Selective Acetamidine-Based Nitric Oxide Synthase Inhibitors: Synthesis, Docking, and Biological Studies

Maccallini, Cristina; Montagnani, Monica; Paciotti, Roberto; Ammazzalorso, Alessandra; Filippis, Barbara De; Matteo, Mauro Di; Silvestre, Sara Di; Fantacuzzi, Marialuigia; Giampietro, Letizia; Potenza, Maria Assunta; Re, Nazzareno; Pandolfi, Assunta; Amoroso, Rosa

doi:10.1021/acsmedchemlett.5b00149

Cited by 25 publications

(13 citation statements)

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“…It is well known that the dysregulated production of NO is implicated in different inflammatory diseases and many small molecules able to inhibit NOS have been published to date . In light of the compelling evidences that NO generated by iNOS fosters gliomas cell survival, proliferation and metastatic expansion, different molecules able to down‐regulate iNOS have been investigated as anti‐glioma agents.…”

Section: Small Molecules Able To Downregulate Inos As Antiglioma Agentsmentioning

confidence: 99%

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

et al. 2020

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Gliomas are the most prevalent primary tumors of the brain and spinal cord. Histologically, they share features of normal glial cells, but whether gliomas originate from normal glial cells, glial or neural precursors, stem cells, or other cell types remains a topic of investigation. The enhanced expression of inducible nitric oxide synthase (iNOS) has been reported as a hallmark of chemoresistance in gliomas, and several lines of evidence have reported that a decreased proliferation of glioma cells could be related to the selective inhibition of iNOS. This review aims to summarize the current understanding of iNOS expression and activity modulation in the regulation of glioma pathogenesis, along with compounds that could act as therapeutic agents against glioma.

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Section: Small Molecules Able To Downregulate Inos As Antiglioma Agentsmentioning

confidence: 99%

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

et al. 2020

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“…Aminoguanidine ( 105 , Figure ) is a prototypical guanidine derivative described as a selective mouse iNOS inhibitor . Most of the amidinic compounds disclosed by different research groups till the year 2002 have been discussed in a review article by Salerno et al During 2009 to 2015, a research group in Department of Pharmacy in University G. d’Annunzio in Italy have designed and synthesized several acetamidine‐based compounds 106 to 112 (Figure ), and evaluated them for iNOS and nNOS inhibitory activities . Subsequently, they reviewed the developments on amidine analogs as selective iNOS inhibitors and concluded that: An alkyl or an aryl moiety is responsible for hydrophobic interactions in the active site of the enzyme. An ionizable group can interact selectively with one isoform through charge‐charge interaction. A benzyl group connected to an amidino nitrogen (as in 1400 W) incurs selectivity toward iNOS, but a phenyl ring connected directly to it shifts the selectivity of compounds from iNOS to nNOS. A bulky group on the benzylic carbon and removal of aminomethyl group from the phenyl ring of 1400 W lead to nNOS‐specific inhibitors.…”

Section: Synthetic Inos Inhibitorsmentioning

confidence: 99%

Inducible nitric oxide synthase inhibitors: A comprehensive update

Minhas

Bansal

2019

Medicinal Research Reviews

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Inducible nitric oxide synthase (iNOS), which is expressed in response to bacterial/proinflammatory stimuli, generates nitric oxide (NO) that provides cytoprotection. Overexpression of iNOS increases the levels of NO, and this increased NO level is implicated in pathophysiology of complex multifactorial diseases like Parkinson's disease, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Selective inhibition of iNOS is an effective approach in treatment of such complex diseases. L-Arginine, being a substrate for iNOS, is the natural lead to develop iNOS inhibitors. More than 200 research reports on development of nitric oxide synthase inhibitors by different research groups across the globe have appeared in literature so far. The first review on iNOS, in 2002, discussed the iNOS inhibitors under two classes that is, amino acid and non-amino acid derivatives. Other review articles discussing specific chemical classes of iNOS inhibitors also appeared during last decade. In the present review, all reports on both natural and synthetic iNOS inhibitors, published 2002 onwards, are studied, classified, and discussed to provide comprehensive information on iNOS inhibitors. The synthetic inhibitors are broadly classified into two categories that is, arginine and non-arginine analogs. The latter are further classified into amidines, five-or six-membered heterocyclics, fused cyclics, steroidal type, and chalcones analogs. Structures of the most/significantly potent compounds from each report are provided to know the functional groups important for incurring iNOS inhibitory activity and selectivity. This review is aimed to provide a comprehensive view to the medicinal chemists for rational designing of novel and potent iNOS inhibitors. K E Y W O R D S arginine, inflammation, inhibitors, multifactorial disease, nitric oxide 1 | INTRODUCTION Nitric oxide (NO) is a relaxing factor derived from endothelium, which is responsible for neuronal transmission, cardiovascular, gastrointestinal, genitourinary, respiratory, antipathogenic, and antitumor responses. The production of NO is effected by nitric oxide synthase (NOS) through catalysis of NADPH-dependent oxidation of L-arginine (the substrate). 1NOS exists in three distinct isoforms, depending on the site of its existence that is, neuronal NOS (nNOS, type I), inducible or inflammatory NOS (iNOS, type II) and endothelial NOS (eNOS, type III). Constitutive NOS are regulated by the binding of calcium-calmodulin protein, whereas iNOS is transcriptionally regulated and calcium-calmodulin independent. NO plays both physiological and pathological roles depending on the magnitude and duration of its production. 2 The physiological roles of NO are executed by soluble guanylate cyclase. Indeed, NO activates it, with the consequent increase of cyclic guanosine-3′,5′-monophosphate (cGMP) level, which subsequently activates intracellular effector molecules, cGMPdependent protein kinases, cGMP-gated ion channels, and cGMP-regulated phosphodiesteras...

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“…In addition, we have synthesized and evaluated the NOS inhibition of compounds with general structures [33] and [34] (Figure 1). These derivatives had more flexible structure containing N,N -disubstituted thiourea and urea rests, isosterics to the terminal guanidine moiety of L-Arg, responsible for the inhibitors binding to the enzyme substrate region; thus it plays an essential role in the enzymatic inhibition [35,36].…”

Section: Introductionmentioning

confidence: 99%

Thiadiazoline- and Pyrazoline-Based Carboxamides and Carbothioamides: Synthesis and Inhibition against Nitric Oxide Synthase

Arias

Camacho

Carriòn

et al. 2018

Journal of Chemistry

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Two new families of pyrazoline and thiadiazoline heterocycles have been developed. Their inhibitory activities against two different isoforms of nitric oxide synthase (inducible and neuronal NOS) are reported. The novel derivatives were synthesized combining the arylthiadiazoline or arylpyrazoline skeleton and a carboxamide or carbothioamide moiety, used as starting material ethyl 2-nitrobenzoates or substituted nitrobenzaldehydes, respectively. The structure-activity relationships of final molecules are discussed in terms of the R1 radical effects in the aromatic ring, the Y atom in the heterocyclic system, the X heteroatom in the main chain, and the R2 substituent in the carboxamide or carbothioamide rest. In general, thiadiazolines (5a–e) inhibit preferentially the neuronal isoform; among them, 5a is the best nNOS inhibitor (74.11% at 1 mM, IC50 = 420 μM). In contrast, pyrazolines (6a–r) behave better as iNOS than nNOS inhibitors, 6m being the best molecule of this series (76.86% at 1 mM of iNOS inhibition, IC50 = 130 μM) and the most potent of all tested compounds.

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Selective Acetamidine-Based Nitric Oxide Synthase Inhibitors: Synthesis, Docking, and Biological Studies

Cited by 25 publications

References 28 publications

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

Inducible nitric oxide synthase inhibitors: A comprehensive update

Thiadiazoline- and Pyrazoline-Based Carboxamides and Carbothioamides: Synthesis and Inhibition against Nitric Oxide Synthase

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