual-functional reversible inhibitor of MAO-B and BChE, that can be used as a treatment agent for neurological disorders.

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Design, synthesis and evaluation of sesamol-derived acetamides as dual inhibitors of monoamine oxidases and cholinesterases

Kumar,

Mitra,

Ayyannan

2024

Med Chem Res

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Exploration of a library of piperonylic acid-derived hydrazones possessing variable aryl functionalities as potent dual cholinesterase and monoamine oxidase inhibitors

Cited by 4 publications

References 48 publications

Design, Synthesis and Evaluation of Thioacetamide‐Tethered Thiadiazole‐1,2,4‐Triazole Hybrids as SHP2 Inhibitors for Cancer Therapy

Design, Synthesis and Evaluation of Thioacetamide‐Tethered Thiadiazole‐1,2,4‐Triazole Hybrids as SHP2 Inhibitors for Cancer Therapy

3-Phenethyl-2-phenylquinazolin-4(3H)-one isolated from marine-derived Acremonium sp. CNQ-049 as a dual- functional inhibitor of monoamine oxidases-B and butyrylcholinesterase

Design, synthesis and evaluation of sesamol-derived acetamides as dual inhibitors of monoamine oxidases and cholinesterases

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