Hydrogen Sulfide: A Worthwhile Tool in the Design of New Multitarget Drugs

Sestito, Simona; Nesi, Giulia; Macchia, Marco; Rapposelli, Simona

doi:10.3389/fchem.2017.00072

Cited by 23 publications

(12 citation statements)

References 73 publications

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“…In recent years, the possibility of linking moieties releasing endogenous gaseous signalling molecules, i.e., gasotransmitters, with a well-known pharmacophore, has assumed particular interest in multitarget drug design [ 69 , 70 ]. Gasotransmitters, such as carbon monoxide (CO), nitric oxide (NO) and hydrogen sulfyde (H 2 S), are endogenously produced by enzymes and play important roles as antioxidants, neuromodulators and antinflammatory agents [ 71 ].…”

Section: Miscellaneous Memantine Derivativesmentioning

confidence: 99%

Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

et al. 2020

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Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer’s disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors.

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Section: Miscellaneous Memantine Derivativesmentioning

confidence: 99%

Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

et al. 2020

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“…ROS are counterbalanced in the body by a net of antioxidants (Xie et al 2016). Recently, Sestito et al (2017) reported that administration of NaHS has resulted in increased expression of anti-oxidants such as glutathione peroxidase, superoxide dismutase, glutathione reductase and heme oxygenase-1 (HO-1) due to the role of H 2 S in regulating the nuclear factor erthyroid 2-related factor 2 (Nrf2) which is a key transcription regulator of antioxidant genes.…”

Section: Immunohistochemical Assessment Of Inosmentioning

confidence: 99%

H2S attenuates acute lung inflammation induced by administration of lipopolysaccharide in adult male rats

Ali¹,

Abdel-Hamid²,

Toni³

2018

gpb

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. Hydrogen sulfide (H2S) is gasotransmitter which plays an important role in human physiology. In this study, we aimed to check the effect of H2S treatment on acute lung inflammation (ALI). Thirty-six adult male albino rats were used and divided into: control group, ALI group which was intraperitoneally (i.p.) injected with lipopolysaccharide (LPS) at a dose of 5 mg/kg body weight, ALI group treated by the H2S donor; sodium hydrosulfide (NaHS) at a dose of 10 mg/kg body weight i.p. and ALI group treated by i.p. injection of 80 mg/kg body weight DL- propargylglycine (PAG) which is an inhibitor of endogenous H2S synthesis. Serum was obtained to determine interleukin-6 (IL-6) levels. Lipid peroxides and total antioxidant capacity (TAC) levels were measured in lung. Lung histopathology and expression of inducible nitric oxide synthase (iNOS) were also done. Results showed that NaHS improved lung inflammation through its inhibitory effect on iNOS expression, decreasing the levels of IL-6 and lipid peroxides and increasing TAC levels. But, ALI was exacerbated with PAG administration. In conclusion, the results proved that H2S has a protective effect against LPS induced ALI due to its anti-nitrative, anti-oxidant and anti-inflammatory properties.

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“…However, the chemical complexity of these precursors limits their versatility in assembly with different vehicle molecules. To develop diversified H 2 S donors of controllable release, precursors that can be selectively activated, conveniently synthesized and flexibly installed on a wide spectrum of chemical scaffolds are highly desired 31 .…”

Section: Introductionmentioning

confidence: 99%

Clopidogrel as a donor probe and thioenol derivatives as flexible promoieties for enabling H2S biomedicine

et al. 2018

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Hydrogen sulfide has emerged as a critical endogenous signaling transmitter and a potentially versatile therapeutic agent. The key challenges in this field include the lack of approved hydrogen sulfide-releasing probes for in human exploration and the lack of controllable hydrogen sulfide promoieties that can be flexibly installed for therapeutics development. Here we report the identification of the widely used antithrombotic drug clopidogrel as a clinical hydrogen sulfide donor. Clopidogrel is metabolized in patients to form a circulating metabolite that contains a thioenol substructure, which is found to undergo spontaneous degradation to release hydrogen sulfide. Model studies demonstrate that thioenol derivatives are a class of controllable promoieties that can be conveniently installed on a minimal structure of ketone with an α-hydrogen. These results can provide chemical tools for advancing hydrogen sulfide biomedical research as well as developing hydrogen sulfide-releasing drugs.

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Hydrogen Sulfide: A Worthwhile Tool in the Design of New Multitarget Drugs

Cited by 23 publications

References 73 publications

Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

H2S attenuates acute lung inflammation induced by administration of lipopolysaccharide in adult male rats

Clopidogrel as a donor probe and thioenol derivatives as flexible promoieties for enabling H2S biomedicine

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