Structure-based design and optimization of pyrimidine- and 1,2,4-triazolo[4,3-a]pyrimidine-based matrix metalloproteinase-10/13 inhibitors via Dimroth rearrangement towards targeted polypharmacology

Ashry, El Sayed H. El; Awad, Laila F.; Teleb, Mohamed; Ibrahim, N.; Abu‐Serie, Marwa M.; Moaty, Mohamed Nabil Abd Al

doi:10.1016/j.bioorg.2020.103616

Cited by 32 publications

(12 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…224 The use of multitarget agents with pleiotropic actions might highlight future trends in the field of neurodegenerative diseases, and especially AD, a complex multicausal disorder. This would imply targeting more than one MMP (among MMP-1, -2, -3, -9, -12, -13, MT1-MMP or MT5-MMP) with pan-specific inhibitors, 225 or combining targeting of one MMP with another target of interest in AD, e.g. cholinesterases.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges

et al. 2020

View full text Add to dashboard Cite

Although matrix metalloproteinases (MMPs) are implicated in the regulation of numerous physiological processes, evidences of their pathological roles have also been obtained in the last decades, making MMPs attractive therapeutic targets for several diseases. Recent discoveries of their involvement in central nervous system (CNS) disorders, and in particular in Alzheimer's disease (AD), have paved the way to consider MMP modulators as promising therapeutic strategies. Over the past few decades, diverse approaches have been undertaken in the design of 2 therapeutic agents targeting MMPs for various purposes, leading, more recently, to encouraging developments. In this article, we will present recent examples of inhibitors ranging from small molecules and peptidomimetics to biologics. We will also discuss the scientific knowledge that has led to the development of emerging tools and techniques to overcome the challenges of selective MMP inhibition.

show abstract

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The synthesized 5,5′-(piperazin-1,4-diyl)bis(1,3,4-thiadiazole-2-thiol) 1 [54] was selected as a precursor to give 1,4-bis(5-hydrazinyl-1,3,4-thiadiazol-2-yl)piperazine 2 and 1,4-bis(5-chloro-1,3,4-thiadiazol-2-yl)piperazine 3 by its reaction with 98% hydrazine hydrate [55] and thionyl chloride in benzene [56], respectively; see Scheme 1. Owing to the above facts and in continuation of the research on enoyl ACP reductase inhibitors, an attempt was made in the present research to design and develop new anti-E. coli agents possessing enoyl ACP reductase inhibition.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Antimicrobial Activity Screening of Piperazines Bearing N,N′-Bis(1,3,4-thiadiazole) Moiety as Probable Enoyl-ACP Reductase Inhibitors

et al. 2022

View full text Add to dashboard Cite

A new N,N′-disubstituted piperazine conjugated with 1,3,4-thiadiazole and 1,2,4-triazole was prepared and the chemical structures were identified by IR, NMR and elemental analysis. All the prepared compounds were tested for their antimicrobial activity. The antimicrobial results indicated that the tested compounds showed significant antibacterial activity against gram-negative strains, especially E. coli, relative to gram-positive bacteria. Docking analysis was performed to support the biological results; binding modes with the active site of enoyl reductase amino acids from E. coli showed very good scores, ranging from −6.1090 to −9.6184 kcal/mol. Correlation analysis was performed for the inhibition zone (nm) and the docking score.

show abstract

“…This makes it difficult to develop a selective and potent MMP-10 inhibitor [17,23]. Nevertheless, there are several studies reporting that selective dual MMP-10/-13 inhibitors possess a clean inhibition profile and outstanding affinity for MMP-10 [44,45]. Furthermore, MMP-10 activity can be regulated by increased or diminished expression at the transcriptional or translational levels.…”

Section: Inhibitors Of Mmp-10mentioning

confidence: 99%

Matrix Metalloproteinase-10 in Kidney Injury Repair and Disease

Sun

Liu

2022

IJMS

View full text Add to dashboard Cite

Matrix metalloproteinase-10 (MMP-10) is a zinc-dependent endopeptidase with the ability to degrade a broad spectrum of extracellular matrices and other protein substrates. The expression of MMP-10 is induced in acute kidney injury (AKI) and chronic kidney disease (CKD), as well as in renal cell carcinoma (RCC). During the different stages of kidney injury, MMP-10 may exert distinct functions by cleaving various bioactive substrates including heparin-binding epidermal growth factor (HB-EGF), zonula occludens-1 (ZO-1), and pro-MMP-1, -7, -8, -9, -10, -13. Functionally, MMP-10 is reno-protective in AKI by promoting HB-EGF-mediated tubular repair and regeneration, whereas it aggravates podocyte dysfunction and proteinuria by disrupting glomerular filtration integrity via degrading ZO-1. MMP-10 is also involved in cancerous invasion and emerges as a promising therapeutic target in patients with RCC. As a secreted protein, MMP-10 could be detected in the circulation and presents an inverse correlation with renal function. Due to the structural similarities between MMP-10 and the other MMPs, development of specific inhibitors targeting MMP-10 is challenging. In this review, we summarize our current understanding of the role of MMP-10 in kidney diseases and discuss the potential mechanisms of its actions.

show abstract

Structure-based design and optimization of pyrimidine- and 1,2,4-triazolo[4,3-a]pyrimidine-based matrix metalloproteinase-10/13 inhibitors via Dimroth rearrangement towards targeted polypharmacology

Cited by 32 publications

References 65 publications

Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges

Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges

Synthesis and Antimicrobial Activity Screening of Piperazines Bearing N,N′-Bis(1,3,4-thiadiazole) Moiety as Probable Enoyl-ACP Reductase Inhibitors

Matrix Metalloproteinase-10 in Kidney Injury Repair and Disease

Contact Info

Product

Resources

About