A Novel Tetrasubstituted Imidazole as a Prototype for the Development of Anti-inflammatory Drugs

Abstract

Although inflammation is a biological phenomenon that exists to protect the host against infections and/or related problems, its unceasing activation results in the aggravation of several medical conditions. Imidazoles, whether natural or synthetic, are molecules related to a broad spectrum of biological effects, including anti-inflammatory properties. In this study, we screened eight novel small molecules of the imidazole class synthesized by our research group for their in vitro anti-inflammatory activity. The effect of the selected molecules was confirmed in an in vivo inflammatory model. We also analyzed whether the effects were caused by inhibition of nuclear factor kappa B (NF-κB) transcription factor transmigration. Of the eight imidazoles tested, methyl 1-allyl-2-(4-fluorophenyl)-5-phenyl-1H-imidazole-4-acetate (8) inhibited nitric oxide metabolites and pro-inflammatory cytokine (TNF-α, IL-6, and IL-1β) secretion in J774 macrophages stimulated with LPS. It also attenuated leukocyte migration and exudate formation in the pleural cavity of mice challenged with carrageenan. Furthermore, imidazole 8 reverted the oxidative stress pattern triggered by carrageenan in the pleural cavity by diminishing myeloperoxidase, superoxide dismutase, catalase, and glutathione S-transferase activities and reducing the production of nitric oxide metabolites and thiobarbituric acid-reactive substances. Finally, these effects can be attributed, at least in part, to the ability of this compound to prevent NF-κB transmigration. In this context, our results demonstrate that imidazole 8 has promising potential as a prototype for the development of a new anti-inflammatory drug to treat inflammatory conditions in which NF-κB and oxidative stress play a prominent role. Graphical Abstract ᅟ.

Titania‐silica nanoparticles ensemblies assisted heterogeneous catalytic strategy for the synthesis of pharmacologically significant 2,3‐diaryl‐3,4‐dihydroimidazo[4,5‐b]indole scaffolds

“…Their several synthetic analogues possess numerous biological properties, i.e. , anti‐inflamatory, antimicrobial, anticancer, antitubercular, anti‐dengue, anti‐analgesic, anthelmintic, antimycotic, antitumor, and antibacterial activities . Also, the imidazole nucleus has displayed a noteworthy role in some advanced areas of technology such as biological imaging, glucagon receptors, fluorescence labelling agents, modulators of p ‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR), and chromophores for nonlinear optic systems (NLOS)…”

Imidazole as a Promising Medicinal Scaffold: Current Status and Future Direction

“…The author concluded that compound I33 demonstrated similar efficacy in both in vitro and in vivo studies suggesting it could serve as a potential anti-inflammatory agent. 49 …”

“…36 The findings shown in Table 9, demonstrated that some anti-inflammatory mechanisms of imidazole derivatives could be due to the interactions with GPCRs, nuclear receptors, ion channels, proteases, kinases, and enzymes. According to the bioactivity scores, the most promising compounds were found to be I30, I31, I33, and I34 with scores of 0.24, 0.32, 0.21, and 0.72, respectively, as an enzyme inhibitor suggesting COX enzyme may be involved in mediating this anti-inflammatory effect that 45,[48][49][50] On the contrary, Katikireddy et al believed that compound I32 works by inhibiting the COX-2 enzyme, however, the target prediction did not show a promising bioactivity score at this target suggesting computational studies should not be used solely for target predictions. 47…”

Mechanisms of Csp3‐H or Nsp2‐H functionalization of 2,3‐diaminoindoles with triplet O2: A density functional theory investigation

“…[ 1 ] Among them, imidazolo‐indole framework has received growing attentions in recent years because of its fused heterocyclic skeleton involved in a large number of natural products and as drug candidate. [ 2 ] Several of their synthetic analogues have many biological properties, that is, antiinflamatory, [ 3 ] antimicrobial, [ 4 ] anticancer, [ 5 ] antitubercular, [ 6 ] antidengue, [ 7 ] anti‐analgesic, [ 8 ] anthelmintic, [ 9 ] antimycotic, [ 10 ] antitumor, [ 11 ] and antibacterial activities. [ 12 ] Also, the imidazole nucleus has displayed an important role in some advanced technology fields such as biological imaging, [ 13 ] glucagon receptors, [ 14 ] fluorescence labeling agents, [ 15 ] modulators of P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR), [ 16 ] and chromophores for nonlinear optic systems (NLOS).…”