Design, Synthesis and Study of Nitrogen Monoxide Donors as Potent Hypolipidaemic and Anti-Inflammatory Agents

Abstract

Inflammation and oxidative stress are involved in cardiovascular diseases. Nitrogen monoxide participates in the regulation of endothelial processes. Thus, derivatives of classic nonsteroidal anti-inflammatory drugs (NSAIDs), trolox or cinnamic acids esterified with 2-(nitrooxy)ethanol were designed and studied. It was found that the nitrogen monoxide (NO) releasing activity was comparable to that of S-nitroso-N-acetylpenicillamine. The nitrooxy derivatives decreased potently lipid indices in the plasma of hyperlipidaemic rats (30–85%). All compounds presented increased anti-inflammatory activity in vivo, inhibiting carrageenan-induced rat paw oedema as high as 76%, up to six times higher than that of the parent acids. Lipoxygenase inhibitory activity was significant for most of them, although the parent molecules exerted a minor effect (IC50 > 0.2 mM). Those compounds incorporating an antioxidant structure inhibited rat microsomal membrane lipid peroxidation strongly and possessed radical scavenging activity. These results indicated that the described compounds could act at different targets in multifactorial diseases, further limiting the possible adverse effects of drug combinations.

Antioxidant Serine-(NSAID) Hybrids with Anti-Inflammatory and Hypolipidemic Potency

“…Ibuprofen derivatives 8 and 9 were more active than ketoprofen derivatives 11 and 12 . This may partly be related to the less rigid structure of the former NSAID, since we have shown that rigid molecules seem to offer diminished activity [ 39 , 40 ]. 4-Hydroxy cinnamic acid shows low potency in LOX inhibition; however, compounds bearing this structure or the ( E )-phenyl-propene moiety show considerable activity on LOX inhibition [ 41 , 42 ].…”

Enhancement of the Anti-Inflammatory Activity of NSAIDs by Their Conjugation with 3,4,5-Trimethoxybenzyl Alcohol

“…The performance of the assay was verified using NDGA as a reference. For the estimation of the type of inhibition, the above experiments were repeated, using 1 mM sodium linoleate, which is higher than the saturating substrate concentration [ 32 ].…”

“…Aliquots were taken from the incubation mixture (37 °C) for 45 min. Lipid peroxidation was assessed spectrophotometrically (535/600 nm) as 2-thiobarbituric acid reactive material [ 32 ].…”

Recent advancement in drug development of nitro(NO2)‐heterocyclic compounds as lead scaffolds for the treatment of Mycobacterium tuberculosis

“…Various nitro(NO 2 )‐based analogues are privileged moieties. These analogues have a wide range of biological activities, including anti‐kinetoplastid (Rodriguez Arce et al, 2017; Brancaglion et al, 2018; Papadopoulou et al, 2012; Elias et al, 2016; Papadopoulou, Bloomer, Rosenzweig, Arena, et al, 2014, Papadopoulou et al, 2015, Papadopoulou et al, 2016; Patterson & Wyllie, 2014; Scarim & Chin, 2019; Silva et al, 2016), anthelmintic (Balaji et al, 2014; Dutta, 2014; Fonseca‐Berzal et al, 2016; Moreno & Docampo, 1985; Satyendra et al, 2015), anti‐malarial (Bekhit et al, 2012; Dohutia et al, 2017; Labaied et al, 2004; Malebo et al, 2020; Maroziene et al, 2019; Roberts et al, 2017), antifungal (Kang et al, 2019; Sadeghpour et al, 2017; Zhu et al, 2017), anti‐proliferative (Ahmad et al, 2007; Chinnapaka et al, 2019; Cho et al, 2020; Cuartas et al, 2019; Dunlap et al, 2008; Sakanyan et al, 2014; Shimamura et al, 2003), antimicrobial (Abd El‐Salam et al, 2015; Alasmary et al, 2015; El Azab & Elkanzi, 2020; El‐Hossary et al, 2018; Kozłowska et al, 2019; Kucerova‐Chlupacova et al, 2016; Mladenović et al, 2010; Serban et al, 2018; Sivasankerreddy et al, 2018; Teran et al, 2019), anti‐Alzheimer (Semenov et al, 2020), anti‐inflammatory (El‐Haggar & Al‐Wabli, 2015; Januario et al, 2018; Liu et al, 2019; Rubbo, 2013; Sugimoto et al, 2017; Theodosis‐Nobelos et al, 2020; Tratrat et al, 2021; Tseng et al, 2018), antioxidant (Alshibl et al, 2020; Gallardo et al, 2016…”