A series of diaryl imidazole derivatives (5a-h) was designed as novel selective COX-2 anti-inflammatory drug candidates. The designed compounds were synthesised, and their structures were characterized by spectroscopic analysis. The anticipated anti-inflammatory activity for the synthesized compounds was assessed by in-vitro cyclooxygenases (COX-1/COX-2) inhibition assay. Most of tested compounds demonstrated moderate COX-2 inhibitory activity and selectivity (IC50 = 0.068 – 0.80 µm, SI = 7.5 - 175) in comparison to indomethacin (IC50 = 0.079 µm, SI = 12.5) and celecoxib (IC50 = 0.046 µm, SI = 315.22). Molecular modelling study of the synthesized compounds into the active site of COX-2 enzyme was performed to rationalize their preferred binding affinity; except for compound 5f, all compounds showed binding with amino acids at the selectivity pocket Additionally, In-silico simulation studies explored the drug drug-likeness parameters of the synthesized compounds, all synthesized compounds exhibited promising physicochemical parameters and pharmacokinetics according to the in-silico simulation results.

Lidocaine, a local anesthetic, is known to possess anti-inflammatory properties. However, its clinical use is limited by inconveniences, such as its local synesthetic effects. This study evaluated lidocaine analogs designed and synthesized to overcome the disadvantages of lidocaine, having anti-inflammatory properties. Interleukin 5 (IL-5)-induced eosinophil activation and survival were evaluated using 36 lidocaine analogs with modified lidocaine structure on the aromatic or the acyl moiety or both. Eosinophil survival was evaluated using a CellTiter 96^® aqueous cell proliferation assay kit. Superoxide production was determined using the superoxide dismutase-inhibitable reduction of cytochrome C method. Eosinophil cationic protein (ECP), IL-8, and transcription factor expression were determined using enzyme-linked immunosorbent assay. The platelet-activating factor (PAF)-induced migration assay was performed using a Transwell insert system. Compounds EI137 and EI341 inhibited IL-5-induced eosinophil survival and superoxide and ECP production in a concentration-dependent manner. These compounds also significantly reduced IL-8 production. Although compounds EI137 and EI341 significantly reduced phosphorylated ERK 1/2 expression, they did not influence other total and phosphorylated transcription factors. Moreover, 1000 µM of compound EI341 only inhibited PAF-induced migration of eosinophils. Lidocaine analogs EI137 and EI341 inhibited IL-5-mediated activation and survival of eosinophils. These compounds could be new therapeutic agents to treat eosinophilic inflammatory diseases.

Mitonafide-loaded liposomes are a promising strategy to overcome the neurotoxicity observed in clinical trials for this drug. This study investigates the influence of loaded mitonafide or a dimer analogue on different liposomal formulations and their therapeutic efficacy in vitro. Physicochemical properties of the liposomes were manipulated using different loading methods (namely bilayer or core loading) and varying the rigidity of the bilayer using distinct phospholipid compositions. Our results demonstrated that the mitonafide dimer analogue had a comparable encapsulation efficiency (EE%) into the liposomes when loaded into rigid or flexible bilayers in contrast to the low mitonafide monomer EE%. A pH gradient core loading method resulted in a more efficient mechanism to load the monomer into the liposomes. DOSY NMR and spectrofluorometric studies revealed key differences in the structure of the vesicles and the arrangement of the monomer or the dimer in the bilayer or the core of the liposomes. The in vitro assessment of the formulations using MDA-MB-231 and RT-112 cells revealed that a flexible lipid bilayer allows a faster drug release, which correlated well with the spectroscopy studies. This study investigated for the first time that the characteristics of the lipid bilayer and the loading method influence the encapsulation efficacy, colloidal properties, photoactivity and stability of mono and bis-naphthalimides loaded in a liposomal carrier, essential factors that will impact the performance of the formulation in a biological scenario.

Allergic rhinitis (AR) is a common chronic disease that significantly impacts the quality of life. Lidocaine is known to have anti-inflammatory and immunomodulatory effects. This study evaluated the effect of lidocaine analogs in a Dermatophagoides pteronyssinus (DP)-induced AR mouse model. An AR model was developed using BALB/c mice via intraperitoneal sensitization with DP and intranasal challenge with DP. One hour before stimulation with DP, lidocaine analogs, EI137 and EI341 (at a dose of 0.5 or 5 ug/g), were administered intranasally. Nasal symptoms and serum total IgE, interleukin (IL)-4, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α levels were evaluated. Reverse-transcription polymerase chain reaction was used to determine IL-4, IL-10, and IFN-γ, as well as the expression of their mRNA transcription factors in the sinonasal mucosa. Histologic changes were evaluated using hematoxylin and eosin and periodic acid–Schiff staining. The DP-induced AR mouse model had increased serum levels of total IgE and cytokines. EI137 and EI341 significantly suppressed the levels of total IgE, IL-4, and TNF-α. Intranasal instillation of EI137 and EI341 significantly inhibited IL-4, IL-10, and IFN-γ mRNA expression, as well as inflammatory cells and mucus-producing goblet cells. Lidocaine analogs also suppressed DP-stimulated IL-4, IFN-γ, and IFN-γ production by splenocytes. Intranasal instillation of EI137 and EI341 exhibited anti-allergic and anti-inflammatory effects, influenced by Th1 and Th2 inflammatory cytokines. These lidocaine analogs suppressed DP-induced sinonasal mucosal inflammation, inflammatory cell infiltration, and mucus hypersecretion.

A series of diaryl imidazole derivatives (5a-h) was designed as novel selective COX-2 anti-inflammatory drug candidates. The designed compounds were synthesised, and their structures were characterized by spectroscopic analysis. The anticipated anti-inflammatory activity for the synthesized compounds was assessed by in-vitro cyclooxygenases (COX-1/COX-2) inhibition assay. Most of tested compounds demonstrated moderate COX-2 inhibitory activity and selectivity (IC50 = 0.068 – 0.80 µm, SI = 7.5 - 175) in comparison to indomethacin (IC50 = 0.079 µm, SI = 12.5) and celecoxib (IC50 = 0.046 µm, SI = 315.22). Molecular modelling study of the synthesized compounds into the active site of COX-2 enzyme was performed to rationalize their preferred binding affinity; except for compound 5f, all compounds showed binding with amino acids at the selectivity pocket. Additionally, In-silico simulation studies explored the drug drug-likeness parameters of the synthesized compounds, all synthesized compounds exhibited promising physicochemical parameters and pharmacokinetics according to the in-silico simulation results